Disulfide Compounds as Medicinal Compounds

Abstract

The present invention provides disulfide compounds of formula (I) as defined in the claims for use as pharmaceuticals, including the use of the compounds as antibacterial agents, such as antibacterial agents, and the use of the compounds in the treatment of cancer. The present invention also provides pharmaceutical compositions comprising the disulfide compounds of formula (I) and one or more other antibiotics, particularly aminoglycoside antibiotics, including the compound fradiomycin, as well as the use of the pharmaceutical compositions as pharmaceuticals, including the use of the compounds as antibacterial agents. [Formula 1] JPEG2024530662000105.jpg11128

Description

[Technical field]

[0001] The present invention relates to disulfide compounds for use as pharmaceuticals. In particular, the present invention relates to such compounds and antibacterial agents comprising said compounds for use as antibacterial agents. [Background technology]

[0002] Bacteria are ubiquitous. They play an important role in maintaining the environment in which we live. Only a small percentage of the world's bacteria cause infection and disease. These bacterial infections can have a major impact on public health.

[0003] Bacteria are unique among prokaryotes in that many are resident flora that colonize the host without causing infection. Human infections may or may not result in clinically evident disease, with only a small subset of infections resulting in clinically significant disease. Bacterial infections can be transmitted by a variety of mechanisms. To spread, sufficient numbers of organisms must survive in the environment and reach susceptible hosts. Clearly, measures to prevent infection have a dramatic impact on morbidity and mortality.

[0004] Prevention is especially important in this era of increasing antibiotic resistance, since treatment can be very difficult to achieve. There are three main principles in the control of bacterial infections: eliminating or containing the source of infection, interrupting the chain of transmission, and protecting the host from infection or disease. There is a constant need for the development of new antibacterial agents.

[0005] The present inventors have unexpectedly discovered that a class of disulfide compounds have antibacterial activity. Such compounds also offer potential for broader use as medicines, as well as use in inhibiting uncontrolled cell proliferation (e.g., cancer cell proliferation). Summary of the Invention

[0006] In a first aspect, the present invention relates to a disulfide compound of formula (I) for use as a medicament.

[0007] [ka]

[0008] and stereochemical isomers thereof, R 1 is a saturated or unsaturated 3- to 20-membered carbocyclic or heterocyclic ring system, R 2 is -(CX2) m (wherein m is 2 to 1000, and each X is -H, -CH3, -(CH2) n CH3 (wherein n is 1 to 1000), -halogen, -OH, O-C1 to C6 alkyl, or an ether, ester, carbamate, carbonate, amide, amine, urea, or thiol bond, -(CX2) m The chain is optionally substituted with alkyl, alkenyl, halogen, alkoxy, amine, ether, alcohol, or acid groups, -Ar(CH2) n or -(CH2) n Ar, where n is 1 to 1000 and Ar is an optionally substituted saturated or unsaturated carbocyclic or heterocyclic ring, C 20 Cycloalkyl, C2-C 50 Alkenyl, and (CH2CH2O) n (CH2) P or (CH(CH3)CH2O) n (CH2) p wherein n is 1 to 1000 and p is 0 to 20; R 3 is a moiety containing a functional group selected from the group consisting of hydrogen or alkyl, alkoxy, amine, hydroxyl, carboxyl, imine, thiol, amide, guanidine, acrylamide, acrylate, methacrylate, acetate, allyl, vinyl, carbonyl, azo, nitrile, epoxide, ester, phosphate, and sulfate; Disulfide compounds of formula (I) and their stereochemical isomers, and pharma- ceutically acceptable salts and prodrugs thereof.

[0009] In a second aspect, the present invention provides a disulfide compound as defined hereinbefore for use as an antibacterial agent.

[0010] In a third aspect, the present invention provides a disulfide compound as defined hereinbefore for use in inhibiting uncontrolled cell proliferation.

[0011] In a fourth aspect, the present invention relates to an antibacterial agent comprising a disulfide compound as defined hereinbefore.

[0012] In a fifth aspect, the present invention relates to the use of a disulfide compound as defined hereinbefore as an antibacterial agent.

[0013] definition The term "antimicrobial agent" is understood to mean an agent capable of inhibiting the growth of microorganisms, where growth may be, for example, either by inhibition of growth, by microbiocidal action (killing the microorganism) or by microbistatic action (inhibiting the growth of the microorganism). It will be further understood to include, for example, antibacterial agents, antifungal agents, and antiviral agents.

[0014] The term "stereochemical isomers" as used herein defines all possible isomers that the disulfide compounds may have. Unless otherwise stated or indicated, the chemical name of the compound indicates a mixture of all possible stereochemical isomers, which mixture includes all diastereomers and enantiomers of the basic molecular structure. The present invention also encompasses each of the individual isomers of the disulfide compounds and their salts substantially free of other isomers, i.e., with less than 10%, preferably less than 5%, particularly less than 2%, and most preferably less than 1%.

[0015] The term "pharmaceutical acceptable" refers to chemical compounds and mixtures thereof that are acceptable for use in drug products. All excipients used in drug products that have been approved by regulatory agencies are pharmaceutical acceptable.

[0016] The term "excipient" refers to a compound for use in a pharmaceutical product that is not itself biologically active in the amounts present when the pharmaceutical product is used as intended or in accordance with regulatory approval.

[0017] The term "prodrug" in the context of the present invention means a compound that is inactive in the intended pharmacological action, but can be converted into a pharmacologically active agent by metabolic or physicochemical transformation. [Brief description of the drawings]

[0018] [Figure 1] Cell survival % (T-24 cells) vs. PDEA concentration (μM) [Diagram 2] Cell survival % (5637 cells) vs. PDEA concentration (μM) DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Disulfide Compounds The present invention relates to a disulfide compound of formula (I)

[0020] [ka]

[0021] and stereochemical isomers thereof, R 1 is a saturated or unsaturated 3- to 20-membered carbocyclic or heterocyclic ring system, R 2 is -(CX2) m (wherein m is 2 to 1000, and each X is -H, -CH3, -(CH2) nCH3 (wherein n is 1 to 1000), -halogen, -OH, O-C1 to C6 alkyl, or an ether, ester, carbamate, carbonate, amide, amine, urea, or thiol bond, -(CX2) m The chain is optionally substituted with alkyl, alkenyl, halogen, alkoxy, amine, ether, alcohol, or acid groups, -Ar(CH2) n or -(CH2) n Ar, where n is 1 to 1000 and Ar is an optionally substituted saturated or unsaturated carbocyclic or heterocyclic ring, C 20 Cycloalkyl, C2-C 50 Alkenyl, and (CH2CH2O) n (CH2) P or (CH(CH3)CH2O) n (CH2) p wherein n is 1 to 1000 and p is 0 to 20; R 3 is a moiety containing a functional group selected from the group consisting of hydrogen or alkyl, alkoxy, amine, hydroxyl, carboxyl, imine, thiol, amide, guanidine, acrylamide, acrylate, methacrylate, acetate, allyl, vinyl, carbonyl, azo, nitrile, epoxide, ester, phosphate, and sulfate; Disulfide compounds of formula (I) and their stereochemical isomers, and pharma- ceutically acceptable salts and prodrugs thereof.

[0022] R of the compound of formula (I) is as defined above. 1 is a saturated or unsaturated 3- to 20-membered carbocyclic or heterocyclic ring system. The ring system may be monocyclic or polycyclic (e.g., bicyclic, tricyclic or tetracyclic). If the ring system is polycyclic, the rings may be fused.

[0023] ring system R 1may be substituted or unsubstituted. When the ring system is substituted, possible substituents include C1-C8 alkyl groups (e.g., methyl, ethyl), halo groups (e.g., chloro), C1-C8 alkoxy groups (e.g., methoxy, ethoxy) and amine groups (e.g., acetamido, amino).

[0024] In a preferred embodiment, R 1 is a saturated or unsaturated 4-16 membered carbocyclic or heterocyclic ring system, more preferably a 5-10 membered carbocyclic or heterocyclic ring system, such as a 6 membered carbocyclic or heterocyclic ring system.

[0025] R 1 Particularly preferred ring systems for include benzyl, p-nitro-benzyl, o-nitro-benzyl, para-trifluoromethyl-benzyl, 2,4,6-trifluoro-benzyl, 4-fluorobenzyl, ortho-pyridyl, meta-pyridyl, para-pyridyl, 4-nitro-pyridine, pyrazine, pyrimidine, quinoxaline, azepine, 1,4-diazepine, quinoline, isoquinoine, purine, pteridine, imidazole, thiazole, benzothiazole, 2-(5,5-dimethyl-1,3,2-dioxaphosphorinane 2-sulfide), aziridine, tetrazole, siloxane and piperidine.

[0026] R 2 In the context of the moiety, optional substituents on the Ar group are C1-C8 alkyl groups (e.g., methyl, ethyl), C2-C 20 It may be selected from the group consisting of alkenyl groups, ether groups, alcohol groups, acid groups, halo groups (eg, chloro), C1-C8 alkoxy groups (eg, methoxy, ethoxy) and amine groups (eg, acetamide, amino).

[0027] In a preferred embodiment, R 2 teeth, - Alkyl chain -(CH2) mwhere m is 2-500 and is optionally substituted with alkyl, alkenyl, halogen, alkoxy, amine, ether, alcohol or acid groups. The alkyl chain may optionally contain ether, ester, carbamate, carbonate, amide, amine, urea or thiol linkages, and thus the alkyl chain may contain alkyl ether, alkyl ester, alkyl carbamate, alkyl carbonate, alkyl amide, alkyl amine, alkyl urea or alkyl thiol groups; - Aryl (Ar) group -Ar(CH2) n or -(CH2) n Ar, where Ar is a saturated or unsaturated carbocyclic or heterocyclic ring optionally substituted with alkyl, alkenyl, halogen, alkoxy, amine, ether, alcohol or acid groups, and n is from 1 to 500, the carbocyclic or heterocyclic ring optionally containing ether, ester, carbamate, carbonate, amide, amine, urea or thiol linkages, such that the carbocyclic or heterocyclic ring may contain alkyl ether, alkyl ester, alkyl carbamate, alkyl carbonate, alkyl amide, alkyl amine, alkyl urea or alkyl thiol groups, - Cycloalkyl (Cy) group -Cy(CH2) o or -(CH2) o Cy, where Cy is optionally substituted with alkyl, alkenyl, halogen, alkoxy, amine, ether, alcohol or acid groups, and o is 1 to 500, and the cycloalkyl group may optionally contain ether, ester, carbamate, carbonate, amide, amine, urea or thiol linkages, and thus the cycloalkyl group may contain alkyl ether, alkyl ester, alkyl carbamate, alkyl carbonate, alkyl amide, alkyl amine, alkyl urea or alkyl thiol groups; and - Ether chain (CH2CH2O) n (CH2) p or (CH(CH3)CH2O) n (CH2) p (In the formula, n is 1 to 500, and p is 0 to 20.) is selected from the group consisting of:

[0028] In another preferred embodiment, R 2 teeth, - Alkyl chain -(CH2) m where m is 2-100 and is optionally substituted with alkyl, alkenyl, halogen, alkoxy, amine, ether, alcohol or acid groups. The alkyl chain may optionally contain ether, ester, carbamate, carbonate, amide, amine, urea or thiol linkages, and thus the alkyl chain may contain alkyl ether, alkyl ester, alkyl carbamate, alkyl carbonate, alkyl amide, alkyl amine, alkyl urea or alkyl thiol groups; - Aryl (Ar) group -Ar(CH2) n or -(CH2) n Ar, where Ar is a saturated or unsaturated carbocyclic or heterocyclic ring optionally substituted with alkyl, alkenyl, halogen, alkoxy, amine, ether, alcohol or acid groups, and n is from 1 to 100, the carbocyclic or heterocyclic ring optionally containing ether, ester, carbamate, carbonate, amide, amine, urea or thiol linkages, such that the carbocyclic or heterocyclic ring may contain alkyl ether, alkyl ester, alkyl carbamate, alkyl carbonate, alkyl amide, alkyl amine, alkyl urea or alkyl thiol groups; - Cycloalkyl (Cy) group -Cy(CH2) o or -(CH2) o Cy, where Cy is optionally substituted with alkyl, alkenyl, halogen, alkoxy, amine, ether, alcohol or acid groups, and o is 1 to 100, and the cycloalkyl group may optionally contain ether, ester, carbamate, carbonate, amide, amine, urea or thiol linkages, and thus the cycloalkyl group may contain alkyl ether, alkyl ester, alkyl carbamate, alkyl carbonate, alkyl amide, alkyl amine, alkyl urea or alkyl thiol groups; and - Ether chain (CH2CH2O)n (CH2) p or (CH(CH3)CH2O) n (CH2) p (wherein n is 1 to 250, and p is 0 to 20). is selected from the group consisting of:

[0029] In yet another preferred embodiment, R 2 teeth, - Alkyl chain -(CH2) m where m is 2-20 and is optionally substituted with alkyl, alkenyl, halogen, alkoxy, amine, ether, alcohol or acid groups. The alkyl chain may optionally contain ether, ester, carbamate, carbonate, amide, amine, urea or thiol linkages, and thus the alkyl chain may contain alkyl ether, alkyl ester, alkyl carbamate, alkyl carbonate, alkyl amide, alkyl amine, alkyl urea or alkyl thiol groups; - Aryl (Ar) group -Ar(CH2) n or -(CH2) n Ar, where Ar is a saturated or unsaturated carbocyclic or heterocyclic ring optionally substituted with alkyl, alkenyl, halogen, alkoxy, amine, ether, alcohol or acid groups, and n is from 1 to 20, the carbocyclic or heterocyclic ring optionally containing ether, ester, carbamate, carbonate, amide, amine, urea or thiol linkages, such that the carbocyclic or heterocyclic ring may contain alkyl ether, alkyl ester, alkyl carbamate, alkyl carbonate, alkyl amide, alkyl amine, alkyl urea or alkyl thiol groups, - Cycloalkyl (Cy) group -Cy(CH2) o or -(CH2) oCy, where Cy is optionally substituted with alkyl, alkenyl, halogen, alkoxy, amine, ether, alcohol or acid groups, and o is 1 to 20, and the cycloalkyl group may optionally contain ether, ester, carbamate, carbonate, amide, amine, urea or thiol linkages, and thus the cycloalkyl group may contain alkyl ether, alkyl ester, alkyl carbamate, alkyl carbonate, alkyl amide, alkyl amine, alkyl urea or alkyl thiol groups; and - Ether chain (CH2CH2O) n (CH2) p or (CH(CH3)CH2O) n (CH2) p (wherein n is 1 to 50, and p is 0 to 20). is selected from the group consisting of:

[0030] In a further preferred embodiment, R 2 teeth, - Alkyl chain -(CH2) m where m is 2 to 20 and is optionally substituted with alkyl, alkoxy, amine, ether, alcohol or acid groups. The alkyl chain may optionally contain ether, ester, amide or amine linkages, and thus the alkyl chain may contain alkyl ether, alkyl ester, alkyl amide or alkyl amine groups; and - Ether chain (CH2CH2O) n (CH2) p or (CH(CH3)CH2O) n (CH2) p (wherein n is 1 to 50, and p is 0 to 20). is selected from the group consisting of:

[0031] In all embodiments of the present invention, R 2 Ga-(CH2) m (wherein m is 2 to 500, more preferably 2 to 100, and even more preferably 2 to 20).

[0032] In a particularly preferred embodiment, R 2 is (CH2)2.

[0033] R of the compound of formula (I) is as defined above. 3 is a moiety containing a functional group selected from the group consisting of hydrogen or alkyl, alkoxy, amine, hydroxyl, carboxyl, imine, thiol, amide, guanidine, acrylamide, acrylate, methacrylate, acetate, allyl, vinyl, carbonyl, azo, nitrile, epoxide, ester, phosphate, and sulfate.

[0034] In a preferred embodiment, R 3 is a moiety containing a functional group selected from the group consisting of hydrogen or alkyl, alkoxy, amine, hydroxyl, carboxyl, imine, thiol, amide, guanidine, acetate, allyl, vinyl, carbonyl, nitrile, epoxide, ester, phosphate, and sulfate.

[0035] In another preferred embodiment, R 3 is a moiety containing a functional group selected from the group consisting of hydrogen or alkyl, alkoxy, amine, hydroxyl, carboxyl, imine, amide, guanidine, acetate, allyl, vinyl, ester, phosphate, and sulfate.

[0036] In yet another preferred embodiment, R 3 is a moiety containing a functional group selected from the group consisting of hydrogen or alkyl, alkoxy, amine, hydroxyl, carboxyl, amide, guanidine, acetate, allyl, vinyl, and ester.

[0037] In a further preferred embodiment, R 3 is a moiety containing a functional group selected from the group consisting of hydrogen or alkyl, alkoxy (e.g., methoxy or ethoxy), amine, hydroxyl, carboxyl (e.g., COOH), amide, guanidine, acetate, allyl, vinyl, and ester.

[0038] In yet another preferred embodiment, R 3 is a moiety containing a functional group selected from the group consisting of hydrogen or alkoxy (e.g., methoxy or ethoxy), amine, hydroxyl, carboxyl (e.g., COOH), amide, guanidine, acetate, allyl, vinyl, and ester.

[0039] Preferably, R 3 contains an amino or carboxyl group.

[0040] The amino group may be a primary, secondary, tertiary or quaternary amine.

[0041] A particularly preferred embodiment is 3 is NR2 (wherein R is H or CH3), or R 3 is COOH.

[0042] In embodiments of the invention where the compound of formula (I) is in the form of a salt, R 3 (NR3) + where R is H or CH3 (methyl) or CH2CH3 (ethyl).

[0043] In a preferred embodiment, the disulfide compound is a compound of formula (II)

[0044] [ka]

[0045] and stereochemical isomers thereof, R 1 is a saturated or unsaturated 3- to 20-membered heterocyclic ring system, R 2 teeth, - Alkyl chain -(CH2) mwhere m is 2-20 and is optionally substituted with alkyl, alkenyl, halogen, alkoxy, amine, ether, alcohol or acid groups. The alkyl chain may optionally contain ether, ester, carbamate, carbonate, amide, amine, urea, or thiol linkages; - Aryl (Ar) group -Ar(CH2) n or -(CH2) n Ar, where Ar is a saturated or unsaturated carbocyclic or heterocyclic ring optionally substituted with alkyl, alkenyl, halogen, alkoxy, amine, ether, alcohol or acid groups, and n is 1 to 20, the carbocyclic or heterocyclic ring optionally containing ether, ester, carbamate, carbonate, amide, amine, urea or thiol linkages; - Cycloalkyl (Cy) group -Cy(CH2) o or -(CH2) o Cy, where Cy may be optionally substituted with alkyl, alkenyl, halogen, alkoxy, amine, ether, alcohol or acid groups, and o is 1 to 20, and the cycloalkyl group may optionally contain an ether, ester, carbamate, carbonate, amide, amine, urea or thiol linkage; and - Ether chain (CH2CH2O) n (CH2) p or (CH(CH3)CH2O) n (CH2) p (wherein n is 1 to 50, and p is 0 to 20). is selected from the group consisting of R 3 is a moiety containing a functional group selected from the group consisting of hydrogen, alkyl, alkoxy, amine, hydroxyl, carboxyl, amide, guanidine, acetate, allyl, vinyl, and ester; Compounds and their stereochemical isomers, and pharma- ceutically acceptable salts and prodrugs thereof.

[0046] In this embodiment, R 1The heterocyclic ring system contains one or more heteroatoms such as nitrogen, oxygen or sulfur. Preferably, the heteroatom or heteroatoms are nitrogen.

[0047] Heterocyclic ring systems may be saturated or unsaturated carbocyclic ring systems and may be monocyclic or polycyclic (e.g., bicyclic, tricyclic or tetracyclic). If the ring system is polycyclic, the rings may be fused.

[0048] Heterocyclic ring system R 1 may be substituted or unsubstituted. When the ring system is substituted, possible substituents include C1-C8 alkyl groups (e.g., methyl, ethyl), halo groups (e.g., chloro), C1-C8 alkoxy groups (e.g., methoxy, ethoxy) and amine groups (e.g., acetamido, amino).

[0049] In a preferred embodiment, R 1 is C4~C 16 Heterocyclic ring systems, more preferably C5-C 10 , for example a C6 heterocyclic ring system.

[0050] Examples of preferred heterocyclic ring systems include pyridine and pyrimidine.

[0051] The -SS bridge in the compound of formula (II) may be at the 2 (ortho) and / or 4 (para) position relative to the heteroatom.

[0052] In formula (II), R 3 is preferably hydrogen or a moiety containing a functional group selected from the group consisting of alkoxy, amine, hydroxyl, carboxyl, amide, guanidine, acetate, allyl, vinyl, and ester.

[0053] In a further preferred embodiment, the disulfide compound is a compound of formula (III)

[0054] [ka]

[0055] and stereochemical isomers thereof, R 2 teeth, - Alkyl chain -(CH2) m where m is 2 to 20 and is optionally substituted with alkyl, alkoxy, amine, ether, alcohol or acid groups. The alkyl chain may optionally contain ether, ester, amide or amine linkages; and - Ether chain (CH2)CH2O) n (CH2) p or (CH(CH3)CH2O) n (CH2) p (wherein n is 1 to 50, and p is 0 to 20). is selected from the group consisting of R 3 is a moiety containing a functional group selected from the group consisting of hydrogen or alkyl, alkoxy (e.g., methoxy or ethoxy), amine, hydroxyl, carboxyl (e.g., COOH), amide, guanidine, acetate, allyl, vinyl, and ester; Compounds and their stereochemical isomers, and pharma- ceutically acceptable salts and prodrugs thereof.

[0056] In formula (III), R 3 is preferably a moiety containing a functional group selected from the group consisting of hydrogen or alkoxy (e.g., methoxy or ethoxy), amine, hydroxyl, carboxyl (e.g., COOH), amide, guanidine, acetate, allyl, vinyl, and ester.

[0057] In a further preferred embodiment, the disulfide compound is a compound of formula (IV)

[0058] [ka]

[0059] and stereochemical isomers thereof, R 2 is -(CH2) m (wherein m is 2 to 500, more preferably 2 to 100, and even more preferably 2 to 20); R 3 contains an amino group or a carboxyl group, Compounds and their stereochemical isomers, and pharma- ceutically acceptable salts and prodrugs thereof.

[0060] Particularly preferred specific examples of the disulfide compound of the present invention are as follows.

[0061] [Table 1-1]

[0062] [Table 1-2]

[0063] [Table 1-3]

[0064] [Table 1-4]

[0065] [Table 1-5]

[0066] A particularly preferred group of compounds of the invention is as follows:

[0067] [Table 2-1]

[0068] [Table 2-2]

[0069] [Table 2-3]

[0070] [Table 2-4]

[0071] [Table 2-5]

[0072] The most preferred examples of the disulfide compounds of the present invention are as follows:

[0073] [Table 3]

[0074] The disulfide compounds may be in the form of single enantiomers or racemic mixtures.

[0075] Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, and acidic or basic amino acid salts. Salts may be naturally occurring or may exist together with one or more molecules of water of crystallization.

[0076] Specific examples of pharma- ceutically acceptable salts include hydrochloride, hydrobromide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citrate, fumarate, benzoate, polyacrylate (e.g., Mw=500-500,000), amino acids, ammonium, sodium, potassium, calcium, iron, and magnesium.

[0077] The compounds may also be in the form of a prodrug which, when metabolized, forms a compound described hereinabove. Such prodrugs are well known to those skilled in the art.

[0078] The compounds according to the invention can generally be prepared by a series of steps, each of which is known to one skilled in the art.

[0079] Compositions and Uses The disulfide compounds as defined hereinbefore may be used as compounds themselves (or their salts or prodrugs) or may be present in pharmaceutical compositions. The present invention therefore further relates to pharmaceutical compositions comprising the disulfide compounds as defined hereinbefore and one or more pharma- ceutically acceptable carriers, diluents or excipients. Such carriers, diluents and excipients are well known in the art.

[0080] The excipients used in the pharmaceutical composition of the present invention vary depending on the nature of the composition. In addition to water, excipients for suspensions are typically selected from among sodium chloride or other physiologically acceptable salts, sugars, surfactants, antioxidants, flavorings, sweeteners, and pH adjusting agents. Typically, oral capsules are capsules prepared from gelatin or hydroxypropylmethylcellulose (HPMC). Typical excipients in such capsules include lactose, microcrystalline cellulose, and inorganic salts. Typically, tablets can be instantaneous disintegration tablets, controlled release tablets, and sustained release tablets. Typical excipients in tablets include, for example, corn starch, lactose, glucose, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

[0081] The pharmaceutical composition may be any pharma- ceutical acceptable formulation depending on the route of administration. For oral administration, aqueous suspension, tablet and capsule are the most preferred formulations, and for dermal use, cream and ointment are the preferred pharmaceutical formulations. For injection, the most preferred injections are intravenous, intramuscular and subcutaneous injections. Injection formulations are typically in the form of sterile aqueous suspensions. Pulmonary formulations according to the present invention in the form of dry powder for inhalation are typically in the form of single or multiple doses, or in the form of suspension of particles. Ophthalmic products are typically sterile aqueous suspensions of particles, while the typical composition for nasal administration may be dry particles or aqueous suspensions.

[0082] In one embodiment, the pharmaceutical composition is formulated for parenteral administration, such as injection or infusion.

[0083] In one particularly preferred embodiment of the present invention, the pharmaceutical composition defined above is formulated for oral administration, for example as a tablet, capsule or suspension.

[0084] The compound or composition thereof is preferably administered in a therapeutically effective amount. "Therapeutically effective amount" refers to the amount necessary to induce the desired therapeutic effect. Depending on the mode of administration, the pharmaceutical composition typically contains 0.05-99% by weight, preferably 0.1-70% by weight, more preferably 0.1-50% by weight of the active ingredient (i.e., disulfide compound), and 1-99.95% by weight, preferably 30-99.9% by weight, more preferably 50-99.9% by weight of a pharma- ceutically acceptable carrier, all percentages being based on the total weight of the composition.

[0085] Any administration route may be used to deliver the compound to the subject.Suitable administration routes include intramuscular injection, transdermal administration, inhalation, topical application, oral administration, rectal or vaginal administration and parenteral administration (e.g., intravenous, peritoneal, intraarterial or subcutaneous).Preferred administration routes are oral, topical and parenteral.

[0086] For oral administration, aqueous suspension, tablet and capsule are the most preferred formulations, and for dermal use, cream and ointment are the preferred pharmaceutical formulations.For injection, the most preferred injections are intravenous, intramuscular and subcutaneous injections.Injection formulations are typically in the form of sterile aqueous suspensions.The pulmonary formulations according to the present invention in the form of dry powder for inhalation are typically in the form of single or multiple doses, or in the form of suspension of particles.Ophthalmic products are typically sterile aqueous suspensions of particles, while the typical composition for nasal administration can be dry particles or aqueous suspensions.

[0087] The exact dosage and frequency of administration will depend on the particular disulfide compound used and the desired application. Moreover, it will be apparent that the effective daily amount may be increased or decreased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compound according to the invention.

[0088] The present invention relates to a disulfide compound as defined hereinbefore for use as a medicament.

[0089] In a further embodiment, the present invention relates to the disulfide compounds according to the invention for use as antibacterial agents.

[0090] In a further embodiment, the present invention relates to an antibacterial agent comprising a disulfide compound as defined hereinbefore.

[0091] An "antimicrobial agent" may preferably be an antibacterial agent, an antiviral agent or an antifungal agent.

[0092] The antimicrobial agent may be suitable for use in the treatment of human or animal subjects, or for use on devices or products that come into contact with potentially harmful microorganisms.

[0093] The antibacterial agents may be used in vitro or in vivo.

[0094] The present invention therefore also relates to the use of the disulfide compounds as defined hereinbefore as antibacterial agents.

[0095] In one preferred embodiment of the present invention, the antimicrobial agent described herein above is an antibacterial agent.

[0096] Examples of microorganisms against which the present invention may be used to prevent the growth and / or proliferation include various species of Staphylococcus, such as S. aureus, Methicillin-resistant S. aureus (MRSA), S. epidermidis and other coagulase-negative staphylococci, S. saphrophyticus, Enterococcus faecalis, and the like. spp), Nesseriae (Meningococci, Gonococcci), Streptococci (Viridans, Streptococcus agalactiae, Streptococcus pyogenes, hemolytic and non-hemolytic, groups B and D, S. pneumoniae), Chlostridia (perfringens, botulinum), Bacillus megaterium, as well as various Gram-positive bacteria selected from, but not limited to, various Enterobacter spp, Escherichia coli, extended spectrum beta-lactamase (ESBL) producing E. coli,coli, Klebsiella spp, Proteus, Campylobacter, Yersinia, Shigella, Salmonella, Haemophilus (influenzae), Bacteriodes (fragilis, bivius), Pseudomonas (aeruginosa, Pseudomonas cepacia), Legionella (Legionella pneumophilia), Neisseria meningitidis, Acinetobacter baumannii baumannii, and viruses selected from, but not limited to, coronaviruses, SARS-Cov-2, Influenza A, Influenza B, Respiratory syncytial virus (RSV), Rhinovirus, and Rotavirus. Also included are various mycoplasma and Candida species, as well as various fungi, such as Candida spp., Candida tropicalis, C. parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Tricosporun, Blastoschizomyces, Stenotrophomonas maltophilia, Malassezia, Bukholderia cepafia, and Aspergillus.

[0097] Thus, in a preferred embodiment, the present invention relates to a disulfide compound as defined hereinbefore for use as an antibacterial agent against bacteria selected from the group consisting of gram positive Cocci, gram negative Cocci, gram positive Bacilli, gram negative Bacilli, mycobacteria, spirochetes, chlamydiaceae and mycoplasmataceae, or against fungi selected from the group consisting of candida spp. and candida albicans.

[0098] In this context, examples of gram-positive cocci include staphylococci, streptococci and enterococci. Examples of gram-negative cocci include Neisseria. Examples of gram-positive bacilli include spore-forming and non-spore-forming bacilli. Examples of gram-negative bacilli include enterobacteria, respiratory bacilli and zoonotic bacilli.

[0099] A further embodiment of the present invention discloses disulfide compounds for use in the inhibition of uncontrolled cell proliferation, such as cancer cells and / or cancer cells with significant regenerative potential, such as cancer stem cells.

[0100] Thus, a preferred embodiment of the present invention relates to the disulfide compounds of the present invention for use in the treatment of cancer.Cancer (cancer cells) may be cells of the following types of cancer: breast cancer, prostate cancer, brain cancer, blood cancer, bone marrow cancer, liver cancer, pancreatic cancer, kidney cancer, colon cancer, ovarian cancer, lung cancer, testicular cancer, penile cancer, thyroid cancer, parathyroid cancer, pituitary cancer, thymus cancer, retina cancer, uveal cancer, conjunctival cancer, spleen cancer, head cancer, neck cancer, trachea cancer, gallbladder cancer, rectal cancer, salivary gland cancer, adrenal gland cancer, pharynx cancer, esophageal cancer, lymph node cancer, sweat gland cancer, sebaceous gland cancer, muscle cancer, heart cancer, and stomach cancer.A particularly preferred group of cancers is bladder cancer, prostate cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, leukemia, liver and intrahepatic bile duct, lung cancer, non-Hodgkin's lymphoma, pancreatic cancer, and thyroid cancer.

[0101] Combination therapy The present invention also relates to pharmaceutical compositions comprising a disulfide compound according to the invention and one or more other antibiotics, and to such compositions for use as medicaments, more particularly for use as antibacterial agents, such as antibacterial agents.

[0102] The present invention also relates to a product comprising a disulfide compound according to the invention, a pharma- ceutically acceptable salt thereof or a prodrug thereof, and one or more other antibiotics as a combined preparation for simultaneous, separate or sequential use as a medicine, and more particularly for simultaneous, separate or sequential use as an antibacterial agent. The different drugs of such a combination or product may be combined in a single preparation together with a pharma- ceutically acceptable carrier or diluent, or each may be present in a separate preparation together with a pharma- ceutically acceptable carrier or diluent.

[0103] In yet a further aspect, the present invention provides a kit comprising (i) a disulfide compound of the invention, and separately (ii) one or more other antibiotics, and optionally (iii) instructions for using (i) and (ii) as antibacterial agents. When used, the active components of the kit (i.e., (i) and (ii)) may be administered simultaneously, separately or sequentially.

[0104] In this embodiment, a particularly preferred class of antibiotics that may be used as the one or more other antibiotics are the aminoglycosides, such as fradiomycin or gentamicin.

[0105] The invention will now be described with reference to the following non-limiting examples. EXAMPLES

[0106] Antibacterial Testing Minimum inhibitory concentration (MIC) protocol Day 1: Preparation of test inoculum / bacteria 1. Using a sterile inoculating loop, transfer the bacteria / Candida albicans from a frozen stock culture and streak the bacteria onto a fresh LA plate. 2. Incubate the plate at 37°C overnight (o / n) (18-24 hours). Day 2 1.20 mL of Mueller-Hinton Broth ( * Prepare the bacterial culture by adding 100 mL of PBS to a 250 mL Erlenmeyer flask with a side arm. 2. Using a sterile inoculating loop, pick approximately 10 colonies from the o / n bacterial culture and transfer the bacteria into a flask. 3. Incubate the E-flask with bacteria at 37°C on a rotary shaker until the OD590 is 0.40. This OD is 1x10 8 should be equal to the approximate bacterial count in cfu / mL ( ** ). This is measured using a colorimeter (or spectrophotometer). Set the standard and measure the bacterial culture by first pressing R (= standard) and then T (= test). 4. At an OD590 of 0.40, serially dilute the bacterial suspension 1:10 000 in Mueller Hinton Broth to obtain 1 × 10 4 Obtain bacterial target concentrations in cfu / mL. Determine initial inoculum by serially diluting 0.1 mL into 0.9 mL blank sterile PBS and plating 0.1 mL aliquots onto preferably LA plates. 5. Prepare different concentrations of test compound in final dilutions of 0.6-0.8 mL of bacterial suspension and place in 2 mL test tubes. 6. Incubate the tubes in an orbital shaker incubator at 37° C. for 24 hours. Day 3 7. Analyze growth visible to the naked eye, i.e. "Foggy" or "Clear". The MIC is defined as the interval between the highest "Foggy" and lowest "Clear" concentrations of the compound. ( * ) When testing for Candida albicans, yeast extract peptone dextrose (YPD) broth is used. ( ** ) For Candida albicans, the bacterial count is 1 × 10 7 is equal to.

[0107] Example 1 Synthesis of 2-(pyridyldithio)ethylamine (hydrochloride) (PDEA) (CAS: 106139-15-5)

[0108] [ka]

[0109] 2-Aminoethanethiol hydrochloride (2.00 g, 17.6 mmol) was dissolved in methanol (3 mL) and acetic acid (1 mL). To this solution was added 2,2-dithiodipyridine (5.00 g, 22.7 mmol) dissolved in methanol (20 mL). The mixture was stirred overnight at 22° C. and then poured into dry diethyl ether (200 mL). A white precipitate formed and was collected by filtration to give 2.826 g, 12.68 mmol, 72% yield.

[0110] Different concentrations of PDEA (example 1) in Mueller-Hinton medium were prepared. Bacteria were inoculated at a concentration of 20 000 CFU / mL and incubated for 24 hours at 37° C. The minimum inhibitory concentration (MIC) was determined by analyzing the growth visible to the naked eye, i.e. the readouts were "clear" and "turbid".

[0111] [Table 4] Result: MIC-0.05~0.1mM

[0112] [Table 5] Result: MIC-0.05~0.1mM

[0113] [Table 6] Result: MIC-0.025~0.05mM

[0114] [Table 7] Result: MIC-0.1~0.2mM

[0115] [Table 8] Result: MIC-0.025~0.05mM

[0116] [Table 9] Result: MIC-0.1~0.2mM

[0117] [Table 10] Result: MIC-0.1~0.2mM

[0118] Different concentrations of PDEA were also prepared in yeast extract peptone dextrose (YPD) broth. Candida albicans was inoculated at a concentration of 20000 CFU / mL and incubated at 37°C for 24 hours. The readouts were "clear" and "turbid."

[0119] [Table 11] Results: MIC 0.4~0.8mM

[0120] Example 2 Synthesis of 2-(2-pyridyldisulfanyl)ethane-(trimethylammonium) chloride

[0121] [ka]

[0122] To a suspension of PDEA (0.5 g, 2.25 mmol) in toluene (10 mL) was added NaH (98%, 190 mg, 7.52 mmol). Methyl iodide (7 mmol, 0.99 g, 436 μL) was added and the mixture was stirred at 22° C. An aliquot of DMF (300 μL) was added after 1 h and the mixture began to form small bubbles. The mixture was stirred overnight and a white solid formed which was collected by filtration. The solid was washed with diethyl ether and (x Cl - and x 3 1.32 g as NaI salt, theoretically yielding 0.605 g of product and 1.124 g of 3 equivalents of NaI, total theoretical weight 1.729 g, 76%).

[0123] Different concentrations of quaternary ammonium PDEA (example 2) in Mueller-Hinton medium were prepared. Bacteria were inoculated at a concentration of 20 000 CFU / mL and incubated for 24 hours at 37° C. The minimum inhibitory concentration (MIC) was determined by analyzing the growth visible to the naked eye, i.e. the readouts were "clear" and "turbid".

[0124] [Table 12] Result: MIC-0.225~0.55mM

[0125] [Table 13] Result: MIC-0.225~0.55mM

[0126] [Table 14] Result: MIC-0.055~0.11mM

[0127] [Table 15] Result: MIC-0.11~0.225mM

[0128] [Table 16] Result: MIC-0.055~0.11mM

[0129] [Table 17] Result: MIC-0.55~1.125mM

[0130] [Table 18] Result: MIC-0.55~1.125mM

[0131] Different concentrations of quaternary ammonium PDEA (Example 2) were also prepared in yeast extract peptone dextrose (YPD) broth. Candida albicans was inoculated at a concentration of 20 000 CFU / mL and incubated at 37°C for 24 hours. The readouts were "clear" and "turbid".

[0132] [Table 19] Result: MIC-0.225~0.55mM

[0133] Example 3 Synthesis of (S)-4-pyridylthiocysteamine, "para-PDEA"

[0134] [ka]

[0135] 2-Aminoethanethiol hydrochloride (2.00 g, 17.6 mmol) was dissolved in methanol (3 mL) and acetic acid (1 mL). To this solution was added 4,4'-dithiodipyridine (5.00 g, 22.7 mmol) dissolved in methanol (20 mL). The mixture was stirred at 22°C overnight and then poured into dry diethyl ether (200 mL). A white precipitate formed and was collected by filtration.

[0136] Different concentrations of the compound were prepared in Mueller-Hinton medium. Bacteria were inoculated at a concentration of 20 000 CFU / mL and incubated for 24 hours at 37° C. The minimum inhibitory concentration (MIC) was determined by analyzing the growth visible to the naked eye, i.e. the readouts were "clear" and "turbid".

[0137] [Table 20] Result: MIC-0.2~0.4mM

[0138] [Table 21] Result: MIC-MIC-0.2~0.4mM

[0139] [Table 22] Result: MIC-0.4~0.8mM

[0140] [Table 23] Result: MIC-MIC-0.2~0.4mM

[0141] [Table 24] Result: MIC-0.1~0.2mM

[0142] [Table 25] Result: MIC-0.2~0.4mM

[0143] [Table 26] Result: MIC-0.1~0.2mM

[0144] Different concentrations of para-PDEA, (S)-4-pyridylthiocysteamine were also prepared in yeast extract peptone dextrose (YPD) broth. Candida albicans was inoculated at a concentration of 20 000 CFU / mL and incubated at 37°C for 24 h. The readouts were "clear" and "turbid".

[0145] [Table 27] Result: MIC-1.6~3.2mM

[0146] Example 4 "PDEA carboxylic acid" is 3-(2-pyridyldithio)propanoic acid (CAS: 68617-64-1).

[0147] [ka]

[0148] Different concentrations of the compound were prepared in Mueller-Hinton Broth. Bacteria were inoculated at a concentration of 20 000 CFU / mL and incubated for 24 hours at 37° C. The minimum inhibitory concentration (MIC) was determined by analyzing the growth visible to the naked eye, i.e. the readouts were "clear" and "turbid".

[0149] [Table 28] Result: MIC-2~4mM

[0150] [Table 29]

[0151] [Table 30] Result: MIC-3.2~6.4mM

[0152] [Table 31]

[0153] [Table 32] Result: MIC-6.4~12.8mM

[0154] [Table 33] Result: MIC-0.5~1mM

[0155] [Table 34] Result: MIC-0.1~0.25mM

[0156] [Table 35] Result: MIC-0.25~0.5mM

[0157] [Table 36] Result: MIC-0.1~0.25mM

[0158] Different concentrations of "carboxylic acid PDEA", 3-(2-pyridyldithio)propanoic acid (CAS: 68617-64-1), were also prepared in yeast extract peptone dextrose (YPD) broth. Candida albicans was inoculated at a concentration of 20 000 CFU / mL and incubated at 37°C for 24 hours. The readouts were "clear" and "turbid".

[0159] [Table 37] Result: MIC-1~2mM

[0160] Example 5 -Cancer Cell Viability Assay Two types of human urothelial carcinoma cells (T24 and 5637) were tested in the XTT assay. "T24" cells were cultured in McCoy's 5A (modified) medium from GIBCO, catalog number: 16600082. "5637" cells were cultured in RPMI 1640 medium from GIBCO, catalog number: 21875034. Different concentrations of 2-(pyridyldithio)ethylamine (hydrochloride) (PDEA) (CAS: 106139-15-5): 12.5, 25, 50, 100 and 200 μM were prepared in each cell culture medium.

[0161] XTT Assay Protocol (96-well assay): Split ratio: 1:10 Day 1 1.5×10 5 Cells were seeded in 24-well plates overnight at 37° C. in 5% CO2. Day 2 2. 80% confluent cells were treated with 200 μL of medium containing different concentrations of PDEA and control. 3. After 24 hours, the medium (MacCoy's 5a for T24, RPMI for 5637) was removed and the cells were washed twice with 200 μL pre-warmed PBS / well. 200 μL (96 wells) of previously prepared fresh medium containing XTT-menadione was added to the wells (see below). 4. The cells were incubated for at least 3 hours at 37° C. Media containing only XTT in empty wells was used as background control. 5. The supernatant was transferred to a 96-well plate and the concentration was measured at 450nm and 690nm. The 690nm was used as a background measurement and subtracted from the 450nm value.

[0162] XTT-Menadione solution preparation Menadione (172.18 g / mol, photosensitive): Dissolve in absolute ethanol at 1 mg / mL. XTT: Dissolve in PBS at 1 mg / mL, sterilize through a 0.2 μm filtrate and store at -20° C. (Sigma X4626). Pre-warm to 37° C. before use.

[0163] Solution preparation: Add 2.15 μL of menadione / mL (final concentration 12.5 μM 0 2.15 mg / L) to 1 mL of XTT immediately prior to use. Prepare an XTT-menadione solution equal to 20% of the culture medium volume to be tested.

[0164] The results are shown below and graphically depicted in Figures 1 and 2. "Blank" is cell culture medium only.

[0165] [Table 38] Results: The cell viability of "T-24" cancer cells was reduced by 10-26% at PDEA concentrations of 50 μM, 20-28% at 100 μM, and 83-100% at 200 μM, respectively.

[0166] [Table 39] Results: The cell viability of "5637" cancer cells was reduced by 17-47% at PDEA concentrations of 100 μM and by 95-100% at PDEA concentrations of 200 μM.

[0167] Example 6: Combination Therapy Different concentrations of fradiomycin in Mueller-Hinton were prepared with three different concentrations of PDEA, inoculated with E. coli and S. aureus (105) and incubated overnight.

[0168] The readouts were "clear" and "cloudy."

[0169] Escherichia coli (E.coli)

[0170] [Table 40]

[0171] [Table 41] * The starting concentration of fradiomycin is 0.28 mM.

[0172] [Table 42]

[0173] [Table 43] * The starting concentration of fradiomycin is 0.28 mM.

[0174] [Table 44]

[0175] [Table 45] *The starting concentration of fradiomycin is 0.28 mM.

[0176] [Table 46]

[0177] [Table 47] * The starting concentration of fradiomycin is 0.28 mM.

[0178] Staphylococcus aureus (S. aureus)

[0179] [Table 48]

[0180] [Table 49] * The starting concentration of fradiomycin is 0.28 mM.

[0181] [Table 50]

[0182] [Table 51] * The starting concentration of fradiomycin is 0.28 mM.

[0183] [Table 52]

[0184] [Table 53] * The starting concentration of fradiomycin is 0.28 mM.

[0185] [Table 54]

[0186] [Table 55] * The starting concentration of fradiomycin is 0.28 mM.

[0187] Example 7: Combination Therapy Different concentrations of gentamicin in Mueller-Hinton were prepared with three different concentrations of PDEA. E. coli and S. aureus were inoculated (10 5 ) and incubated O / N.

[0188] The readouts were "clear" and "cloudy."

[0189] Escherichia coli (E.coli)

[0190] [Table 56]

[0191] [Table 57] * The starting concentration of gentamicin is 0.44 mM.

[0192] [Table 58]

[0193] [Table 59] * The starting concentration of gentamicin is 0.44 mM.

[0194] [Table 60]

[0195] [Table 61] * The starting concentration of gentamicin is 0.44 mM.

[0196] [Table 62]

[0197] [Table 63] * The starting concentration of gentamicin is 0.44 mM.

[0198] Staphylococcus aureus (S. aureus)

[0199] [Table 64]

[0200] [Table 65] * The starting concentration of gentamicin is 0.44 mM.

[0201] [Table 66]

[0202] [Table 67] * The starting concentration of gentamicin is 0.44 mM.

[0203] [Table 68]

[0204] [Table 69] * The starting concentration of gentamicin is 0.44 mM.

[0205] [Table 70]

[0206] [Table 71] * The starting concentration of gentamicin is 0.44 mM.

Claims

1. An antibacterial agent comprising a disulfide compound selected from the following compound group A, or a stereochemical isomer thereof, or a pharmaceutically acceptable salt thereof. 【Table 4】

2. The antibacterial agent according to claim 1, wherein the antibacterial agent is an antibacterial agent.

3. Use of a disulfide compound selected from the following compound group A, or a stereochemical isomer thereof, or a pharmaceutically acceptable salt thereof as an antibacterial agent. 【Table 5】

4. A pharmaceutical composition comprising a disulfide compound selected from the following compound group A, or a stereochemical isomer thereof, or a pharmaceutically acceptable salt thereof, and one or more other antibiotics. 【Table 6】

5. The pharmaceutical composition according to claim 4, wherein the one or more other antibiotics are aminoglycosides.

6. The pharmaceutical composition according to claim 5, wherein the aminoglycoside is fradiomycin or gentamicin.

7. The pharmaceutical composition according to claim 4 for use as a medicine or for use as an antibacterial agent.

8. The pharmaceutical composition according to claim 5 for use as a medicine or for use as an antibacterial agent.

9. The pharmaceutical composition according to claim 6 for use as a medicine or for use as an antibacterial agent.

10. The disulfide compound has the following structure, the antibacterial agent according to claim 1 or 2, the use according to claim 3, or the pharmaceutical composition according to any one of claims 4 to 9. 【Chemical Formula 5】

11. The disulfide compound has the following structure, the antibacterial agent according to claim 1 or 2, the use according to claim 3, or the pharmaceutical composition according to any one of claims 4 to 9. [Chemical Formula 6]

12. The disulfide compound has the following structure, the antibacterial agent according to claim 1 or 2, the use according to claim 3, or the pharmaceutical composition according to any one of claims 4 to 9. 【Chemical Formula 7】

13. The disulfide compound has the following structure, the antibacterial agent according to claim 1 or 2, the use according to claim 3, or the pharmaceutical composition according to any one of claims 4 to 9. 【Chemical Formula 8】

Images