Antibacterial 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]

[0001] The present invention relates to new compounds and their uses. [Background technology]

[0002] For example, many compounds are known for the treatment of cancer in a patient or for the treatment of a microbial infection in a patient. Summary of the Invention [Problem to be solved by the invention]

[0003] There remains a need in the art for new compounds that have more potent anti-neoplastic and anti-bacterial activity, less toxicity and side effects, and less resistance to treatment of tumor or microbial cells. [Means for solving the problem]

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

[0005] In one aspect, the present disclosure provides a compound of formula I: [ka] (wherein R1 is -CO-aryl, or C1-C6 branched or unbranched alkyl, and R2 is H).

[0006] In one aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: [ka] The compound includes a compound selected from:

[0007] In one aspect, the disclosure includes pharmaceutical compositions comprising the compounds of the disclosure.

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

[0009] In one aspect, 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 aspect, the disclosure includes a method of treating a subject suffering from cancer by administering to the subject a compound, composition, or oral dosage form of the disclosure.

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

[0012] In one aspect, the disclosure includes a method of treating a subject in need of inhibiting angiogenesis by administering to the subject a compound, composition, or oral dosage form of the disclosure.

[0013] In one aspect, the disclosure includes a method of treating a subject in need of inhibiting tubule formation by administering to the subject a compound, composition, or oral dosage form of the disclosure.

[0014] In one aspect, the disclosure includes a method of treating a subject suffering from a bacterial infection by administering to the subject a compound, composition, or oral dosage form of the disclosure.

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

[0016] In one aspect, the present disclosure includes a co-therapy composition or regimen comprising taurolidine and / or taurultam in combination with at least one compound, pharmaceutical composition or oral dosage form of the present disclosure.

[0017] In one aspect, the present disclosure includes a method of extending the pharmacokinetic effect of taurolidine and / or taurultam in a human subject with at least two compounds having different half-lives, comprising administering taurolidine and / or taurultam in combination with at least one compound, pharmaceutical composition or oral dosage form of the present disclosure to the human subject.

[0018] In one aspect, the disclosure includes a co-therapy composition or co-therapy regimen comprising: a) at least one compound, pharmaceutical composition, or oral dosage form of the disclosure; b) in combination 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 agents, docetaxel, irinotecan (including Onivyde™), doxorubicin, erlotinib, olaparib, lapatinib, topotecan, capecitabine, oxaliplatin, cyclophosphamide, ifosfamide, or combinations thereof. [Brief description of the drawings]

[0019] [Figure 1] FIG. 1 shows a cell migration assay using MDA MB 468 cells. [Diagram 2] FIG. 1 shows an MTT assay for cell viability. [Diagram 3] FIG. 1 shows a BrdU assay for cell proliferation. [Figure 4]Figure 1 shows the results of the MTT cytotoxicity assay on Panc TuI cells with various concentrations of compounds 2289, 2293 and 2296 compared to the negative control=NC untreated cells and the positive control 1000μM GP2250 after 24h, 48h and 72h incubation periods. All substances show a significant effect on the cell viability of the cell line Panc TuI analyzed from a concentration of 100μM compared to the untreated control (NC) after 24h. Measurements were performed in eightfold determinations and p-values ​​were calculated by t-test (*p≦0.05 significant, **p≦0.01 very significant, ***p≦0.001 extremely significant). [Diagram 5] Figure 1 shows the results of the MTT cytotoxicity assay for AsPc1 cells with various concentrations of compounds 2289, 2293 and 2296 compared to the negative control=NC untreated cells and the positive control 1000 μM GP2250 after 24 h, 48 h and 72 h incubation period. Substances 2289 and 2296 show a significant effect on the cell viability of the cell line AsPc1 analyzed from a concentration of 100 μM compared to the untreated control (NC) after 24 h. Substance 2293 shows a significant effect on the cell viability from a concentration of 500 μM compared to the untreated control (NC) after 24 h. Measurements were performed in eight replicate determinations and p values ​​were calculated by t-test (*p≦0.05 significant, **p≦0.01 very significant, ***p≦0.001 extremely significant). [Figure 6] Figure 1 shows the results of the MTT cytotoxicity assay for BxPc3 cells with various concentrations of compounds 2289, 2293 and 2296 compared to the negative control=NC untreated cells and the positive control 1000μM GP2250 after 24h, 48h and 72h incubation periods. All substances show a significant effect on the cell viability of the cell line BxPc3 analyzed from a concentration of 100μM compared to the untreated control (NC) after 24h. Measurements were performed in eight replicate determinations and p values ​​were calculated by t-test (*p≦0.05 significant, **p≦0.01 very significant, ***p≦0.001 extremely significant). [Figure 7]Figure 1 shows the results of a proliferation assay of the cell lines Panc TuI, AsPc1 and BxPc3 under the influence of various concentrations of substances 2289, 2293 and 2296 compared to the negative control = NC untreated cells and the positive control 1000 μM GP2250 after a 6 hour incubation period. All substances show a significant effect on cell proliferation of all analyzed cell lines from a concentration of 500 μM compared to the untreated control (NC). Measurements were performed in eight replicate determinations and p values ​​were calculated by t-test (*p≦0.05 significant, **p≦0.01 very significant, ***p≦0.001 extremely significant). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] While aspects of the subject matter of the present disclosure may be embodied in a variety of forms, the following description is intended to disclose merely some of these forms as illustrative examples of the subject matter encompassed by the present disclosure, and therefore, the subject matter of the present disclosure is not intended to be limited to the forms or embodiments so described and illustrated.

[0021] To facilitate understanding of the present invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by one of ordinary skill in the art relevant to the present invention. Terms such as "a," "an," and "the" are not intended to refer to a singular entity only, but include general classifications that may serve to describe specific examples. While the terminology herein is used to describe specific aspects of the present invention, their use does not define the invention except as outlined in the claims.

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

[0023] The compounds of the present disclosure can be administered to any subject in need of therapy according to the present disclosure. Such subjects may be at risk of or suffering from a variety of diseases, disorders, and conditions. For example, such diseases, disorders, and conditions may be characterized by infection with a microbial agent. In some aspects, 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 a positive genetic marker associated with cancer risk.

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

[0025] In certain embodiments, the compounds of the present invention are useful for the treatment of cancer and tumors, particularly 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 cancer, including glioblastoma, glioma, neuroblastoma, astrocytoma and meningeal carcinoma, 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 that are contemplated for treatment by certain embodiments of the present invention. In some embodiments, the patient is diagnosed with cancer of the biliary tract; 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; mouth cancer; gastric cancer; renal cancer; hematological tumors, including acute lymphoblastic and myeloid leukemia; multiple myeloma; AIDS-related leukemia and adult T-cell leukemia-lymphoma; intraepithelial neoplasia, including Bowen's disease and Paget's disease; liver cancer (hepatocarcinoma); 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 tumours; oral cancer including squamous cell carcinoma; adrenal gland cancer; anal cancer; angiosarcoma; appendix cancer; bile duct cancer; bone cancer; carcinoid tumours; soft tissue sarcomas; rhabdomyosarcoma; eye cancer; ovarian cancer including those arising from epithelial, stromal, germ and mesenchymal cells and fallopian tube cancer; gallbladder cancer; pancreatic cancer; prostate cancer; rectal cancer; leiomyosarcoma, rhabdomyosarcoma The patient is suffering from cancer or tumors including, but not limited to, sarcoma, including liposarcoma, fibrosarcoma, and osteosarcoma; skin cancer, including melanoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell carcinoma; testicular cancer, including germ cell tumors (seminoma, non-seminoma (teratoma, choriocarcinoma)), stromal tumors, and germ cell tumors; penile cancer; hemangioendothelioma; gastrointestinal cancer; ureteral cancer; urethral cancer; spinal cord cancer; pituitary cancer; primary central nervous system (CNS) lymphoma; thyroid cancer, including goiter and medullary carcinoma; and renal cancer, including adenocarcinoma and Wilms' tumor.In some aspects, the cancer or tumor includes breast cancer, prostate cancer, colon cancer, lymphoma, multiple myeloma, and melanoma. In certain embodiments, the compounds of the present invention are also effective against drug-resistant tumors, such as multi-drug resistant (MDR) tumors, including drug-resistant tumors that are solid tumors, non-solid tumors, and lymphomas. It is currently believed that any neoplastic cell may be treated using the methods described herein.

[0026] As used herein, the terms "substantially" and "substantially" refer to a considerable degree or extent. For example, when used in conjunction with an event, circumstance, characteristic, or property, the terms can refer not only to the exact occurrence of the event, circumstance, characteristic, or property, but also to a close approximation of the event, circumstance, characteristic, or property, such as to illustrate the typical tolerance level or variability of the examples described herein.

[0027] As used herein, the term "about" is used to provide flexibility to the endpoints of a numerical range by specifying that a given value may be "a little above" or "a little below" the endpoint. The flexibility of this term may depend on the particular variable, and is within the knowledge of one of ordinary skill in the art to determine based on experience and the relevant descriptions herein. For example, in one embodiment, the flexibility may be within about ±10% of the numerical value. In another embodiment, the flexibility may be within about ±5% of the numerical value. In further embodiments, the flexibility may be within about ±2%, ±1%, or ±0.05% of the numerical value.

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

[0029] As used herein, a plurality of compounds or processes may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, unless indicated to the contrary, each member of such a list should not be construed as being de facto equivalent to any other member of the same list solely based on their presentation in a common group.

[0030] The compounds of the present invention may be useful in one or more of the following forms: free acid form, free base form, pharma- ceutically acceptable salt, pharma-ceutically acceptable hydrate, pharma-ceutically acceptable ester, pharma-ceutically acceptable solvate, pharma-ceutically acceptable prodrug, pharma-ceutically acceptable metabolite form, and pharma-ceutically acceptable stereoisomer form, as is evident based on their chemical structures. The disclosed compounds are within the scope of the present invention in each of their forms.

[0031] "Pharmaceutically acceptable salt", "hydrate", "ester" or "solvate" refers to a salt, hydrate, ester or solvate of a compound of the present invention that has the desired pharmacological activity and is not biologically or otherwise undesirable. Organic acids can be used to form salts, hydrates, esters or solvates, such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, p-toluenesulfonate, bisulfate, sulfamate, sulfate, naphthylate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, tosylate and undecanoate salts. Inorganic acids can be used to form salts, hydrates, esters or solvates, such as hydrochloride, hydrobromide, hydroiodide and thiocyanate salts. Other pharma-ceutically acceptable salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, phosphate, tartrate, fumarate, maleate, oxalate, acetate, propionate, succinate, mandelate, mesylate, besylate and tosylate salts.

[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, magnesium carbonate, ammonia, primary, secondary and tertiary amines, etc. Aluminum salts of the present compounds can also be obtained by treating the corresponding sodium salt with a suitable aluminum complex, such as aluminum chloride hexahydrate. Non-toxic organic bases include, but are not limited to, triethylamine, butylamine, piperazine and tri(hydroxymethyl)-methylamine. Examples of suitable base salts, hydrates, esters or solvates include hydroxides, carbonates and bicarbonates of ammonia, 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. Suitable organic bases for forming pharma-ceutically acceptable base addition salts, hydrates, esters or solvates of the compounds of the present invention include organic bases that are non-toxic and strong enough to form such salts, hydrates, esters or solvates.For illustrative purposes, such organic bases can include mono-, di- and trialkylamines such as methylamine, dimethylamine, triethylamine and dicyclohexylamine; mono-, di- 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; (trihydroxy-methyl)aminoethane and the like.See, for example, "Pharmaceutical Salts," J. Pharm. Sci., 66:1, 1-19 (1977).Thus, basic nitrogen-containing groups can be quaternized with agents 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 the oxathiazine-like compound in an aqueous or aqueous alcoholic solution or other suitable solvent containing the appropriate acid or base and isolating the salt by evaporating the solution. Alternatively, the free base of the oxathiazine-like compound can be reacted with an acid and the oxathiazine-like compound bearing an acidic group can be reacted with a base, the reaction being carried out in an organic solvent, in which case the salt can be isolated directly or obtained by concentrating the solution.

[0034] A "pharmaceutical acceptable prodrug" refers to a derivative of a compound of the present invention that exhibits its pharmacological effect(s) after undergoing biotransformation. Prodrugs are formulated to improve chemical stability, improve patient acceptance and compliance, improve bioavailability, extend duration of action, improve organ selectivity, improve formulation (e.g., increase hydrosolubility), and / or reduce side effects (e.g., toxicity). Prodrugs can be readily prepared from the compounds 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 compounds of the present invention can be modified into prodrugs by converting one or more of the hydroxy or carboxy groups into esters.

[0035] "Pharmaceutically acceptable metabolite" refers to a drug that has undergone metabolic transformation. Most drugs become substrates for chemical reactions that can change their physical properties and biological effects after entering the body. These metabolic transformations usually affect the polarity of the compound, changing the way the drug is distributed in and excreted from the body. Also, in some cases, drug metabolism is required for therapeutic effect. For example, anticancer drugs from the antimetabolite group need to be converted to their active form after being transported to cancer cells. Since most drugs undergo some metabolic transformation, the biochemical reactions involved in drug metabolism can be diverse. The main site of drug metabolism is the liver, but other tissues may also be involved.

[0036] Furthermore, certain compositions, concentrations, administration regimens, dosage amounts, syndromes or conditions, steps, etc. may be discussed in the context of a particular embodiment. This is merely for convenience, and it is understood that such disclosure applies to other embodiments found herein as well. For example, a list of method steps, active agents, kits, or compositions described in relation to a method of administering a compound of the present disclosure directly supports the embodiment related to the method steps, active agents, kits, or compositions of treating, preventing, suppressing, or alleviating at least one sign or symptom of a disease, disorder, or condition caused by or associated with, for example, infection, or the presence or risk of a positive genetic marker associated with cancer, tumor, cancer stem cell, family history of cancer, or cancer risk, even if those method steps, active agents, kits, or compositions are not described again in the context of that embodiment herein.

[0037] The term "treat" or "treatment" as used herein and well understood in the art, refers to an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or pathology, whether detectable or undetectable, reduction in the extent of disease, stabilization (i.e., not worsening) of the disease state, delay or slowing of disease progression, improvement or mitigation of the disease state, reduction in recurrence of disease, and remission (whether partial or complete). "Treat" and "treatment" may also mean prolonging survival compared to expected survival in the absence of treatment. In addition to being useful as a method of treatment, the methods described herein may be useful for prevention or prophylaxis of disease. As used herein, the term "treating" may refer to any administration of a compound of the invention and includes (i) preventing or inhibiting a disease in a mammal, e.g., a human, experiencing or manifesting the pathology or symptomology of a disease (i.e., halting further progression of the pathology and / or symptomology), or (ii) ameliorating a disease in a mammal, e.g., a human, experiencing or manifesting the pathology or symptomology of a disease (i.e., reversing the pathology and / or symptomology). The term "controlling" includes preventing, treating, eradicating, ameliorating, or otherwise reducing the severity of the condition being controlled.

[0038] Concentrations, amounts, and other numerical data may be expressed or presented in a range format herein. It should be understood that such range formats are used merely for convenience and brevity, and should be interpreted flexibly to include not only the numerical values ​​explicitly recited as the limits of the range, but also all individual numerical values ​​or subranges subsumed within the range, as if each numerical value and subrange were explicitly recited. For example, a numerical range of "about 0.01 to 2.0" should be interpreted to include not only the explicitly recited values ​​of about 0.01 to about 2.0, but also the individual values ​​and subranges within the specified range. Thus, 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. Moreover, such interpretation should be applied regardless of the breadth of the range or the properties described. In addition, it should be noted that all percentages are weight percentages unless otherwise specified.

[0039] In understanding the scope of the present disclosure, the terms "including" or "comprising" and its derivatives, as used herein, are intended to be open-ended terms specifying the presence of the stated features, elements, components, groups, integers, and / or steps, but not excluding the presence of other unstated features, elements, components, groups, integers, and / or steps. The above also applies to words of similar meaning, such as the terms "comprising" and "having" and their derivatives. The term "consisting" and its derivatives, as used herein, are intended to be closed terms specifying the presence of the stated features, elements, components, groups, integers, and / or steps, but excluding the presence of other unstated features, elements, components, groups, integers, and / or steps. The term "consisting essentially of," as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps, as well as those that do not substantially affect the basic novel property(s) of the features, elements, components, groups, integers, and / or steps. It is understood that reference to any one of these transitional terms (i.e., "comprising," "consisting," or "consisting essentially of") directly supports the substitution of any other transitional term not specifically used. For example, modifying the term "comprising" to "consisting essentially of" is directly supported by this definition.

[0040] Tumor stem cells, also called cancer stem cells (CSCs), are thought to be the primary drivers of metastasis development and tumor regrowth after resection.

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

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

[0043] In certain embodiments, the compounds of the invention are particularly useful for producing an anti-angiogenic effect in a subject.

[0044] In certain embodiments, compounds of the invention are particularly useful for producing a tubule formation inhibitory effect in a 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 by inhibiting the growth of new blood vessels at the tumor site. The main 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 the growth of tumor cells by their antiangiogenic and antitubule formation effects, and therefore these compounds are useful for palliative treatment.

[0046] The compounds of the present invention are metabolized in the bloodstream much slower than taurolidine and taurultam, therefore lower doses of such compounds can be administered to patients and achieve similar effects.

[0047] The compounds of the invention are also useful in certain embodiments for the treatment of microbial infections in a subject, such as a human patient. Microbial infections that may be treated according to certain embodiments include bacterial infections, fungal infections, and / or viral infections.

[0048] Cancer patients tend to be immunocompromised and therefore are particularly susceptible to microbial infections, especially during and / or after surgery.

[0049] In certain embodiments, the compounds of the present invention are utilized to treat glioblastoma in a subject.

[0050] In certain embodiments, the compounds of the present invention are utilized to treat a S. aureus infection in a subject.

[0051] In certain embodiments, compounds of the invention are utilized in accordance with the present invention to treat a Methicillin-resistant Staphylococcus aureus (MRSA) infection in a subject.

[0052] In certain embodiments, the compounds of the present invention are utilized in accordance with the present invention to treat an E. coli infection in a subject.

[0053] In certain embodiments, the compounds of the invention are utilized in accordance with the present invention to treat H. pylori infection in a subject and / or H. pylori associated cancer(s) in a subject.

[0054] In certain embodiments, compounds of the invention are utilized in accordance with the present invention to treat a Staphylococcus epidermidis infection in a subject.

[0055] In certain embodiments, compounds of the invention are utilized in accordance with the present invention to treat a Streptococcus pneumoniae infection in a subject.

[0056] In certain embodiments, compounds of the invention are utilized in accordance with the present invention to treat a Streptococcus pyogenes infection in a subject.

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

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

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

[0060] In certain embodiments, the compounds of the present invention are effective against the following bacteria: Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Clostridium difficile, Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Citrobacter freundii, Escherichia coli, Klebsiella pneumoniae, Morganelle morganii, Bacteroides fragilis, and the like. The present invention is useful in treating a subject suffering from an infection with at least one of Helicobacter fragilis and Helicobacter pylori.

[0061] In certain embodiments, the compounds of the invention are utilized in accordance with the invention to treat a viral infection in a subject, including, but not limited to, 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 papilloma virus, varicella zoster virus, cytomegalovirus, and the like. , 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, virus), Tyuleniy virus, Hantavirus, Enterovirus, Echovirus, Calicivirus, Sindbis virus, Ross River virus, Coronavirus, SARS-coronavirus, Rhabdovirus family, Vesiculovirus, Lyssavirus, Paramyxovirus family, Paramyxovirus, Mumps virus, Newcastle disease virus, Morbillivirus, Pneumonia virus, Respiratory syncytial virus, Orthomyxovirus, Bunyavirus, Hantavirus, Arenavirus family, Lassa fever virus, Orbivirus, Colorado tick fever virus.

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

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

[0064] In certain embodiments, compounds according to formula I are utilized in accordance with the present invention.

[0065] [ka]

[0066] R1 can be -CO-aryl, or C1-C6 branched or unbranched alkyl, such as CH3, COH, COCH3, COCH2CH3, COCH2CH2CH3. R2 can 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 new compound, 2289, is utilized in accordance with the present invention. Compound 2289 has the following structure: [ka] has.

[0070] Compound 2289 can be used to treat and inhibit tumor and cancer stem cells, viral, bacterial and / or fungal infections.

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

[0072] Compound 2293 can be used to treat and inhibit tumor and cancer stem cells, viral, bacterial and / or fungal infections.

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

[0074] Compound 2296 can be used to treat and inhibit tumor 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 with one or more compounds. The compound can be administered before, during or after the tumor-reducing surgery. The compound according to the present invention can be administered by any suitable method, including but not limited to, by capsule, by tablet, intravenously (IV), intraperitoneally (IP), intravesically, and / or directly to the tumor.

[0076] It has been unexpectedly found that the compounds can be administered during and immediately after surgery because they do not inhibit wound healing like other chemotherapeutic agents.

[0077] The compounds of the present disclosure have been unexpectedly found to kill tumor stem cells, which is extremely rare and perhaps unknown among conventional chemotherapeutic agents, which, if effective against tumor stem cells at all, are generally only effective at very high doses that are highly toxic to human patients.

[0078] It has unexpectedly been found that lower doses of taurolidine and / or taurultam kill tumor stem cells than are required to kill tumor cells.

[0079] It has been unexpectedly found that the compounds of formula I have a half-life in human blood that is significantly longer than that of taurolidine and taurultam.Therefore, these compounds are not rapidly removed from the bloodstream of patients, thereby effectively slowing down the loss of efficacy caused by the body's clearance mechanisms.

[0080] Therefore, the half-life of each of compounds 2289, 2293 and 2296 is about 5 to 6 hours in human blood.

[0081] In some embodiments, one or more compounds of the disclosure, such as Formula I, 2289, 2293, and 2296, are administered in the composition at a concentration of about 0.01 μg / ml to about 1000 μg / ml. In some embodiments, the compounds are administered in the composition at a concentration of about 1 μg / ml to about 100 μg / ml. In some embodiments, the compounds are administered in the composition at a concentration of about 10 μg / ml to about 50 μg / ml. The composition may contain 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 of taurolidine and / or taurultam.

[0082] In some embodiments, one or more compounds of the present disclosure are administered in the composition at a concentration of about 0.001% to about 5%, about 0.01% to about 3.5%, about 0.1% to about 3%, about 0.5% to about 2.5%, or about 1% to about 2% by weight. In some embodiments, the oxathiazine-like compound is provided in the composition at a concentration of about 0.01% to about 1.5%. In some embodiments, the compound is provided in the composition at a concentration of about 0.1% to about 1%. In some embodiments, the compound is provided in the 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 recited 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% taurolidine and / or taurultam.

[0083] In some embodiments, one or more compounds of the present disclosure are provided in a composition in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of compound suitable for administration to an animal, such as a mammal, e.g., a human subject, in a single dose in accordance with good medical practice. These compositions may contain from about 0.1 mg (milligram) to about 500 mg of compound, e.g., from about 5 mg to about 350 mg. The frequency of treatment with the compositions of the present invention can be varied to achieve and maintain the desired target plasma levels. Thus, non-limiting examples of treatment schedules include daily, twice daily, three times daily, weekly, biweekly, monthly, and combinations thereof. Alternatively, the compositions of the present invention can be administered as a continuous infusion or bolus followed by one, two, three or more different continuous infusions, e.g., differing rates and doses of drug administered, with such regimens optionally interrupted by one or more additional bolus injections.

[0084] In one aspect, one or more compounds of the present disclosure are provided in a composition administered to a subject in need thereof in a total daily dosage that may be about 0.001 g to about 1000 g, e.g., about 0.01 g to about 500 g, 0.1 g to 300 g, 0.5 g to 200 g, 1 g to 100 g, or any amount within the ranges recited. The daily dosage may be administered in the form of an orally administrable composition. The daily dosage may be administered in the form of a capsule, tablet, or pharma- ceutically acceptable solution. The daily dosage may be administered in a form that contains one or more compounds of the present disclosure in a concentration 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 dosage may be administered in a form containing one or more compounds of the present disclosure at a concentration of about 0.001 μg / ml to about 1000 μg / ml, about 0.01 μg / ml to about 750 μg / ml, about 0.05 μg / ml to about 500 μg / ml, about 0.1 μg / ml to about 300 μg / ml, about 0.5 μg / ml to about 200 μg / ml, about 1 μg / ml to about 100 μg / ml, about 5 μg / ml to about 50 μg / ml, about 10 μg / ml to about 25 μg / ml, or about 15 μg / ml to about 20 μg / ml. The daily dosage may be administered in a form containing one or more solubilizing agents, such as polyols.

[0086] Effective dosages provided in the compositions may include dosage units containing about 0.01 mg / kg to 500 mg / kg per day, about 1 mg / kg to 100 mg / kg per day, or about 5 mg / kg to 50 mg / kg per day of one or more compounds of the present disclosure, hi some embodiments, dosage units are administered every other day, every other week, or every week.

[0087] In one embodiment, the compound of formula I can be administered as a co-therapy with taurolidine and / or taurultam to kill tumor stem cells. According to such an embodiment, it has been unexpectedly found that the co-therapy requires a lower dosage to kill tumor stem cells than is required to kill normal tumor cells.

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

[0089] An effective dosage of the compound is a unit dosage within the range of about 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 isotonic solutions containing one or more solubilizing agents, such as sugars, polyols, surfactants, osmolytes, to provide a solution with increased compound concentration. Such solutions are described in EP 253662. The solutions may be made isotonic with Ringer's solution or lactated Ringer's solution. The concentration of the compound in such solutions may range from 1 g / liter to 60 g / liter.

[0091] As used herein, the term "polyol" refers to a sugar that has more hydroxyl (-OH) groups than normal sugars. 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 at least one activity, e.g., as described herein, of the above compounds, e.g., at least 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 100% or more of said activity.

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

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

[0095] Synthesis of 2289 Compound 2289 was prepared according to the following non-limiting synthetic protocol. 1. The following compound: [ka] was reacted with acetic anhydride in the presence of pyridine at a temperature of about 100° C. to form compound 2289. Compound 2289 was isolated from the reaction mixture by adding water and filtering the precipitate. Yield (crude): 89%. 2. The following compound: [ka] was reacted with acetyl chloride in the presence of pyridine at a temperature of about 60° C. to form compound 2289. 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 from ethyl acetate / petroleum ether

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

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

[0099] In some embodiments, the disclosure includes a method of making compound 2289 by the following reaction:

[0100] [ka]

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

[0102] Synthesis of 2293 Compound 2293 was prepared according to the following non-limiting synthetic protocol.

[0103] The following compounds: [ka] was reacted with propionyl chloride in the presence of pyridine to form compound 2293. Compound 2293 remains in the pyridine phase and can 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] The identity was confirmed by NMR, IR and MS.

[0107] In some embodiments, the disclosure includes a method of making compound 2293 by the following reaction:

[0108] [ka]

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

[0110] Synthesis of 2296 Compound 2296 was prepared according to the following non-limiting synthetic protocol.

[0111] 1-Hydroxypropane-2-sulfonamide was dissolved in water and reacted with methylene glycol to form compound 2296. Yield (crude): 51%

[0112] purification: Recrystallization from alcohol solvents

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

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

[0115] In some embodiments, the disclosure includes a method of making compound 2296 by the following reaction:

[0116] [ka]

[0117] The reactants shown above are alternatives and are non-limiting. One skilled in the art will recognize that other alternative reactants can 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), ethyl acetate, etc.

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

[0119] In one embodiment, the disclosure includes a method of killing tumor stem cells by administering to a subject in need thereof a tumor stem cell-killing effective amount of taurolidine, taurultam, or a mixture thereof, in combination with one or more compounds of formula I. The tumor stem cell-killing effective amount of taurolidine and / or taurultam is less than the amount of taurolidine and / or taurultam 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 agents, 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 the compound of Formula I is co-administered with carboplatin, paclitaxel, topotecan, bevacizumab, one or more PARP inhibitors, one or more anti-PD-1 agents, or a combination thereof. For example, the one or more PARP inhibitors can include olaparib (Lynparza™), niraparib (Zejula™), rucaparib (Rubraca™), and talazoparib (Talzenna™), veliparib, pamiparib, CEP9722, E7016, iniparib, 3-aminobenzamide, or a combination thereof. For example, the one or more anti-PD1 agents can include pembrolizumab (Keytruda™), nivolumab (Opdivo™), cemiplimab (Libtayo™), atezolizumab (Tecentriq™), avelumab (Bavencio™), and durvalumab (Imfinzi™).For example, co-administered drugs can include pembrolizumab (Keytruda™), nivolumab (Opdivo™), cemiplimab (Libtayo™), spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, retifanlimab, sasunlimab, budigalimab, zimblerimab, BI754091, JTX-4014, AMP-224, AMP-514, atezolizumab (Tecentriq™), avelumab (Bavencio™), durvalumab (Imfinzi™), cosibelimab, 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 compounds described above suitable for treating pancreatic cancer.

[0120] The phrases "co-administered" or "administered in combination" as used herein mean that two (or more) agents are administered in tandem. Co-administration or combination can be achieved by mixing the two agents in a single formulation, or by administering the two agents separately but simultaneously or with a short time interval between them. For example, typically, the two agents are co-administered within a time range of 6 hours to 168 hours. In this case, the agents can be administered in any order, i.e., the chemotherapeutic agent can be administered first, or one or more compounds of the present disclosure can be administered first. In some embodiments, the two agents are co-administered in a single formulation, or sequentially and separately.

[0121] In some embodiments, taurolidine, taurultam or mixtures thereof are administered in the tumor stem cell killing composition at a concentration of about 0.01 μg / ml to about 500 μg / ml. In some embodiments, taurolidine, taurultam or mixtures thereof are administered in the tumor stem cell killing composition at a concentration of about 0.1 μg / ml to about 100 μg / ml. In some embodiments, taurolidine, taurultam or mixtures thereof are administered in the tumor stem cell killing effective composition at a concentration of about 10 μg / ml to about 50 μg / ml. Taurolidine is effective in killing tumor stem cells in in vitro tissue culture at 0.01 μg / ml.

[0122] In some embodiments, taurolidine, taurultam or mixtures thereof are administered in the tumor stem cell killing composition at a concentration of about 0.001% to about 2%. In some embodiments, taurolidine, taurultam or mixtures thereof are administered in the tumor stem cell killing composition at a concentration of about 0.01% to about 1.5%. In some embodiments, taurolidine, taurultam or mixtures thereof are 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 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 to a subject in need thereof for the killing of tumor stem cells.

[0124] The effective tumor stem cell killing dose of taurolidine, taurultam or a mixture thereof is a dosage unit within the range of about 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 present disclosure includes a method for killing tumor stem cells by administering one or more compounds of the present disclosure alone or in combination with taurolidine and / or taurultam to a subject in need thereof. Such techniques provide a method for killing tumor stem cells with at least two compounds having different half-lives, thereby broadening the pharmacokinetic effect obtained.

[0126] In some aspects, the present disclosure includes increasing the therapeutic window of taurolidine and / or taurultam therapy by co-administering taurolidine and / or taurultam with one or more compounds of the present disclosure.

[0127] In one particular embodiment, the following experimental protocol was performed.

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

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

[0130] Cell migration assay Cells are plated in 60 mm dishes to create a confluent monolayer and incubated for 24 hours to allow the cells to attach and spread. The number of cells required for a confluent monolayer varies with the specific cell type. After creating a scratch in the cell monolayer, the gap area is examined by phase contrast microscopy. Images are acquired at the beginning and at regular intervals (48 h, 72 h, and 120 h (5 days)) during cell migration to fill the scratch to semi-quantify the migration rate of the cells.

[0131] MTT cytotoxicity assay Cells are seeded individually to obtain subconfluent monolayers in a 96-well plate format and incubated for 24 hours before treatment. To investigate the dose response on antineoplastic activity, cells are incubated with increasing concentrations (100 μmol / l, 200 μmol / l, 500 μmol / l, 1000 μmol / l, 1500 μmol / l, 2000 μmol / l) of all oxathiazinane derivatives and ddH2O as a control for 24 and 48 hours. After the exposure time, 10 μl of MTT (3-(4,5-dimethylthiazol-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 by using a microplate absorbance reader (ASYS, UVM340, Anthos Mikrosystheme GmbH, Germany) by measuring OD560. The assay is performed with eight replicates of three independent experiments with serial passages.

[0132] ROS analysis To gain further insight into functional aspects, the effect of compounds on cellular levels of reactive oxygen species (ROS) is analyzed using the Cellular ROS / Superoxide Detection Assay KIT (Abcam, Cambridge, UK) according to the manufacturer's instructions.

[0133] BrdU proliferation assay Cells are seeded individually to obtain subconfluent monolayers in a 96-well plate format and incubated for 24 hours before treatment. To investigate the dose response of the cells with respect to antiproliferative activity, cells are incubated with increasing concentrations (100 μmol / l, 200 μmol / l, 500 μmol / l, 1000 μmol / l, 1500 μmol / l and 2000 μmol / l) of all oxathiazinan derivatives and ddH2O as control for 6 hours, 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 in previous experiments to be adequate for the BrdU proliferation assay. 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. BrdU assays are performed using eight replicates of three independent experiments with serial passaging.

[0134] Disk diffusion test The antibacterial potential of the compounds is examined by the Kirby-Bauer disk diffusion test using Mueller-Hinton agar. Disks with a diameter of 10 mm soaked in 150 μl of distilled water containing 10 mg of the test substance are placed on Mueller-Hinton agar (bioMeieux, Geneva, Switzerland) carrying the pre-lawn of the corresponding test bacteria. The plates are incubated at 37° C. for 24 hours and the zones of inhibition are recorded. Culture medium and sterile distilled water are used as controls. N-acetylcysteine ​​(NAC) is used as an antioxidant control.

[0135] statistics MTT and BrdU assay results (percentage of viable / proliferating cells) are expressed as mean ± SEM. One-way ANOVA was used, followed by Tukey's post-hoc test for comparing experimental groups with normal distribution and Fisher's exact test for categorical data, as appropriate. A p-value of 0.05 or less was considered statistically significant. EXAMPLES

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

[0137] [Table 1]

[0138] A cell migration assay was used to semi-quantify the migration speed of different cancer cell entities under treatment with 2289, a negative control and a positive control (2250). Figure 1 shows the results after 2-5 days, as exemplified by a confluent monolayer of MDA MB 468.

[0139] As shown in Figure 1, the migration rate of cultures treated with 2250 was clearly inhibited compared to the untreated control where cells migrated up to the scratch area and filled the gap. Cell cultures treated with 2289 also showed a lower migration rate, although not as slow as with 2250 treatment. All other derivatives tested did not show a decrease in migration rate and showed almost completely filled gaps after 5 days, comparable to the untreated control. Results are representative of all cell lines tested.

[0140] Example 2: The antitumor activities of compounds 2289, 2293 and 2296 were 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 cancer cell lines tested (MDA MB 468, HT29, MCC 14.2, Panc TuI) with various sensitivities to both agents (MDA MB 468 showed the highest response rate, HT 29 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. 2250 shows an overall higher anti-proliferative potential compared to 2289.

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

[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: 19.5 mm Staphylococcus aureus (ATCC 6538), Gram-positive: 31.5 mm Staphylococcus aureus (MRSA no. 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 no. 2065), Gram-positive: 43.0 mm

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

[0149] All substances show a significant effect on the cell viability of the cell line Panc TuI analysed from a concentration of 100 μM compared to the non-treated control (NC) after 24 hours.

[0150] MTT cytotoxicity assay of cell line AsPc1 with different oxathiazine derivatives was performed. Figure 5 shows cell viability under the influence of different concentrations of substances 2289, 2293 and 2296 compared to the negative control=NC untreated cells and the positive control 1000 μM GP2250 after incubation periods of 24 h, 48 h and 72 h.

[0151] Substances 2289 and 2296 show a significant effect on cell viability of the cell line AsPc1 analyzed from a concentration of 100 μM compared to the non-treated control (NC) after 24 hours. Substance 2293 shows a significant effect on cell viability from a concentration of 500 μM compared to the non-treated control (NC) after 24 hours.

[0152] The MTT cytotoxicity assay of the cell line BxPc3 with different oxathiazine derivatives was carried out. Figure 6 shows the cell viability under the influence of different concentrations of substances 2289, 2293 and 2296 compared to the negative control=NC untreated cells and the positive control GP2250 1000 μM after 24 hours of incubation. All substances show a significant effect on the cell viability of the cell line BxPc3 analyzed from a concentration of 100 μM compared to the untreated control (NC) after 24 hours.

[0153] Proliferation assays of the cell lines Panc TuI, AsPc1 and BxPc3 with different oxathiazine derivatives were carried out. Figure 7 shows the cell proliferation under the influence of different concentrations of substances 2289, 2293 and 2296 compared to the negative control = NC untreated cells and the positive control 1000 μM GP2250 after an incubation period of 6 hours. All substances show a significant effect on the cell proliferation of all analyzed cell lines from a concentration of 500 μM compared to the untreated control (NC).

[0154] Example 5: It has previously been reported that taurolidine has a half-life of approximately 30 minutes, with compound 2250 having 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 to 2250, K2-EDTA human blood was spiked with 256 μM 2289 or 2293, 26 μM 2250, and 26 μM 2244 (n=1). The pool was kept at 37°C for 20-25 min, after which an aliquot was centrifuged (2500g at 4°C for at least 5 min). Human plasma was collected after centrifugation and immediately frozen at -80°C. This aliquot represented TO.

[0156] The remaining pool was aliquoted and kept at 37° C. Aliquots were taken after at least 0.25, 0.5, 1, 6, 8, 24 and 48 hours, centrifuged (2500 g for at least 5 minutes at 4° C.) and the collected 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 TO.

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

[0159] The pool was kept at 37° C. for 20-25 min, after which an aliquot was centrifuged (2500 g for at least 5 min at 4° C.) Human plasma was collected after centrifugation and immediately frozen at −80° C. This aliquot represented TO.

[0160] The remaining pool was aliquoted and kept at 37° C. Aliquots were taken after at least 0.5, 1, 3, 6, 8 and 24 hours, centrifuged (2500 g for at least 5 minutes at 4° C.) and the collected plasma was frozen at −80° C.

[0161] Stability was determined by measuring the 2296 peak area at each time point compared to TO.

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

[0163] [Table 3]

[0164] [Table 4]

[0165] The results unexpectedly demonstrated that compounds 2289 and 2293 have a human blood stability profile very similar to that of 2250 in that they are metabolized or degraded to 2250 within about 20-25 minutes, which shows a similar stability profile to the experiments performed with 2250.

[0166] [Table 5]

[0167] [Table 6]

[0168] [Table 7]

[0169] [Table 8]

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

[0171] Although the subject matter of the present disclosure has been described and illustrated in some detail with reference to certain illustrative embodiments including various combinations and subcombinations of features, those skilled in the art will readily appreciate that other aspects and variations and modifications thereof are encompassed within the scope of the present disclosure. Moreover, the description of such aspects, combinations and subcombinations is not intended to imply that the claimed subject matter requires features or combinations of features other than those expressly recited in the claims. Accordingly, the scope of the present disclosure is intended to include all modifications and variations encompassed within the spirit and scope of the appended claims.

Claims

1. Formula I: 【Chemistry 1】 (In the formula, R １ is —CO-aryl, R ２ is H, 【Chemistry 2】 The compound selected from the group consisting of compounds

2. 10. A pharmaceutical composition comprising at least one compound of claim 1 and a pharma- ceutically acceptable carrier.

3. 3. The pharmaceutical composition of claim 2 in the form of an orally administrable composition.

4. 3. The pharmaceutical composition of claim 2 in the form of a capsule, tablet or a pharma- ceutically acceptable solution.

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

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

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

8. The pharmaceutical composition of claim 2 comprising a polyol.

9. The pharmaceutical composition according to claim 2 , which is a formulation for injection and / or infusion containing a pharma- ceutically acceptable carrier for injection or infusion.

10. 13. An oral dosage form comprising at least one compound of claim 1.

11. Use of a compound according to claim 1 in the manufacture of a pharmaceutical composition according to any one of claims 2 to 9 or an oral dosage form according to claim 10 for treating a subject suffering from cancer.

12. 12. The use according to claim 11, wherein the cancer is glioblastoma, glioma, neuroblastoma, astrocytoma, meningeal carcinoma, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, breast cancer, prostate cancer, lung cancer, mesothelioma, melanoma, renal 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 metastasis thereof.

13. Use of a compound according to claim 1 in the manufacture of a pharmaceutical composition according to any one of claims 2 to 9 or an oral dosage form according to claim 10 for treating a subject suffering from a microbial infection.

14. Use of a compound according to claim 1 in the manufacture of a pharmaceutical composition according to any one of claims 2 to 9 or an oral dosage form according to claim 10 for treating tumor stem cells in a subject.

15. Use of a compound according to claim 1 in the manufacture of a pharmaceutical composition according to any one of claims 2 to 9 or an oral dosage form according to claim 10 for treating a subject in need of angiogenesis inhibition.

16. Use of a compound according to claim 1 in the manufacture of a pharmaceutical composition according to any one of claims 2 to 9 or an oral dosage form according to claim 10 for treating a subject in need of inhibiting tubule formation.

17. Use of a compound according to claim 1 in the manufacture of a pharmaceutical composition according to any one of claims 2 to 9 or an oral dosage form according to claim 10 for treating a subject suffering from a bacterial infection.

18. Use of a compound according to claim 1 in the manufacture of a pharmaceutical composition according to any one of claims 2 to 9 or an oral dosage form according to claim 10 for treating a subject suffering from a viral infection.

19. Use of at least one compound of claim 1, a pharmaceutical composition of any one of claims 2 to 9, or an oral dosage form of claim 10 in the manufacture of a kit for providing a conjoint therapy regimen to a subject, comprising administering taurolidine and / or taurultam in combination with said at least one compound of claim 1, said pharmaceutical composition, or said oral dosage form as a conjoint therapy to the subject.

20. Use of at least one compound according to claim 1 in the manufacture of a kit for broadening the pharmacokinetic effect of taurolidine and / or taurultam in a human subject using at least two compounds having different half-lives, comprising administering taurolidine and / or taurultam in combination with the at least one compound according to claim 1 to the human subject.

21. 20. The use according to claim 19, comprising administering said at least one compound in a dosage of 0.1 mg / kg to 1000 mg / kg in combination with taurolidine and / or taurultam in a dosage of 0.01 mg / kg to 500 mg / kg.

22. The use of claim 19, comprising administering at least one compound 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 according to claim 1, a pharmaceutical composition according to any one of claims 2 to 9 or an oral dosage form according to claim 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, pharmaceutical composition, or oral dosage form in the manufacture of a kit for providing a co-therapy regimen to a subject, comprising administering to the subject as co-therapy with one or more anti-PD-1 drugs, docetaxel, irinotecan (including Onivyde™), doxorubicin, erlotinib, olaparib, lapatinib, topotecan, capecitabine, oxaliplatin, cyclophosphamide, ifosfamide, or combinations thereof.

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