Antibacterial agents and anticancer agents

Abstract

Compounds of the formula (I): [Formula 1] The compounds of TIFF2024515215000024.tif36170 are disclosed, as are compositions and methods of using the anti-neoplastic and anti-bacterial compounds.

Description

Technical Field

[0008] , , , ,

[0007] , , , , , , ,

[0006]

[0001] The present invention relates to new compounds and their use.

Background Art

[0002] For example, many compounds are known for the treatment of cancer in patients or the treatment of microbial infections in patients.

Summary of the Invention

Problems to be Solved by the Invention

[0003] In the art, there is still a need for new compounds that have stronger anti-tumor activity and antibacterial activity, fewer toxicities and side effects, and lower resistance to the treatment of tumor cells or microbial cells.

Means for Solving the Problems

[0004] According to the present invention, new compounds and their use are disclosed.

[0005] In one aspect, the present disclosure is of Formula I:

Chemical Formula

[0006] In one aspect, the present disclosure is

Chemical Formula

[0007] In one aspect, the present disclosure includes a pharmaceutical composition comprising the compounds of the present disclosure.

[0008] In one aspect, the present disclosure includes an oral dosage form comprising the compounds of the present disclosure.

[0009] In one embodiment, the Disclosure includes a method of treating a subject by administering to the subject a compound, composition or oral dosage form of the Disclosure.

[0010] In one embodiment, the Disclosure includes a method for treating a subject suffering from cancer by administering a compound, composition, or oral dosage form of the Disclosure to the subject.

[0011] In one embodiment, the Disclosure includes a method for treating tumor stem cells in a subject by administering a compound, composition, or oral dosage form of the Disclosure to the subject.

[0012] In one embodiment, the Disclosure includes a method for treating a subject requiring angiogenesis inhibition by administering a compound, composition, or oral dosage form of the Disclosure to the subject.

[0013] In one embodiment, the Disclosure includes a method for treating a subject requiring tubule formation inhibition by administering a compound, composition, or oral dosage form of the Disclosure to the subject.

[0014] In one embodiment, the Disclosure includes a method for treating a subject suffering from a bacterial infection by administering the compounds, compositions, or oral dosage forms of the Disclosure to the subject.

[0015] In one embodiment, the Disclosure includes a method for treating a subject suffering from a viral infection by administering a compound, composition, or oral dosage form of the Disclosure to the subject.

[0016] In one embodiment, the Disclosure includes a synergistic therapy composition or synergistic therapy regimen comprising tauroridine and / or taurultam in combination with at least one compound, pharmaceutical composition or oral dosage form of the Disclosure.

[0017] In one embodiment, the Disclosure includes a method for enhancing the pharmacokinetic effects of tauroridine and / or taurultam in a human subject using at least two compounds having different half-lives, which includes administering tauroridine and / or taurultam to a human subject in combination with at least one compound, pharmaceutical composition or oral dosage form of the Disclosure.

[0018] In one embodiment, the Disclosure includes a) a combination of at least one compound, pharmaceutical composition or oral dosage form of the Disclosure, and b) a combination of carmustine, cytarabine, gemcitabine, nab-paclitaxel, asparaginase, procarbazine, mitomycin, 5-FU, methotrexate, vinblastine, dacarbazine, cisplatin, carboplatin, paclitaxel, bevacizumab, one or more checkpoint inhibitors, one or more PARP inhibitors, one or more anti-PD-1 agents, docetaxel, irinotecan (including Onivyde®), doxorubicin, erlotinib, olaparib, lapatinib, topotecan, capecitabine, oxaliplatin, cyclophosphamide, ifosfamide, or a combination thereof. [Brief explanation of the drawing]

[0019] [Figure 1] This figure shows a cell migration assay using MDA MB 468 cells. [Figure 2] This figure shows the MTT assay for cell viability. [Figure 3] This figure shows the BrdU assay for cell proliferation. [Figure 4]Figure showing the results of the MTT cytotoxicity assay for Panc TuI cells using various concentrations of compounds 2289, 2293, and 2296 compared to non-treated cells of the negative control = NC and 1000 μM GP2250 of the positive control after incubation periods of 24 hours, 48 hours, and 72 hours. All substances showed a significant effect on the cell viability of the cell line Panc TuI analyzed at a concentration of 100 μM compared to the non-treated control (NC) after 24 hours. Measurements were made in an eightfold determination, and the p-values were calculated by the t-test (*p ≤ 0.05 significant, **p ≤ 0.01 very significant, ***p ≤ 0.001 extremely significant). [Figure 5] Figure showing the results of the MTT cytotoxicity assay for AsPc1 cells using various concentrations of compounds 2289, 2293, and 2296 compared to non-treated cells of the negative control = NC and 1000 μM GP2250 of the positive control after incubation periods of 24 hours, 48 hours, and 72 hours. Substances 2289 and 2296 showed a significant effect on the cell viability of the cell line AsPc1 analyzed at a concentration of 100 μM compared to the non-treated control (NC) after 24 hours. Substance 2293 showed a significant effect on cell viability at a concentration of 500 μM compared to the non-treated control (NC) after 24 hours. Measurements were made in an eightfold determination, and the p-values were calculated by the t-test (*p ≤ 0.05 significant, **p ≤ 0.01 very significant, ***p ≤ 0.001 extremely significant). [Figure 6] Figure showing the results of the MTT cytotoxicity assay for BxPc3 cells using various concentrations of compounds 2289, 2293, and 2296 compared to non-treated cells of the negative control = NC and 1000 μM GP2250 of the positive control after incubation periods of 24 hours, 48 hours, and 72 hours. All substances showed a significant effect on the cell viability of the cell line BxPc3 analyzed at a concentration of 100 μM compared to the non-treated control (NC) after 24 hours. Measurements were made in an eightfold determination, and the p-values were calculated by the t-test (*p ≤ 0.05 significant, **p ≤ 0.01 very significant, ***p ≤ 0.001 extremely significant). [Figure 7]Results of proliferation assays of cell lines Panc TuI, AsPc1, and BxPc3 under the influence of various concentrations of substances 2289, 2293, and 2296 compared to non-treated cells of the negative control = NC and the positive control of 1000 μM GP2250 after a 6-hour incubation period are shown. All substances show a significant effect on cell proliferation of all cell lines analyzed from a concentration of 500 μM compared to the non-treated control (NC). Measurements were made in octuplicate determinations, and p-values were calculated by t-test (*p ≤ 0.05 significant, **p ≤ 0.01 very significant, ***p ≤ 0.001 extremely significant).

Mode for Carrying Out the Invention

[0020] Aspects of the subject matter of the present disclosure can be embodied in various forms, but the following description is merely intended to disclose some of these forms as specific examples of the subject matter encompassed by the present disclosure. Accordingly, the subject matter of the present disclosure is not intended to be limited to the forms or aspects so described and illustrated.

[0021] To facilitate understanding of the present invention, a number of terms are defined below. The terms 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 entities, but include general classifications that can be used to illustrate specific examples. The technical terms in this specification are used to describe specific aspects of the present invention, but their use does not define the present invention except as outlined in the claims.

[0022] The terms "inhibit", "reduce", or "prevent", or any variation of these terms, when used in the claims and / or this specification, include any measurable decrease or complete inhibition to achieve the desired result.

[0023] The compounds of this disclosure can be administered to any subject in need of the therapy provided herein. Such subjects are at risk of or may have a variety of diseases, disorders, and conditions. For example, such diseases, disorders, and conditions may be characterized by infection with microbial factors. In some embodiments, the diseases, disorders, and conditions may be characterized by the presence or risk of cancer, tumors, cancer stem cells, a family history of cancer, or positive genetic markers associated with cancer risk.

[0024] According to certain embodiments, the present invention relates to compounds having antitumor activity, antibacterial activity and / or other activities.

[0025] In certain embodiments, the compounds of the present invention are particularly useful for the treatment of cancer and tumors in subjects such as human patients. Therefore, in certain embodiments, the present invention also relates to the treatment of cancer and tumors using the compounds described herein. For example, cancers such as central nervous system cancers including glioblastoma, glioma, neuroblastoma, astrocytoma and carcinomatous meningitis, colon cancer, rectal cancer and colorectal cancer, ovarian cancer, breast cancer, prostate cancer, lung cancer, mesothelioma, melanoma, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, esophageal cancer, bladder cancer, cervical cancer, cardia cancer, gallbladder cancer, skin cancer, bone cancer, head and neck cancer, leukemia, lymphoma, lymphosarcoma, adenocarcinoma, fibrosarcoma and their metastases are diseases targeted for treatment according to certain embodiments of the present invention. In some aspects, the patient may have: biliary tract cancer; brain cancer including glioblastoma and medulloblastoma; breast cancer; triple-negative breast cancer; uterine cancer; fallopian tube cancer; cervical cancer; choriocarcinoma; colon cancer; bladder cancer; endometrial cancer; retinoblastoma; vaginal cancer; vulvar cancer; esophageal cancer; oral cancer; gastric cancer; kidney cancer; hematological malignancies including acute lymphoblastic and myeloid leukemia; multiple myeloma; AIDS-related leukemia and adult T-cell leukemia / lymphoma; carcinoma in situ including Bowen's disease and Paget's disease; liver cancer; lung cancer; head and neck cancer or oral cancer. Cancers (oral cavity, throat, esophagus, nasopharynx, jaw, tonsils, nose, lips, salivary glands, tongue, etc.); lymphomas including Hodgkin's disease and lymphocytic lymphoma; neuroblastoma; neuroendocrine tumors; oral cancers including squamous cell carcinoma; adrenal cancer; anal cancer; angiosarcoma; appendiceal cancer; bile duct cancer; bone cancer; carcinoid tumors; soft tissue sarcoma; rhabdomyosarcoma; eye cancer; ovarian cancers arising from epithelial cells, stromal cells, germ cells and mesenchymal cells, and including fallopian duct carcinoma; gallbladder cancer; pancreatic cancer; prostate cancer; rectal cancer; leiomyosarcoma, rhabdomyosarcoma Having cancer or tumors including, but not limited to, sarcomas such as tumors, liposarcomas, fibrosarcomas and osteosarcomas; skin cancers such as melanoma, Kaposi's sarcoma, basal cell carcinoma and squamous cell carcinoma; testicular cancers such as germ cell tumors (seminomas, nonseminomas (teratomas, choriocarcinomas)), stromal tumors and germ cell tumors; penile cancer; hemangioendothelioma; gastrointestinal cancers; ureteral cancers; urethral cancers; spinal cord cancers; pituitary cancers; primary central nervous system (CNS) lymphomas; thyroid cancers such as goiter and medullary carcinoma; and renal cancers such as adenocarcinoma and Wilms' tumor.In some embodiments, cancer or tumors include breast cancer, prostate cancer, colorectal cancer, lymphoma, multiple myeloma, and melanoma. In certain embodiments using the compounds of the present invention, drug-resistant tumors, including solid tumors, non-solid tumors, and lymphomas, are also effective against drug-resistant tumors, such as multidrug-resistant (MDR) tumors. It is now conceivable that any neoplastic cells may be treated using the methods described herein.

[0026] As used herein, the terms “substantially” and “substantial” refer to a reasonable degree or scope. For example, when used with events, situations, characteristics or properties, these terms may refer not only to events, situations, characteristics or properties occurring exactly as described herein, but also to events, situations, characteristics or properties occurring very similarly to illustrate typical acceptable levels or variability of the examples described herein.

[0027] Where used herein, the term “about” is used to give a degree of freedom to the endpoints of a numerical range by specifying that a given value may be “slightly above” or “slightly below” the endpoint. The degree of freedom in this term may be determined by certain variables, and the determination based on experience and the relevant descriptions herein is within the scope of the knowledge of those skilled in the art. For example, in one embodiment, the degree of freedom may be within about ±10% of the numerical value. In another embodiment, the degree of freedom may be within about ±5% of the numerical value. In a further embodiment, the degree of freedom may be within about ±2%, ±1%, or ±0.05% of the numerical value.

[0028] In general, in this specification, the term "or" includes "and" and "and / or".

[0029] Where used herein, multiple compounds or processes may be presented in a common list for convenience. However, these lists should be interpreted as if each member of the list were individually identified as a separate, unique member. Therefore, unless otherwise indicated, individual members of such lists should not be interpreted as being substantially equivalent to any other member of the same list solely on the basis that they are presented in a common group.

[0030] The compounds of the present invention may be useful in the form of a free acid, one or more free bases, a pharmaceutically acceptable salt, a pharmaceutically acceptable hydrate, a pharmaceutically acceptable ester, a pharmaceutically acceptable solvate, a pharmaceutically acceptable prodrug, a pharmaceutically acceptable metabolite, and a pharmaceutically acceptable stereoisomer, as will be evident from their chemical structure. Each of the disclosed compounds falls within the scope of the present invention.

[0031] "Pharmacologically acceptable salt," "hydrate," "ester," or "solvate" refers to a salt, hydrate, ester, or solvate of the compound of the present invention that has the desired pharmacological activity and is not biologically or otherwise undesirable. Salts, hydrates, esters, or solvates of acetates, adipines, alginates, aspartates, benzoates, benzenesulfons, p-toluenesulfons, bisulfates, sulfamates, sulfates, naphthylates, butyrates, citrates, camphorates, camphorsulfons, cyclopentanepropionates, diglucons, dodecyl sulfates, ethanesulfons, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, 2-hydroxyethanesulfons, lactates, maleates, methanesulfons, 2-naphthalenesulfons, nicotinates, oxalates, tosylates, and undecanoates can be produced using organic acids. Salts, hydrates, esters, or solvates of hydrochlorides, hydrobroms, hydroiodides, and thiocyansides can be produced using inorganic acids. Other pharmaceutically acceptable salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, phosphates, tartrates, fumarates, maleates, oxalates, acetates, propions, succinates, mandelates, mesylates, besylates, and tosylates.

[0032] Salts, hydrates, esters, or solvates can also be formed with organic bases. Pharmaceutically acceptable base addition salts of acidic compounds can be formed with organic and inorganic bases by conventional methods. Examples include hydroxides, carbonates, and bicarbonates of alkali metals and alkaline earth metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium bicarbonate, and magnesium carbonate, as well as ammonia, primary, secondary, and tertiary amines. Aluminum salts of these compounds can be obtained by treating the corresponding sodium salt with a suitable aluminum complex, such as aluminum chloride hexahydrate. Examples of non-toxic organic bases include, but are not limited to, triethylamine, butylamine, piperazine, and tri(hydroxymethyl)-methylamine. Suitable examples of base salts, hydrates, esters, or solvates include ammonia hydroxide, carbonate, and bicarbonate; alkali metal salts such as sodium salt, lithium salt, and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; and zinc salt. Organic bases suitable for forming pharmaceutically acceptable base addition salts, hydrates, esters, or solvates of the compounds of the present invention include non-toxic organic bases that are sufficiently potent to form such salts, hydrates, esters, or solvates. For illustrative purposes, such organic bases include monoalkylamines, dialkylamines, and trialkylamines such as methylamine, dimethylamine, triethylamine, and dicyclohexylamine; monohydroxyalkylamines, dihydroxyalkylamines, or trihydroxyalkylamines such as monoethanolamine, diethanolamine, and triethanolamine; amino acids such as arginine and lysine; guanidine; N-methyl-glucosamine; N-methyl-glucamine; L-glutamine; N-methyl-piperazine; morpholine; ethylenediamine; N-benzyl-phenethylamine; (trihydroxymethyl)aminoethane, etc. See, for example, "Pharmaceutical Salts," J. Pharm. Sci., 66:1, 1-19 (1977).Therefore, the basic nitrogen-containing group can be quaternized by active substances including lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; long-chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and aralkyl halides such as benzyl and phenethyl bromides.

[0033] Salts, hydrates, esters, or solvates of basic compounds can be prepared by dissolving the free base of an oxathiazine-like compound in an aqueous solution containing a suitable acid or base, an aqueous alcohol solution, or another suitable solvent, and then evaporating the solution to isolate the salt. Alternatively, the free base of an oxathiazine-like compound may be reacted with an acid, and the oxathiazine-like compound having an acidic group may be reacted with a base, the reaction carried out in an organic solvent, in which case the salt can be obtained by direct separation or by concentrating the solution.

[0034] A "pharmaceutically acceptable prodrug" refers to a derivative of the compound of the present invention that exhibits its pharmacological effects (which may include multiple effects) after undergoing in vivo modification. Prodrugs are formulated to improve chemical stability, patient consent and compliance, bioavailability, duration of action, organ selectivity, formulation (e.g., increased hydrosolubility), and / or reduce side effects (e.g., toxicity). Prodrugs can be readily prepared from the compound of the present invention using methods known in the art, such as those described in Burger's Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp. 172-178, 949-982 (1995). For example, the compound of the present invention can be converted into a prodrug by converting one or more hydroxyl or carboxyl groups to esters.

[0035] "Pharmacologically acceptable metabolites" refer to drugs that have undergone metabolic transformation. Most drugs, after entering the body, become substrates for chemical reactions that can alter their physical properties and biological effects. These metabolic transformations typically affect the polarity of the compound and change how the drug is distributed in and eliminated from the body. In some cases, drug metabolism is necessary for therapeutic effects. For example, antimetabolites, which are anticancer drugs, need to be converted into their active form after being transported to cancer cells. Since most drugs undergo some form of metabolic transformation, the biochemical reactions involved in drug metabolism can be diverse. The liver is the main site of drug metabolism, but other tissues may also be involved.

[0036] Furthermore, certain compositions, concentrations, administration regimens, dosages, syndromes or conditions, processes, etc., may be discussed in relation to a particular embodiment. This is merely for convenience, and it is understood that such disclosures apply similarly to other embodiments found herein. For example, the list of methods, processes, activators, kits, or compositions described relating to methods of administering the compounds of this disclosure directly supports embodiments relating to methods, processes, activators, kits, or compositions that treat, prevent, suppress, or alleviate at least one sign or symptom of a disease, disorder, or condition resulting from or associated with infection or the presence or risk of positive genetic markers associated with cancer, tumors, cancer stem cells, a family history of cancer, or cancer risk, even if these methods, processes, activators, kits, or compositions are not described again herein in relation to that embodiment.

[0037] As used herein and as well understood in the art, the terms “to treat” or “to cure” mean an approach to obtain beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes include, but are not limited to, relief or improvement of one or more symptoms or conditions, whether detectable or undetectable; reduction of the scope of the disease; stabilization of the disease state (i.e., no exacerbation); delay or slowing of disease progression; improvement or relief of the disease state; reduction of disease recurrence; and remission (whether partial or complete). “To treat” and “to cure” may also mean extending survival compared to the survival expected without treatment. In addition to being useful as treatments, the methods described herein may be useful for the prevention or preventive measures of disease. As used herein, the term “treat” may refer to any administration of the compounds of the present invention and include (i) preventing or suppressing the disease in a mammal, e.g., human, that is experiencing or exhibiting the pathology or overall symptoms of the disease (i.e., halting further progression of the pathology and / or overall symptoms), or (ii) improving the disease in a mammal, e.g., human, that is experiencing or exhibiting the pathology or overall symptoms of the disease (i.e., reversing the pathology and / or overall symptoms). The term “control” includes preventing, treating, eradicating, improving, or otherwise reducing the severity of the controlled condition.

[0038] Concentration, quantity, and other numerical data may be expressed or presented in range format as described herein. Such range format is used solely for convenience and conciseness, and it should be understood that it should be interpreted flexibly to include not only the numbers explicitly listed as limits of the range, but also all individual numbers or subranges contained within that range, as if each number and subrange were explicitly listed. For example, the numerical range "approximately 0.01 to 2.0" should be interpreted to include not only the explicitly listed values ​​of approximately 0.01 to approximately 2.0, but also the individual values ​​and subranges within the specified range. Therefore, individual values ​​such as 0.5, 0.7, and 1.5, as well as subranges such as 0.5 to 1.7, 0.7 to 1.5, and 1.0 to 1.5, are included in this numerical range. Furthermore, such interpretation should apply regardless of the breadth of the range or the characteristics described. In addition, note that all percentages are weight percentages unless otherwise specified.

[0039] For the purposes of understanding the scope of this disclosure, the terms "including" or "comprising" and their derivatives are intended, when used herein, to be open-ended terms that identify the presence of described features, elements, components, groups, integers and / or processes, but do not exclude the presence of other undescribed features, elements, components, groups, integers and / or processes. The same applies to similar terms such as "including," "having," and their derivatives. The terms "consisting" and their derivatives are intended, when used herein, to be closed terms that identify the presence of described features, elements, components, groups, integers and / or processes, but exclude the presence of other undescribed features, elements, components, groups, integers and / or processes. The terms "essentially becoming from" are intended, when used herein, to identify the presence of features, elements, components, groups, integers and / or processes, as well as any fundamental new characteristics of those features, elements, components, groups, integers and / or processes that do not substantially affect them. It is understood that any reference to any one of these transitional words (i.e., “include,” “become,” or “become essentially”) directly supports the substitution of any of the other transitional words that are not specifically used. For example, the modification of the term from “include” to “become essentially” receives direct support from this definition.

[0040] Tumor stem cells (also known as cancer stem cells (CSCs)) are considered to be the main drivers of metastasis and tumor regrowth after resection.

[0041] In certain embodiments, the compounds of the present invention are particularly useful for treating tumor stem cells in subjects.

[0042] In certain embodiments, the compounds of the present invention are particularly useful for treating glioblastoma tumor stem cells in subjects.

[0043] In certain embodiments, the compounds of the present invention are particularly useful in inducing angiogenesis inhibitory effects in subjects.

[0044] In certain embodiments, the compounds of the present invention are particularly useful in inducing a tubule formation inhibitory effect in the subject.

[0045] In certain embodiments, the present invention kills or inhibits the growth of tumor cells and / or CSCs by oxidative stress, apoptosis, and / or inhibition of neovascularization at the tumor site. The primary mechanism of action for killing tumor cells and / or CSCs is oxidative stress. Tumor cells and / or CSCs can also be killed by apoptosis according to the present invention. At lower blood concentrations, the compounds according to the present invention are effective in inhibiting tumor cell growth through their angiogenesis inhibitory effect and their tubule formation inhibitory effect, and therefore these compounds are useful for palliative treatment.

[0046] The compounds of the present invention are metabolized in the bloodstream much more slowly than taurolidine and taurultam. Therefore, similar effects can be achieved by administering lower doses of these compounds to patients.

[0047] In certain embodiments, the compounds of the present invention are also useful for treating microbial infections in subjects such as human patients. Microbial infections that can be treated according to certain embodiments include bacterial infections, fungal infections, and / or viral infections.

[0048] Because cancer patients tend to have immunodeficiency, they are particularly susceptible to microbial infections, especially during and / or after surgery.

[0049] In certain embodiments, the compounds of the present invention are used to treat glioblastoma in subjects.

[0050] In certain embodiments, the compounds of the present invention are used to treat S. aureus infections in subjects.

[0051] In certain embodiments, the compounds of the present invention are used in accordance with the present invention to treat methicillin-resistant Staphylococcus aureus (MRSA) infections in subjects.

[0052] In certain embodiments, the compounds of the present invention are used in accordance with the present invention to treat E. coli infections in subjects.

[0053] In certain embodiments, the compounds of the present invention are used in accordance with the present invention to treat H. pylori infection and / or H. pylori-related cancers (or more) in subjects.

[0054] In certain embodiments, the compounds of the present invention are used in accordance with the present invention to treat Staphylococcus epidermidis infections in subjects.

[0055] In certain embodiments, the compounds of the present invention are used in accordance with the present invention to treat Streptococcus pneumoniae infections in subjects.

[0056] In certain embodiments, the compounds of the present invention are used in accordance with the present invention to treat Streptococcus pyogenes infections in subjects.

[0057] In certain embodiments, the compounds of the present invention are used in accordance with the present invention to treat Enterococcus faecalis infection in a subject.

[0058] In certain embodiments, the compounds of the present invention are used in accordance with the present invention to treat Haemophilus influenzae infection in a subject.

[0059] In certain embodiments, the compounds of the present invention are used in accordance with the present invention to treat Moraxella catarrhalis infection in a subject.

[0060] In certain embodiments, the compounds of the present invention are found in the following bacteria: Enterococcus faecalis, Enterococcus faecilum, Staphylococcus aureus, Clostridium difficile, Acineobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Citrobacter freundii, Escherichia coli, Klebsiella pneomoniae, Morganelle morganii, and Bacteroides fragilis. This invention is used to treat subjects suffering from infections caused by at least one of Helicobacter pylori and Helicobacter fragilis.

[0061] In certain embodiments, the compounds of the present invention are used in accordance with the present invention to treat viral infections in subjects. Viral infections treated include human immunodeficiency virus (HIV), herpes simplex virus, Epstein-Barr virus, SV-40 virus, cytomegalovirus, adenovirus-5, West Nile virus (WNV), dengue virus (DENV), tick-borne encephalitis virus (TBEV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), influenza virus, poxvirus, smallpox virus, Ebola virus, Marburg virus, parainfluenza virus, respiratory syncytial virus, measles virus, human papillomavirus, varicella-zoster virus, and cytomegalovirus. JC virus, rhabdovirus, rotavirus, rhinovirus, adenovirus, papillomavirus, parvovirus, picornavirus, poliovirus, mumps virus, rabies virus, reovirus, rubella virus, togavirus, orthomyxovirus, retrovirus, hepadnavirus, coxsackievirus, equine encephalitis virus, etheroviruses, Rift Valley fever virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus or hepatitis E virus, Zika virus, aroavirus Examples include viruses such as tyuleniy virus, hantavirus, enterovirus, echovirus, calicivirus, Sindbisvirus, Ross River virus, coronavirus, SARS-coronavirus, rhabdovirus family, becyclovirus, lyssavirus, paramyxovirus family, paramyxovirus, mumps virus, Newcastle disease virus, morbillivirus, pneumonia virus, respiratory syncytial virus, orthomyxovirus, bunyavirus, hantavirus, arenavirus family, Lassa fever virus, orbivirus, and Colorado tick fever virus.

[0062] In certain embodiments, the compounds of the present invention are used in accordance with the invention to treat fungal infections in subjects. The compounds of this disclosure are useful for the therapeutic or prophylactic treatment of fungal infections in animals, including humans. For example, the compounds are useful for treating localized fungal infections in humans caused by species of the genera Candida, Trichophyton, Microsporum, or Epidermophyton, or for treating mucosal infections caused by Candida albicans. The compounds can also be used to treat systemic fungal infections caused by, for example, Candida albicans, Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus, Coccidioides, Torulopsis glabrata, Paracoccidioides, Histoplasma, or Blastomyces.

[0063] For human use, the antifungal compounds of formula (I) and their salts may be administered alone, but are generally administered in combination with a pharmaceutical carrier selected in accordance with the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing excipients such as starch or lactose, or alone or in combination with excipients in capsules or ovules, or in the form of elixirs or suspensions containing flavorings or colorings. In some embodiments, orally disintegrating tablets may be used. These may be administered parenterally, for example, by intravenous, intramuscular, intravesical or subcutaneous injection. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, such as salts or glucose sufficient to make the solution isotonic with blood.

[0064] In certain embodiments, a compound according to formula I is used in accordance with the present invention.

[0065] [ka]

[0066] R1 may be a -CO-aryl or a branched or unbranched alkyl group of C1-C6, such as CH3, COH, COCH3, COCH2CH3, or COCH2CH2CH3. R2 may be H.

[0067] In certain embodiments, R1 is not H. In certain embodiments, R1 is not benzyl. In certain embodiments, R1 is not aryl.

[0068] In certain embodiments, R2 is not alkyl.

[0069] In certain embodiments, a novel compound 2289 is used in accordance with the present invention. Compound 2289 has the following structure: [ka] It has.

[0070] Compound 2289 can be used for the treatment and suppression of tumors and cancer stem cells, viral infections, bacterial infections and / or fungal infections.

[0071] In certain embodiments, a novel compound 2293 is used in accordance with the present invention. Compound 2293 has the following structure: [ka] It has.

[0072] Compound 2293 can be used for the treatment and suppression of tumors and cancer stem cells, viral infections, bacterial infections and / or fungal infections.

[0073] In certain embodiments, a novel compound 2296 is used in accordance with the present invention. Compound 2296 has the following structure: [ka] It has.

[0074] Compound 2296 can be used for the treatment and suppression of tumors and cancer stem cells, viral infections, bacterial infections and / or fungal infections.

[0075] The amount of compound required depends on the tumor size. In one embodiment, the present invention includes surgically reducing the tumor size and treating it with one or more compounds. The compounds can be administered before, during, or after the surgical procedure to reduce the tumor. The compounds according to the present invention can be administered by any preferred method, for example, by capsules, by tablets, intravenously (IV), intraperitoneally (IP), intravesically, and / or directly to the tumor.

[0076] It was unexpectedly discovered that the compound could be administered during and immediately after surgery because it does not inhibit wound healing like other chemotherapeutic agents.

[0077] The compounds disclosed herein were unexpectedly found to kill tumor stem cells, which is extremely rare and perhaps unknown among conventional chemotherapeutic agents. Conventional chemotherapeutic agents, even if effective against tumor stem cells, are generally only effective at very high doses that are extremely toxic to human patients.

[0078] Unexpectedly, it was found that taurolidine and / or taurultam, at lower doses than required to kill tumor cells, were effective in killing tumor stem cells.

[0079] It was unexpectedly discovered that the compound of formula I has a significantly longer half-life in human blood than taurolidine and taurultam. Therefore, these compounds are not removed very rapidly from the patient's bloodstream, thereby effectively delaying the loss of drug efficacy caused by the body's clearance mechanisms.

[0080] Therefore, the half-lives of compounds 2289, 2293, and 2296 are approximately 5 to 6 hours in human blood.

[0081] In some embodiments, one or more compounds of the present disclosure, for example, formulas I, 2289, 2293, and 2296, are administered in the composition at concentrations of about 0.01 μg / ml to about 1000 μg / ml. In some embodiments, the compounds are administered in the composition at concentrations of about 1 μg / ml to about 100 μg / ml. In some embodiments, the compounds are administered in the composition at concentrations of about 10 μg / ml to about 50 μg / ml. The composition may contain taurolidine and / or taurulutam in concentrations of about 0.01 μg / ml to about 1000 μg / ml, about 1 μg / ml to about 100 μg / ml, or about 10 μg / ml to about 50 μg / ml.

[0082] In some embodiments, one or more compounds of the present disclosure are administered in a composition at concentrations of about 0.001% to about 5% by weight, about 0.01% to about 3.5% by weight, about 0.1% to about 3% by weight, about 0.5% to about 2.5% by weight, or about 1% to about 2% by weight. In some embodiments, the oxathiazine-like compound is given in a composition at a concentration of about 0.01% to about 1.5%. In some embodiments, the compound is given in a composition at a concentration of about 0.1% to about 1%. In some embodiments, the compound is given in a composition at a concentration of about 100 μM to about 5000 μM, about 250 μM to about 2500 μM, about 500 μM to about 2000 μM, about 750 μM to about 1500 μM, about 1000 μM to about 1250 μM, or any other concentration within the enumerated range. The composition may additionally contain about 0.01% to about 3%, about 0.1% to about 2.5%, or about 1% to about 2% of tauroridine and / or taururutum.

[0083] In some embodiments, one or more compounds of the present disclosure are given in a unit dosage form composition. As used herein, “unit dosage form” is a composition containing an amount of the compound suitable for administration to an animal, such as a mammal, in a single dose in accordance with proper medical practice, e.g., a human subject. These compositions may contain about 0.1 mg to about 500 mg of the compound, for example, about 5 mg to about 350 mg. The frequency of treatment with the compositions of the present invention can be modified so that a desired target plasma level is achieved and maintained. For this reason, non-limiting examples of treatment schedules include daily, twice daily, three times daily, weekly, bi-weekly, monthly, and combinations thereof. Alternatively, the compositions of the present invention may also be administered as a continuous infusion or as one, two, three or more different continuous infusions with different rates and doses of the drug being administered, following a bolus, and such regimens may be optionally interrupted by one or more additional bolus injections.

[0084] In one embodiment, one or more compounds of the Disclosure are given in a composition administered to a subject requiring them in a total daily dose of about 0.001 g to about 1000 g, for example, about 0.01 g to about 500 g, 0.1 g to about 300 g, 0.5 g to about 200 g, 1 g to 100 g, or any amount within the enumerated range. The daily dose may be administered in the form of an orally administered composition. The daily dose may be administered in the form of a capsule, tablet, or pharmaceutically acceptable solution. The daily dose may be administered in a form containing one or more compounds of the Disclosure at concentrations of about 0.01% to about 5% (w / v), about 0.1% to about 3% (w / v), about 0.5% to about 2.5% (w / v), or about 1% to about 2% (w / v).

[0085] The daily dose may be administered in a form containing one or more of the compounds of this disclosure at concentrations of approximately 0.001 μg / ml to approximately 1000 μg / ml, approximately 0.01 μg / ml to approximately 750 μg / ml, approximately 0.05 μg / ml to approximately 500 μg / ml, approximately 0.1 μg / ml to approximately 300 μg / ml, approximately 0.5 μg / ml to approximately 200 μg / ml, approximately 1 μg / ml to approximately 100 μg / ml, approximately 5 μg / ml to approximately 50 μg / ml, approximately 10 μg / ml to approximately 25 μg / ml, or approximately 15 μg / ml to approximately 20 μg / ml. The daily dose may also be administered in a form containing one or more solubilizers, such as polyols.

[0086] The effective dose given in the composition may consist of a dosage unit containing one or more compounds of this disclosure in an amount of approximately 0.01 mg / kg to 500 mg / kg per day, approximately 1 mg / kg to 100 mg / kg, or approximately 5 mg / kg to 50 mg / kg per day. In some embodiments, the dosage unit is administered every other day, every other week, or every week.

[0087] In one embodiment, the compound of formula I can be administered as a combination therapy with taurolidine and / or taurultam to kill tumor stem cells. According to this embodiment, it was unexpectedly found that the combination therapy required a lower dose to kill tumor stem cells than the dose required to kill normal tumor cells.

[0088] In one embodiment, the compound of formula I is administered to the subject in a total daily dose of approximately 0.1 g to approximately 100 g, approximately 1 g to approximately 80 g, approximately 2 g to approximately 50 g, or approximately 5 g to approximately 30 g.

[0089] The effective dose of the compound is approximately 0.1 mg / kg to 1000 mg / kg per day, preferably 150 mg / kg to 450 mg / kg, and most preferably 300 mg / kg to 450 mg / kg per day.

[0090] Formulations suitable for injection or infusion may include an isotonic solution containing one or more solubilizers, such as sugars, polyols, surfactants, and osmotic regulators, to provide a solution with a higher concentration of the compound. Such a solution is described in European Patent No. 253662. The solution can be made isotonic with Ringer's solution or Ringer's lactate solution. The concentration of the compound in such a solution may range from 1 g / liter to 60 g / liter.

[0091] As used herein, the term "polyol" refers to a sugar having more hydroxyl (-OH) groups than ordinary sugars. Examples of polyols include alcohols and carbohydrates such as mannitol, sorbitol, maltitol, xylitol, isomalt, erythritol, lactitol, sucrose, glucose, galactose, fructose, fucose, ribose, lactose, maltose, and cellobiose.

[0092] In certain embodiments, the present invention also relates to derivatives of the above compounds having, for example, at least one activity of the above compounds as described herein, for example, at least 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% or more of said activity.

[0093] In certain embodiments, the present invention also relates to compositions containing the compounds described herein, including pharmaceutically acceptable solutions of the compounds, and orally administered compositions such as capsules and tablets containing the compositions.

[0094] In certain embodiments, the compounds of the present invention can be administered to a subject or patient by any suitable means, for example, in a solution, for example, locally, systemically, for example, by intravenous injection.

[0095] 2289 synthesis Compound 2289 was prepared according to the following non-restrictive synthetic protocol. 1. The following compounds: [ka] Compound 2289 was formed by reacting with acetic anhydride in the presence of pyridine at a temperature of approximately 100°C. Compound 2289 was isolated from the reaction mixture by adding water and filtering the precipitate. Yield (fresh): 89%. 2. The following compounds: [ka] Compound 2289 was formed by reacting with acetyl chloride in the presence of pyridine at a temperature of approximately 60°C. Compound 2289 was isolated from the reaction mixture by adding water and filtering the precipitate. Yield (crude): 57%.

[0096] purification: for example, ethanol ethyl acetate Recrystallization with ethyl acetate / petroleum ether

[0097] physical properties Melting range: 79℃~83℃ Solubility in water: Approximately 1.5% at room temperature

[0098] Identity was confirmed by NMR, IR, and elemental analysis.

[0099] In some embodiments, the present disclosure includes a method for producing compound 2289 by the following reaction:

[0100] [ka]

[0101] In some embodiments, X is a leaving group. For example, X may be an acyl halide where the halogen is, for example, Cl, Br, or I. In another example, X may be an anhydride such as CO=OR. In yet another example, X may be a thioester SR or ester OR. In yet another example, X may be a mesylate or tosylate. In yet another example, X may be a halogen.

[0102] 2293 synthesis Compound 2293 was prepared according to the following non-restrictive synthetic protocol.

[0103] The following compounds: [ka] Compound 2293 was formed by reacting it with propionyl chloride in the presence of pyridine. Compound 2293 remained in the pyridine phase and could be isolated, for example, by column chromatography.

[0104] purification: Column chromatography: Eluent: Hexane / ethyl acetate 50:50

[0105] physical properties Melting range: 52℃~53℃ Solubility in water: Less than 1.5% at room temperature

[0106] Identity was confirmed by NMR, IR, and MS.

[0107] In some embodiments, the present disclosure includes a method for producing compound 2293 by the following reaction:

[0108] [ka]

[0109] In some embodiments, X is a leaving group. For example, X may be an acyl halide where the halogen is, for example, Cl, Br, or I. In another example, X may be an anhydride such as CO=OR. In yet another example, X may be a thioester SR or ester OR. In yet another example, X may be a mesylate or tosylate. In yet another example, X may be a halogen.

[0110] 2296 synthesis Compound 2296 was prepared according to the following non-restrictive synthetic protocol.

[0111] Compound 2296 was formed by dissolving 1-hydroxypropane-2-sulfonamide in water and reacting it with methylene glycol. Yield (crude): 51%

[0112] purification: Recrystallization using an alcohol solvent

[0113] physical properties Melting range: 74℃~75℃ Solubility in water: Minimum 1% at room temperature

[0114] Identity was confirmed by NMR, IR, and elemental analysis.

[0115] In some embodiments, the present disclosure includes a method for producing compound 2296 by the following reaction:

[0116] [ka]

[0117] The reactants listed above are alternatives and non-limiting. Those skilled in the art will recognize that other alternative reactants may be used in the reaction. A variety of solvents can be used, including, but not limited to, alcohols such as ethanol or methanol, acetonitrile, tetrahydrofuran (THF), and ethyl acetate.

[0118] In certain embodiments, a sublimation apparatus consisting of laboratory glassware known in the art can be used in the sublimation technique for purifying the compound according to the present invention. In certain embodiments, the sublimation vessel is heated under vacuum and reduced pressure. The compound volatilizes and condenses on a cooled surface as a purified compound, leaving behind non-volatile residual impurities. This cooled surface often takes the form of a cold finger. After heating is stopped and the vacuum is released, the sublimated compound can be recovered from the cooled surface.

[0119] In one embodiment, the present disclosure includes a method for killing tumor stem cells by administering to a subject requiring the use of a tumor stem cell-killing effective amount of tauroridine, taururutam, or a mixture thereof in combination with one or more compounds of Formula I. The tumor stem cell-killing effective amount of tauroridine and / or taururutam is less than the amount of tauroridine and / or taururutam required to kill tumor cells. In some embodiments, the compound of formula I is co-administered with carmustine, cytarabine, gemcitabine, nab-paclitaxel, asparaginase, procarbazine, mitomycin, 5-FU, methotrexate, vinblastine, dacarbazine, cisplatin, carboplatin, paclitaxel, bevacizumab, one or more checkpoint inhibitors, one or more PARP inhibitors, one or more anti-PD-1 drugs, docetaxel, irinotecan (including Onivyde®), doxorubicin, erlotinib, olaparib, lapatinib, topotecan, capecitabine, oxaliplatin, cyclophosphamide, ifosfamide, or a combination thereof. In some embodiments, the treatment is for ovarian cancer and involves co-administration of a compound of formula I with carboplatin, paclitaxel, topotecan, bevacizumab, one or more PARP inhibitors, one or more anti-PD-1 drugs, or a combination thereof. For example, one or more PARP inhibitors may include olaparib (Lynparza®), niraparib (Zejula®), rucaparib (Rubraca®), and talazoparib (Talzenna®), veliparib, pamiparib, CEP9722, E7016, iniparib, 3-aminobenzamide, or a combination thereof. For example, one or more anti-PD1 drugs may include pembrolizumab (Keytruda®), nivolumab (Opdivo®), semiprimab (Libtayo®), atezolizumab (Tecentriq®), avelumab (Bavencio®), and durvalumab (Imfinzi®).For example, co-administered drugs may include pembrolizumab (Keytruda®), nivolumab (Opdivo®), semiprimab (Libtayo®), spartalizumab, camrelizumab, cintilimab, tisrelizumab, tripalimab, dostallimab, retifanlimab, sasanlimab, budigalimab, zinberelimab, BI754091, JTX-4014, AMP-224, AMP-514, atezolizumab (Tecentriq®), avelumab (Bavencio®), durvalumab (Imfinzi®), cosiberimab, KN035, CK-301, AUNP12, CA-170, BMS-986189, or combinations thereof. In some embodiments, the treatment is for pancreatic cancer, and the compound of formula I is co-administered with one or more of the aforementioned compounds suitable for the treatment of pancreatic cancer.

[0120] The expressions “co-administered” or “administered in combination,” as used herein, mean that two (or more) active ingredients are administered in a chronological sequence. Co-administration or combination can be achieved by mixing the two active ingredients in a single formulation, or by administering the two active ingredients separately but simultaneously or at short time intervals. For example, generally, the two active ingredients are co-administered within a time range of 6 to 168 hours. In this case, the active ingredients may be administered in any order, i.e., the chemotherapeutic agent may be administered first, or one or more compounds of this disclosure may be administered first. In some embodiments, the two active ingredients are co-administered in a single formulation or co-administered sequentially and separately.

[0121] In some embodiments, tauroridine, taururutam, or a mixture thereof is administered in a tumor stem cell killing composition at a concentration of about 0.01 μg / ml to about 500 μg / ml. In some embodiments, tauroridine, taururutam, or a mixture thereof is administered in a tumor stem cell killing composition at a concentration of about 0.1 μg / ml to about 100 μg / ml. In some embodiments, tauroridine, taururutam, or a mixture thereof is administered in an effective tumor stem cell killing composition at a concentration of about 10 μg / ml to about 50 μg / ml. Tauroridine is effective in killing tumor stem cells at 0.01 μg / ml in in vitro tissue culture.

[0122] In some embodiments, tauroridine, taururutam, or a mixture thereof is administered in the tumor stem cell killing composition at a concentration of about 0.001% to about 2%. In some embodiments, tauroridine, taururutam, or a mixture thereof is administered in the tumor stem cell killing composition at a concentration of about 0.01% to about 1.5%. In some embodiments, tauroridine, taururutam, or a mixture thereof is administered in the tumor stem cell killing composition at a concentration of about 0.1% to about 1%.

[0123] In one embodiment, taurolidine, taurultam, or a mixture thereof is administered to a subject requiring it for the purpose of killing tumor stem cells in a total daily dose of about 0.01 g to about 50 g, about 0.1 g to about 30 g, about 0.5 g to about 10 g, or about 1 g to about 5 g.

[0124] The effective dose of taurolidine, taurultam, or a mixture thereof for tumor stem cell death is approximately 0.01 mg / kg to 500 mg / kg per day, preferably 1 mg / kg to 100 mg / kg, and most preferably 5 mg / kg to 50 mg / kg per day.

[0125] In another embodiment, the Disclosure includes a method for killing tumor stem cells by administering one or more of the compounds of the Disclosure alone or in combination with taurolidine and / or taurultam to a subject requiring the same. Such a technique results in a method of broadening the pharmacokinetic effect obtained by killing tumor stem cells using at least two compounds having different half-lives.

[0126] In some embodiments, the Disclosure includes extending the therapeutic concentration range of tauroridine and / or taurultam therapy by co-administering tauroridine and / or taurultam with one or more compounds of the Disclosure.

[0127] In a particular embodiment, the following experimental protocol was followed.

[0128] Cell lines and culture conditions Four different human cancer cell lines—pancreatic cancer cells Panc TuI (CLS Cell Lines Service, Eppelheim, Germany), colon cancer cells HCT116 (ATCC-LGC Standards GmbH, Wessel, Germany), Merkel cell carcinoma cells MCC 14.2, and mammary gland / breast cancer cells MDA MB 468 (ATCC-LGC Standards GmbH, Wessel, Germany)—were used to test the compounds of this disclosure. HCT116 cells, MDA MB 468 cells, and Panc TuI cells were cultured in Dulbecco's Modified Eagle Medium (DMEM), and MCC 14.2 cells were maintained in RPMI 1640. Penicillin (100 U / ml), streptomycin (100 U / ml), and 2 mM L-glutamine were added to all cultures. MCC 14.2 cells were further supplemented with 25 nM HEPES. The cells are grown as a monolayer in a humidified atmosphere at 37°C and 5% CO2.

[0129] Various Gram-negative and Gram-positive bacteria: Staphylococcus aureus and Escherichia coli (ATCC-LGC Standards GmbH, Wessel, Germany), Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Clostridium difficile, Acinetobacter baumannii, Pseudomonas erginosa, Stenotrophomonas maltophilia, Citrobacter frownii, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Bacteroides fragilis, and Helicobacter pylori (fresh clinical isolates) are used to test the compounds of this disclosure. All isolates except Bacteroides fragilis and Helicobacter pylori are cultured on Mueller-Hinton agar. Bacteroides fragilis is cultured in Mueller-Hinton agar containing 5% horse blood and 20 mg / l β-NAD. Helicobacter pylori is cultured in Chocolat PolyViteX agar.

[0130] Cell migration assay Cells are plated onto a 60 mm dish to create a confluent monolayer, which is incubated for 24 hours to allow the cells to adhere and spread. The number of cells required for a confluent monolayer varies depending on the specific cell type. After creating a scratch in the cell monolayer, the gap area is examined using phase-contrast microscopy. Images are acquired at the start and at regular intervals (48 hours, 72 hours, and 120 hours (5 days)) during cell migration to fill the scratch, and the cell migration velocity is semi-quantified.

[0131] MTT cytotoxicity assay Cells are individually seeded and subconfluent monolayers are obtained in a 96-well plate format and incubated for 24 hours before treatment. To investigate the dose-response for antitumor activity, cells are incubated for 24 and 48 hours with escalating concentrations (100 μmol / l, 200 μmol / l, 500 μmol / l, 1000 μmol / l, 1500 μmol / l, 2000 μmol / l) of any oxathiazinane derivative and ddH2O as a control. After exposure time, 10 μl of MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) reagent (5 mg / ml) is added and incubated for 2 hours, after which the purple formazan crystals are dissolved in 100 μl of DMSO (dimethyl sulfoxide). Cell viability can be analyzed using a microplate absorbance reader (ASYS, UVM340, Anthos Mikrosystheme GmbH, Germany) with OD560 measurement. The assay is performed using eight replicates of three independent experiments by serial passage.

[0132] ROS analysis To gain further insights into the functional aspects, the effects of the compound on reactive oxygen species (ROS) at the cellular level will be analyzed using the Cellular ROS / Superoxide Detection Assay KIT (Abcam, Cambridge, UK) according to the manufacturer's instructions for use.

[0133] BrdU Growth Assay Cells are individually seeded and a subconfluent monolayer is obtained in a 96-well plate format, incubated for 24 hours before processing. To investigate the dose-response of the cells' antiproliferative activity, cells are incubated for 6 hours with escalating concentrations (100 μmol / l, 200 μmol / l, 500 μmol / l, 1000 μmol / l, 1500 μmol / l, and 2000 μmol / l) of any oxathiazinane derivative and ddH2O as a control, followed by a BrdU proliferation assay (5-bromo-2-deoxyuridine)-ELISA (Roche Applied Science, Mannheim, Germany) according to the manufacturer's instructions. A 6-hour incubation period has been shown to be appropriate for the BrdU proliferation assay in previous experiments. The amount of synthesized DNA is detected using a microplate absorbance reader (ASYS, UVM340, Anthos Mikrosysteme GmbH, Krefeld, Germany) measuring at 370 nm with a reference wavelength of 492 nm. The BrdU assay is performed using eight replicates of three independent experiments using sequential passage.

[0134] Disk diffusion test The antibacterial activity of the compound was investigated by the Kirby-Bauer disk diffusion test using Mueller-Hinton agar. A 10 mm diameter disk immersed in 150 μl of distilled water containing 10 mg of the test substance was placed on Mueller-Hinton agar (bioMeieux, Geneva, Switzerland) that retains the pre-lawn of the relevant test bacteria. The plate was incubated at 37°C for 24 hours, and the inhibition zone was recorded. Culture medium and sterile distilled water were used as controls. N-acetylcysteine ​​(NAC) was used as an antioxidant control.

[0135] statistics The results of the MTT assay and BrdU assay (ratio of viable cells to proliferating cells) are expressed as mean ± SEM. A one-way ANOVA is used, followed by Tukey's post-hoc test to compare experimental groups with a normal distribution, and Fisher's exact test for categorical data, as needed. A p-value of 0.05 or less is considered statistically significant. [Examples]

[0136] Example 1: Cell migration assay: Cell migration of compounds 2289, 2244, 2287, 2255, and 2256 was compared with untreated control (NK) and positive control (compound 2250). The comparison compounds 2244, 2287, 2255, and 2256 have the following structures.

[0137] [Table 1]

[0138] Using a cell migration assay, the migration rates of various cancer cell entities were semi-quantified under treatment with 2289, a negative control, and a positive control (2250). Figure 1 shows the results after 2 to 5 days, exemplifying the results using a confluent monolayer of MDA MB 468.

[0139] As shown in Figure 1, the migration rate of cell cultures treated with 2250 was clearly inhibited compared to the untreated control, where cells migrated to the scratch area and filled the gap. Cell cultures treated with 2289 also showed a lower migration rate, though not as significantly as those treated with 2250. No decrease in migration rate was observed in any of the other test derivatives, and the gap was almost completely filled after 5 days, comparable to the untreated control. The results are representative of all cell lines tested.

[0140] Example 2: The antitumor activity of compounds 2289, 2293, and 2296 was determined according to the MTT assay and BrdU assay described above.

[0141] As shown in Figure 2, in the MTT assay for cell viability, 2250 and 2289 showed a significant reduction in viable cells in all tested cancer cell lines (MDA MB 468, HT29, MCC 14.2, Panc TuI) with varying sensitivities to both substances (MDA MB 468 showed the highest response rate, and HT29 showed the lowest response rate).

[0142] As shown in Figure 3, in the BrdU assay for cell proliferation, 2250 and 2289 showed a significant reduction in proliferating cells in all cancer cell lines tested, with MDA MB 468 showing the highest response rate and MCC 14.2 showing the lowest response rate. Overall, 2250 showed higher antiproliferative capacity compared to 2289.

[0143] Example 3: The antibacterial activity of compounds 2289, 2250, 2244, 2255, 2256, 2287, 2289, 2293, and 2296 was determined using an agar diffusion test. The results are summarized below.

[0144] [Table 2]

[0145] 2289: Inhibition zones of various bacterial strains Escherichia coli (ATCC 8739), Gram-negative: 18.5 mm Staphylococcus aureus (ATCC 6538), Gram-positive: 27.5 mm

[0146] 2293: Inhibition zones of various bacterial strains Escherichia coli (ATCC 8739), Gram-negative: 19.5mm Staphylococcus aureus (ATCC 6538), Gram-positive: 31.5 mm Staphylococcus aureus (MRSA, case number 2065), Gram positive: 32.5 mm

[0147] 2296: Inhibition zones of various bacterial strains Escherichia coli (ATCC 8739), Gram-negative: 23.0 mm Staphylococcus aureus (ATCC 6538), Gram-positive: 38.0 mm Staphylococcus aureus (MRSA, case number 2065), Gram positive: 43.0 mm

[0148] Example 4: MTT cytotoxicity assays were performed on the Panc TuI cell line using various oxathiazine derivatives. Figure 4 shows the cell viability under various concentrations of substances 2289, 2293, and 2296 compared to untreated cells (negative control = NC) and positive control (1000 μM GP2250) after 24, 48, and 72-hour incubation periods.

[0149] All substances showed a significant effect on the cell viability of the Panc TuI cell line, analyzed at a concentration of 100 μM after 24 hours compared to the untreated control (NC).

[0150] MTT cytotoxicity assays were performed on the AsPc1 cell line using various oxathiazine derivatives. Figure 5 shows the cell viability under various concentrations of substances 2289, 2293, and 2296 compared to untreated cells (negative control = NC) and positive control (1000 μM GP2250) after incubation periods of 24, 48, and 72 hours.

[0151] Substances 2289 and 2296 showed a significant effect on cell viability of the AsPc1 cell line at a concentration of 100 μM compared to the untreated control (NC) after 24 hours. Substance 2293 showed a significant effect on cell viability at a concentration of 500 μM compared to the untreated control (NC) after 24 hours.

[0152] MTT cytotoxicity assays were performed on the cell line BxPc3 using various oxathiazine derivatives. Figure 6 shows the cell viability under various concentrations of substances 2289, 2293, and 2296 compared to untreated cells (negative control = NC) and positive control (1000 μM GP2250) after 24, 48, and 72-hour incubation periods. All substances showed a significant effect on the cell viability of the BxPc3 cell line, analyzed from a concentration of 100 μM compared to the untreated control (NC) after 24 hours.

[0153] Growth assays were performed on cell lines Panc TuI, AsPc1, and BxPc3 using various oxathiazine derivatives. Figure 7 shows cell proliferation under various concentrations of substances 2289, 2293, and 2296 after a 6-hour incubation period, compared to untreated cells (negative control = NC) and positive control (1000 μM GP2250). All substances showed a significant effect on cell proliferation in all cell lines analyzed from a concentration of 500 μM compared to the untreated control (NC).

[0154] Example 5: It has been previously reported that tauroridine has a half-life of approximately 30 minutes, while compound 2250 has a significantly longer half-life. The half-lives of compounds 2289, 2293, and 2296 in fresh human blood were measured in vitro at 37°C.

[0155] For 2289 and 2293 through 2250, human K2-EDTA blood was spiked with 256 μM of 2289 or 2293, 26 μM of 2250, and 26 μM of 2244 (n=1). After holding the pool at 37°C for 20–25 minutes, the aliquots were centrifuged (at 4°C at 2500 g for at least 5 minutes). After centrifugation, human plasma was collected and immediately frozen at -80°C. This aliquot was considered to correspond to T0.

[0156] The remaining pool was separated and maintained at 37°C. Aliquots were taken at least 0.25 hours, 0.5 hours, 1 hour, 6 hours, 8 hours, 24 hours, and 48 hours, centrifuged (at 2500g for at least 5 minutes at 4°C), and the recovered plasma was frozen at -80°C.

[0157] Stability was determined by measuring the peak areas of 2289 and 2293 at each time point compared to T0.

[0158] For 2296 and its metabolite 1-hydroxypropane-2-sulfonamide, human blood in K2-EDTA was spiked with 256 μM of 2296 and 26 μM of 1-hydroxypropane-2-sulfonamide (n=1).

[0159] After holding the pool at 37°C for 20-25 minutes, the aliquots were centrifuged (at 4°C for at least 5 minutes at 2500g). Human plasma was collected after centrifugation and immediately frozen at -80°C. This aliquot was considered to correspond to T0.

[0160] The remaining pool was separated and maintained at 37°C. Aliquots were taken at least 0.5 hours, 1 hour, 3 hours, 6 hours, 8 hours, and 24 hours later, centrifuged (at 2500g for at least 5 minutes at 4°C), and the recovered plasma was frozen at -80°C.

[0161] Stability was determined by measuring the peak area of ​​2296 points at each time point compared to T0.

[0162] The results unexpectedly demonstrated that compound 2296 possesses human blood stability with a profile very similar to that of compound 2250.

[0163] [Table 3]

[0164] [Table 4]

[0165] The results unexpectedly demonstrated that compounds 2289 and 2293 are metabolized or degraded into 2250 within approximately 20–25 minutes, exhibiting a human blood stability profile very similar to that of 2250, in that they show a stability profile similar to that of 2250 in experiments conducted using 2250.

[0166] [Table 5]

[0167] [Table 6]

[0168] [Table 7]

[0169] [Table 8]

[0170] The half-lives of compounds 2296, 2289, and 2293 (after metabolism to 2250) are significantly longer than those of taurolidine.

[0171] [1] Formula I: [ka] (In the formula, R1 is a -CO-aryl and R2 is H The compound of ) , [ka] A compound selected from the following. A pharmaceutical composition comprising at least one compound described in [2][1] and a pharmaceutically acceptable carrier. [3] The pharmaceutical composition according to [2], which is in the form of an orally administrative composition. [4] The pharmaceutical composition according to [2], in the form of a capsule, tablet, or pharmaceutically acceptable solution. [5] A pharmaceutical composition according to any one of [2] to [4], containing the compound in a concentration of 0.01% to 3% (w / v). [6] A pharmaceutical composition according to any one of [2] to [5], containing the compound at a concentration of 0.01 μg / ml to 1000 μg / ml. [7] A pharmaceutical composition according to any one of [2] to [6], comprising one or more solubilizing agents. [8] A pharmaceutical composition according to any one of [2] to [6], comprising a polyol. [9] A pharmaceutical composition according to any one of [2] to [8], which is an injection and / or infusion preparation comprising a pharmaceutically acceptable carrier for injection or infusion. An oral dosage form comprising at least one compound described in

[10] [1].

[11] Use of the compound described in [1] in the manufacture of any of the pharmaceutical compositions described in [2] to [9] or the oral dosage form described in

[10] for the treatment of a subject suffering from cancer.

[12] Use according to

[11] , wherein the cancer is glioblastoma, glioma, neuroblastoma, astrocytoma, carcinomatous meningitis, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, breast cancer, prostate cancer, lung cancer, mesothelioma, melanoma, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, esophageal cancer, bladder cancer, cervical cancer, cardia cancer, gallbladder cancer, skin cancer, bone cancer, head and neck cancer, leukemia, lymphoma, lymphosarcoma, adenocarcinoma, fibrosarcoma or metastases thereof.

[13] Use of the compound described in [1] in the manufacture of any of the pharmaceutical compositions described in [2] to [9] or the oral dosage form described in

[10] for the treatment of subjects suffering from microbial infections.

[14] Use of the compound described in [1] in the manufacture of any of the pharmaceutical compositions described in [2] to [9] or the oral dosage form described in

[10] for treating tumor stem cells in a subject.

[15] Use of the compound described in [1] in the manufacture of any of the pharmaceutical compositions described in [2] to [9] or the oral dosage form described in

[10] for the treatment of subjects requiring inhibition of angiogenesis.

[16] Use of the compound described in [1] in the manufacture of any of the pharmaceutical compositions described in [2] to [9] or the oral dosage form described in

[10] for the treatment of subjects requiring inhibition of tubule formation.

[17] Use of the compound described in [1] in the manufacture of any of the pharmaceutical compositions described in [2] to [9] or the oral dosage form described in

[10] for the treatment of subjects suffering from bacterial infections.

[18] Use of the compound described in [1] in the manufacture of any of the pharmaceutical compositions described in [2] to [9] or the oral dosage form described in

[10] for the treatment of a subject suffering from a bacterial infection.

[19] Use of the at least one compound, the pharmaceutical composition, or the oral dosage form in the manufacture of a kit for providing a subject with a collaborative therapy regimen, comprising administering to the subject as collaborative therapy in combination with at least one compound described in [1], a pharmaceutical composition described in any of [2] to [9], or an oral dosage form described in

[10] .

[20] Use of the at least one compound in the preparation of a kit for enhancing the pharmacokinetic effects of tauroridine and / or taurultam in a human subject using at least two compounds having different half-lives, comprising administering tauroridine and / or taurultam to a human subject in combination with at least one compound described in [1].

[21] The use according to

[19] , comprising administering at least one of the compounds in doses of 0.1 mg / kg to 1000 mg / kg in combination with taurolidine and / or taurultam in doses of 0.01 mg / kg to 500 mg / kg.

[22] The use according to

[19] , comprising administering at least one of the compounds in a total daily dose of 0.1 g to 100 g in combination with taurolidine and / or taurultam in a total daily dose of 0.01 g to 50 g.

[23] a) at least one compound described in [1], a pharmaceutical composition described in any of [2] to [9] or an oral dosage form described in

[10] , b) carmustine, cytarabine, gemcitabine, nab-paclitaxel, asparaginase, procarbazine, mitomycin, 5-FU, methotrexate, vinblastine, dacarbazine, cisplatin, carboplatin, paclitaxel, bevacizumab, one or more checkpoint inhibitors, one or more PARP inhibitors, Use of the at least one compound, the pharmaceutical composition, or the oral dosage form in the manufacture of a kit for providing a subject with a co-therapy regimen, which includes administering to the subject as co-therapy one or more anti-PD-1 drugs, docetaxel, irinotecan (including Onivyde®), doxorubicin, erlotinib, olaparib, lapatinib, topotecan, capecitabine, oxaliplatin, cyclophosphamide, ifosfamide, or a combination thereof.

Claims

【Request Item 1】 【Chemistry 1】 A compound selected from the following.

2. A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 2, in the form of an orally administrative composition.

4. The pharmaceutical composition according to claim 2, in the form of a capsule, a tablet, or a pharmaceutically acceptable solution.

5. The pharmaceutical composition according to claim 2, comprising the compound in a concentration of 0.01% to 3% (w / v).

6. The pharmaceutical composition according to claim 2, comprising the compound in a concentration of 0.01 μg / ml to 1000 μg / ml.

7. The pharmaceutical composition according to claim 2, comprising one or more solubilizing agents.

8. The pharmaceutical composition according to claim 2, comprising a polyol.

9. The pharmaceutical composition according to claim 2, which is an injection and / or injectable formulation comprising a pharmaceutically acceptable carrier for injection or infusion.

10. A capsule or tablet comprising at least one compound according to claim 1.

11. In the manufacture of pharmaceutical compositions for treating subjects suffering from cancer, 【Chemistry 2】 Use.

12. The use according to claim 11, wherein the cancer is glioblastoma, glioma, neuroblastoma, astrocytoma, carcinomatous meningitis, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, breast cancer, prostate cancer, lung cancer, mesothelioma, melanoma, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, esophageal cancer, bladder cancer, cervical cancer, cardia cancer, gallbladder cancer, skin cancer, bone cancer, head and neck cancer, leukemia, lymphoma, lymphosarcoma, adenocarcinoma, fibrosarcoma, or metastases thereof.

13. In the manufacture of pharmaceutical compositions for treating subjects suffering from microbial infections, 【Transformation 3】 Use.

14. In the manufacture of a pharmaceutical composition for treating tumor stem cells in a test subject, 【Chemistry 4】 Use.

15. In the manufacture of pharmaceutical compositions for treating subjects requiring angiogenesis inhibition, 【Transformation 5】 Use.

16. In the manufacture of pharmaceutical compositions for treating subjects requiring inhibition of tubule formation, 【Transformation 6】 Use.

17. In the manufacture of pharmaceutical compositions for treating subjects suffering from bacterial infections, 【Transformation 7】 Use.

18. In the manufacture of pharmaceutical compositions for treating subjects suffering from viral infections, 【Transformation 8】 Use.

19. Tauroridine and / or taurultam 【Chemistry 9】 The use of compound 2289, 2293, or 2296 in the manufacture of a kit for providing a subject with a co-therapy regimen, which includes administering to the subject as co-therapy in combination with at least one of the compounds.

20. Tauroridine and / or taurultam 【Chemistry 10】 The use of compound 2289, 2293, or 2296 in the preparation of a kit for enhancing the pharmacokinetic effects of taurolidine and / or taurultam in human subjects using at least two compounds having different half-lives, including administering them to human subjects in combination with at least one of the compounds.

21. The use according to claim 19, comprising administering at least one of compounds 2289, 2293, and 2296 in doses of 0.1 mg / kg to 1000 mg / kg in combination with taurolidine and / or taurultam in doses of 0.01 mg / kg to 500 mg / kg.

22. The use according to claim 19, comprising administering at least one of compounds 2289, 2293, and 2296 in a total daily dose of 0.1 g to 100 g in combination with tauroridine and / or taurultam in a total daily dose of 0.01 g to 50 g.

23. a) 【Chemistry 11】 The use of compound 2289, 2293, or 2296 in the manufacture of a kit for providing a subject with a collaborative therapy regimen, comprising administering at least one of the following to the subject as collaborative therapy: b) carmustine, cytarabine, gemcitabine, nab-paclitaxel, asparaginase, procarbazine, mitomycin, 5-FU, methotrexate, vinblastine, dacarbazine, cisplatin, carboplatin, paclitaxel, bevacizumab, one or more checkpoint inhibitors, one or more PARP inhibitors, one or more anti-PD-1 drugs, docetaxel, irinotecan (including Onivyde®), doxorubicin, erlotinib, olaparib, lapatinib, topotecan, capecitabine, oxaliplatin, cyclophosphamide, ifosfamide, or a combination thereof.

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