Organic sulfur compounds

Abstract

To provide organosulfur compounds of formula (I), and pharmaceutical compositions comprising these organosulfur compounds.SOLUTION: The invention provides organosulfur compounds of formula (I), where R1 and R2 are as defined herein, and pharmaceutical compositions comprising these organosulfur compounds. The organosulfur compounds and the pharmaceutical compositions are used for treating infection and / or for treating inflammation and / or for reducing the formation of blood clots.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Technical field The present invention generally relates to an organosulfur compound of formula (I) and a pharmaceutical composition comprising one or more organosulfur compounds of formula (I). The present invention also relates to a method for producing an organosulfur compound of formula (I). The present invention further relates to various uses of the organosulfur compound of formula (I), for example, as an antibacterial agent, as an anti-inflammatory agent, as an antithrombotic agent, for the treatment of wounds and / or cystic fibrosis and / or epidermolysis bullosa. [Background technology]

[0002] background Many organosulfur compounds are known to have physiological effects. For example, ajoene, an organosulfur compound found in garlic extract, is known to have antibacterial, anti-inflammatory, and antithrombotic effects. Therefore, it is desirable to obtain novel alternative or improved organosulfur compounds that may possess one or more advantageous physiological effects. [Overview of the project]

[0003] Abstract According to a first aspect of the present invention, a compound of formula (I) is provided.

[0004] [ka] Equation (I) (In the above formula, R1 is phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl, and R2 is phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, or alkenyl.

[0005] The compound of formula (I) may have an E or Z configuration. Therefore, in certain embodiments, the compound may be of formula (IA) or formula (IB). [ka] (In the above formula, R1 is phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl, and R2 is phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, or alkenyl.

[0006] Compositions comprising mixtures of the E and Z stereoisomers of the compound of formula (I) are also provided herein.

[0007] A second aspect of the present invention provides a pharmaceutical composition comprising a compound of the first aspect of the present invention and a pharmaceutically acceptable excipient and / or carrier and / or diluent.

[0008] A third aspect of the present invention provides compounds or pharmaceutical compositions (including all embodiments thereof) of any aspect of the present invention for use in therapeutic methods for treating microbial infections, and / or inflammation, and / or reducing blood clot formation, and / or treating wounds, and / or treating cystic fibrosis, and / or treating epidermolysis bullosa.

[0009] A fourth aspect of the present invention provides the use of any compound or pharmaceutical composition of the present invention (including all embodiments thereof) in the manufacture of a pharmaceutical for treating microbial infections, and / or inflammation, and / or reducing blood clot formation, and / or treating wounds, and / or treating cystic fibrosis, and / or treating epidermolysis bullosa.

[0010] According to a fifth aspect of the present invention, there is provided a treatment method for treating a microbial infection and / or for treating an inflammation and / or for reducing the formation of blood clots and / or for treating a wound and / or for treating cystic fibrosis and / or for treating epidermolysis bullosa, the method comprising administering to a subject a compound or pharmaceutical composition of any aspect of the present invention (including all embodiments thereof).

[0011] According to a sixth aspect of the present invention, there is provided a non-therapeutic use of a compound or pharmaceutical composition of any aspect of the present invention (including all embodiments thereof) as an antibacterial agent and / or as an anti-inflammatory agent and / or as an anti-thrombotic agent. For example, provided herein is an in vitro use of a compound or pharmaceutical composition of any aspect of the present invention (including all embodiments thereof) as an antibacterial agent and / or as an anti-inflammatory agent and / or as a thrombotic agent.

[0012] According to a seventh aspect of the present invention, there is provided a method for producing a compound of a first aspect of the present invention. This method can proceed, for example, via the following reaction scheme.

[0013] [Chemical formula]

[0014] Details, examples and preferences provided with respect to any particular one or more of the described aspects of the present invention are further described herein and are equally applicable to all aspects of the present invention. Any combination of the embodiments, examples and preferences described herein in all possible variations thereof is included in the present invention unless otherwise indicated herein or unless clearly inconsistent with the context. [Brief Description of the Drawings]

[0015] [Brief Description of the Figures] The present invention may be described with reference to the following non-limiting drawings.

[0016] [Figure 1] Figure 1 shows a plot of concentration versus % Staphylococcus aureus biofilm mass for the compounds of formula (I) tested in Example 4, compared to ajoene and DMSO. [Figure 2] Figure 2 shows a plot of concentration versus % Pseudomonas aeruginosa biofilm mass for the compounds of formula (I) tested in Example 4, compared to ajoene and DMSO. [Figure 3] Figure 3 shows a plot of concentration versus % Pseudomonas aeruginosa biofilm mass for the compounds of formula (I) tested in Example 6, compared to ajoene, HDMF, cysteamine, gallium nitrate and C-30. [Figure 4] Figure 4 shows a plot of concentration versus % Staphylococcus aureus biofilm mass for the compounds of formula (I) tested in Example 6, compared to ajoene, HDMF, cysteamine, gallium nitrate and C-30. [Figure 5] Figure 5 shows a microscopic image of a sample of the scratch test described in Example 7. [Figure 6] Figure 6 shows a plot of time (h) versus scratch area for the compounds of formula (I) tested in Example 7, compared to vehicle control, sulforaphane, EGF positive control and BAY 61-3606 hydrochloride hydrate negative control. **DETAILED DESCRIPTION OF THE INVENTION**

[0017] Detailed Description Compounds and Pharmaceutical Compositions The present invention is based, at least in part, on the surprising discovery that the compounds of formula (I) have advantageous antibacterial and / or wound healing activity. For example, embodiments of the present invention are based on the surprising discovery that the compounds of formula (I) provide improved antibacterial and / or wound healing activity compared to other organosulfur compounds.

[0018] Hereinafter, the present invention will be described by reference to the accompanying description in accordance with preferred embodiments of the invention. However, it should be understood that limiting the description to preferred embodiments of the invention is merely for the purpose of facilitating the discussion of the invention, and it is conceivable that those skilled in the art can devise various modifications without departing from the scope of the appended claims.

[0019] Terms used herein and herein by reference, unless otherwise indicated, preferably have the meanings set forth below, and more specific meanings may be used independently of the general definitions in preferred embodiments of the present invention, and these more specific meanings describe particularly preferred embodiments of the present invention.

[0020] Where the terms “at least one” or “one or more” appear in this and subsequent text, this means, for example, 1 to 10, preferably 1 to 3, and especially one or two more, of the enumerated features such as components. When indicating ranges, such as mass percentage ranges, these include the indicated limits. Thus, for example, “X to Y” means “from X (including X) to Y (including Y).”

[0021] The compound of the present invention is given by formula (I). [ka] Equation (I) (In the above formula, R1 is phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl, and R2 is phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, or alkenyl.

[0022] The compounds of the present invention may be represented by formula (IA) and / or formula (IB). [ka] (In the above formula, R1 is phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl, and R2 is phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, or alkenyl.

[0023] As used herein, the term "phenyl" refers to a group having the formula C6H5 derived from benzene by the removal of a hydrogen atom.

[0024] The term "substituted phenyl," as used herein, refers to a group derived from benzene by the removal of a hydrogen atom, wherein one or more of the remaining hydrogen atoms on the benzene ring are substituted with a functional group. A substituted phenyl may, for example, contain one, two, three, four, or five functional groups. A substituted phenyl may, for example, contain one or two functional groups. A substituted phenyl may, for example, contain only one functional group. The substitution may occur, for example, at the meta, ortho, or para position of the phenyl ring.

[0025] Each functional group can be independently selected from, for example, alkyl groups, haloalkyl groups, ester groups, alkoxy groups, halogen groups, alkylsulfone groups, haloalkoxy groups, or amine groups. Therefore, substituted phenyls can be, for example, alkylphenyls, haloalkylphenyls, alkyl benzoates, alkoxyphenyls, halophenyls, alkylphenylsulfones, haloalkoxyphenyls, or aminophenyls.

[0026] As used herein, the term "alkyl" refers to a group derived from saturated linear or branched hydrocarbons by the removal of hydrogen atoms. Alkyl groups may, for example, contain 1 to 8 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms.

[0027] As used herein, the term "haloalkyl" refers to a group derived from a saturated linear or branched hydrocarbon by the removal of a hydrogen atom, wherein one or more of the remaining hydrogen atoms of the alkyl group are substituted with a halogen. A haloalkyl group may contain, for example, 1 to 8 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms. A haloalkyl group may contain, for example, 1 to 8 halogen atoms, 1 to 5 halogen atoms, 1 to 4 halogen atoms, or 1 to 3 halogen atoms. The halogen atoms can each be independently selected from iodine, chlorine, bromine, and fluorine. A haloalkyl group may, for example, be a halomethyl group. A haloalkyl group may, for example, be a trihalomethyl group. A haloalkyl group may, for example, be a trifluoromethyl group. Therefore, a haloalkylphenyl may, for example, be a halomethylphenyl group. A haloalkylphenyl may, for example, be a trihalomethylphenyl group. A haloalkylphenyl may, for example, be a trifluoromethylphenyl group. The trifluoromethyl group may be located, for example, at the para position of the phenyl ring.

[0028] As used herein, the term "ester" refers to a group having the formula -C(=O)OR, where R is an alkyl group. Alkyl groups are saturated linear or branched hydrocarbons. Alkyl groups can contain, for example, 1 to 8 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms. Alkyl groups can contain one carbon atom (methyl group), for example, alkyl benzoate is methyl benzoate. Ester groups can be located, for example, at the para position of a phenyl ring.

[0029] As used herein, the term "alkoxy" refers to a group having the formula -OR, where R is an alkyl group. Alkyl groups are saturated linear or branched hydrocarbons. Alkyl groups can contain, for example, 1 to 8 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms. Alkyl groups can contain one carbon atom (methyl group), for example, alkoxyphenyl is methoxyphenyl. Alkoxy groups can be located, for example, at the meta, ortho, or para position of a phenyl ring.

[0030] As used herein, the term "haloalkoxy" refers to a group having the formula -OR, where R is an alkyl group, and one or more hydrogen atoms of the alkyl group are substituted with halogens. A haloalkoxy may, for example, contain 1 to 8 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms. A haloalkoxy may, for example, contain 1 to 8 halogen atoms, 1 to 5 halogen atoms, 1 to 4 halogen atoms, or 1 to 3 halogen atoms. The halogen atoms can each be independently selected from iodine, chlorine, bromine, and fluorine. The haloalkoxy group may, for example, be located at the para position of a phenyl ring. A haloalkoxy may, for example, be a fluoroalkoxy. A haloalkoxy may, for example, be a halomethoxy. A haloalkoxy may, for example, be a trihalomethoxy. A haloalkoxy may, for example, be a trifluoromethoxy. Therefore, a haloalkoxyphenyl may, for example, be a halomethoxyphenyl. A haloalkoxyphenyl may, for example, be a trihalomethoxyphenyl. A haloalkoxyphenyl may, for example, be a trifluoromethoxyphenyl. The trifluoromethoxy group can be located, for example, at the para position of a phenyl ring.

[0031] As used herein, the term "halo" or "halogen" refers to any of fluorine, chlorine, bromine, iodine, and astatine. In certain embodiments, the halogen is selected from fluorine, chlorine, bromine, and iodine. In certain embodiments, the halogen is selected from fluorine, chlorine, and bromine. In certain embodiments, the halogen is fluorine or chlorine. In certain embodiments, the halogen is fluorine. Therefore, the substituted phenyl can be a fluorophenyl. The halogen may be located, for example, at the para position of the phenyl ring.

[0032] As used herein, the term “alkylsulfone” refers to a group having the formula -S(O)(O)R, where R is an alkyl group. The alkyl group may contain, for example, 1 to 8 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms. The alkyl group may also contain, for example, one carbon atom (methyl group), such that the alkylsulfone is a methylsulfone (and thus the substituted phenyl is a methylphenylsulfone). The alkylsulfone may be located, for example, at the para position of a phenyl ring.

[0033] As used herein, the term “amine” refers to a group having the formula -NRR', where R and R' are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, carbonyl(-C(O)R'') (wherein R'' is an alkyl group), ester, or alkylsulfone. Thus, as used herein, the term “aminophenyl” refers to a group derived from benzene by the removal of a hydrogen atom, wherein one or more of the remaining hydrogen atoms on the benzene ring are substituted with an amine group as defined herein. In certain embodiments, R and R' of the amino group are independently selected from hydrogen and alkyl, respectively. In certain embodiments, both R and R' are alkyl groups, for example, both R and R' may be alkyl groups containing 1 to 4 carbon atoms. In certain embodiments, both R and R' are methyl. Thus, the substituted phenyl may be dimethylaminophenyl. In certain embodiments, both R and R' may be hydrogen.

[0034] When R1 is a substituted phenyl, the substituted phenyl can preferably be a halophenyl, haloalkylphenyl, alkoxyphenyl, or alkylphenyl sulfone. Halophenyl can be, for example, iodophenyl, chlorophenyl, bromophenyl, or fluorophenyl, and preferably fluorophenyl. Haloalkylphenyl can be, for example, halomethylphenyl, for example, trihalomethylphenyl, or for example, trifluoromethylphenyl. Alkoxyphenyl can be, for example, methoxyphenyl, ethoxyphenyl, or propoxyphenyl, and preferably methoxyphenyl. Alkylphenyl sulfone can be, for example, methylphenyl sulfone, ethylphenyl sulfone, or propylphenyl sulfone, and preferably methylphenyl sulfone.

[0035] When R1 is a substituted phenyl, the substituted phenyl may preferably be a haloalkylphenyl. The halogen may be one or more of, for example, iodine, chlorine, bromine, or fluorine. The halogen may be, for example, fluorine. When there is more than one halogen atom, all halogen atoms may be the same. The haloalkylphenyl may be, for example, a halomethylphenyl. The halomethylphenyl may be, for example, a trihalomethylphenyl. The trihalomethylphenyl may be, for example, a trifluoromethylphenyl.

[0036] When R2 is a substituted phenyl, the substituted phenyl can be a haloalkylphenyl, an alkyl benzoate, or an alkoxyphenyl. In a haloalkylphenyl, the halogen can be one or more of, for example, iodine, chlorine, bromine, or fluorine. When there is more than one halogen atom, all halogen atoms can be the same. A haloalkylphenyl can be, for example, a halomethylphenyl. A halomethylphenyl can be, for example, a trihalomethylphenyl. A trihalomethylphenyl can be, for example, a trifluoromethylphenyl. An alkyl benzoate can be, for example, methyl benzoate, ethyl benzoate, or propyl benzoate. An alkyl benzoate can be, for example, methyl benzoate. An alkoxyphenyl can be, for example, methoxyphenyl, ethoxyphenyl, or propoxyphenyl. An alkoxyphenyl can be, for example, methoxyphenyl.

[0037] The term "cycloalkyl," as used herein, refers to a group derived from a monocyclic saturated hydrocarbon by the removal of a hydrogen atom. A cycloalkyl group may contain, for example, 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, or 3 to 4 carbon atoms. A cycloalkyl group may be, for example, cyclopropyl, cyclobutyl, or cyclopentyl. A cycloalkyl group may be, for example, cyclopropyl.

[0038] The term "substituted cycloalkyl," as used herein, refers to a group derived from a monocyclic saturated hydrocarbon by the removal of a hydrogen atom, wherein one or more of the remaining hydrogen atoms on the monocyclic saturated hydrocarbon are substituted by a functional group. A substituted cycloalkyl can contain, for example, one, two, three, four, or five functional groups. A substituted cycloalkyl can contain, for example, one or two functional groups. A substituted cycloalkyl can contain, for example, only one functional group. The substitution can be located, for example, at the meta, ortho, or para position of the phenyl ring. Each functional group can be independently selected from, for example, alkyl groups, haloalkyl groups, ester groups, alkoxy groups, halogen groups, alkylsulfone groups, haloalkoxy groups, or amino groups, as described above.

[0039] As used herein, the term “heterocyclyl” refers to a group derived from a saturated or unsaturated cyclic structure having atoms of at least two different elements as ring components by the removal of a hydrogen atom. A heterocyclyl may, for example, be a heteroaryl. A heterocyclyl may, for example, have one or more carbon atoms and one or more atoms selected from nitrogen, oxygen, and sulfur as ring components. A heterocyclyl may, for example, be an isoxazole, furan, pyrimidine, or thiophene. For example, a heterocyclyl may be furan or thiophene.

[0040] As used herein, the term “substituted heterocyclyl” refers to a group derived from a saturated or unsaturated cyclic structure having atoms of at least two different elements as ring components, wherein one or more of the remaining hydrogen atoms on the heterocyclyl are substituted by a functional group. A substituted heterocyclyl can be, for example, a substituted heteroaryl. A substituted heterocyclyl can contain, for example, one, two, three, four, or five functional groups. A substituted heterocyclyl can contain, for example, one or two functional groups. A substituted heterocyclyl can contain, for example, only one functional group. Each functional group can be, for example, an alkyl group (e.g., methyl) or an alkoxy group (e.g., methoxy). The substitution can occur, for example, on a carbon atom. A heterocyclyl can contain, for example, an oxazole ring, an isoxazole ring, a furan ring, a pyrimidine ring, or a thiophene ring. A substituted heterocyclyl can be, for example, a substituted furan ring or a substituted thiophene ring. Each functional group can be independently selected from, for example, alkyl groups, haloalkyl groups, ester groups, alkoxy groups, halogen groups, sulfonyl groups (e.g., alkylsulfonyl) groups, haloalkoxy groups, or amine groups.

[0041] The term "alkenyl," as used herein, refers to a group derived from an unsaturated linear or branched hydrocarbon. An alkenyl group may contain, for example, one, two, or three carbon-carbon double bonds. For example, an alkenyl group may contain one carbon-carbon double bond. An alkenyl may contain, for example, two to eight carbon atoms, two to four carbon atoms, or two to three carbon atoms. An alkenyl may, for example, be an ethenyl.

[0042] R1 can be selected from, for example, phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, cycloalkyl, and substituted cycloalkyl. For example, R1 can be selected from phenyl, halophenyl, halomethylphenyl, alkoxyphenyl, alkylphenylsulfone, cycloalkyl, and substituted cycloalkyl. For example, R1 can be selected from phenyl, fluorophenyl, trifluoromethylphenyl, methoxyphenyl, methylphenylsulfone, cycloalkyl, and substituted cycloalkyl. The alkyl group of haloalkylphenyl can contain, for example, 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms. The cycloalkyl or cycloalkyl portion of substituted cycloalkyl can contain, for example, 3 to 6 carbon atoms or 3 to 4 carbon atoms. The cycloalkyl or substituted cycloalkyl can be, for example, cyclopropyl or substituted cyclopropyl.

[0043] R1 can be selected from, for example, phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. For example, R1 can be selected from phenyl, halophenyl, halomethylphenyl, alkoxyphenyl, alkylphenylsulfone, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. For example, R1 can be selected from phenyl, fluorophenyl, trifluoromethylphenyl, methoxyphenyl, methylphenylsulfone, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. The alkyl group of haloalkylphenyl can contain, for example, 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms. The cycloalkyl or cycloalkyl portion of substituted cycloalkyl can contain, for example, 3 to 6 carbon atoms or 3 to 4 carbon atoms. The cycloalkyl or substituted cycloalkyl can be, for example, cyclopropyl or substituted cyclopropyl. The heterocyclyl or heterocyclyl moiety of a substituted heterocyclyl may, for example, contain 3 to 6 carbon atoms and 1 or 2 heteroatoms (e.g., oxygen or sulfur). For example, the heterocyclyl or heterocyclyl moiety of a substituted heterocyclyl may contain 4 or 5 carbon atoms and 1 heteroatom (e.g., oxygen or sulfur). The heterocyclyl or substituted heterocyclyl may, for example, be furan, thiophene, substituted furan, or substituted thiophene.

[0044] R1 can be selected from, for example, phenyl, substituted phenyl, and cycloalkyl. R1 can be selected from, for example, phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, and cycloalkyl. For example, R1 can be selected from phenyl, halophenyl, halomethylphenyl, alkoxyphenyl, alkylphenylsulfone, and cycloalkyl. For example, R1 can be selected from phenyl, fluorophenyl, trifluoromethylphenyl, methoxyphenyl, methylphenylsulfone, and cycloalkyl. The alkyl group of a haloalkylphenyl can contain, for example, 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms. The cycloalkyl can contain, for example, 3 to 6 carbon atoms or 3 to 4 carbon atoms. The cycloalkyl can be, for example, cyclopropyl.

[0045] R1 can be selected from, for example, phenyl, substituted phenyl, and cycloalkyl. R1 can be selected from, for example, phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, cycloalkyl, and heterocyclyl. For example, R1 can be selected from phenyl, halophenyl, halomethylphenyl, alkoxyphenyl, alkylphenylsulfone, cycloalkyl, and heterocyclyl. For example, R1 can be selected from phenyl, fluorophenyl, trifluoromethylphenyl, methoxyphenyl, methylphenylsulfone, and cycloalkyl. The alkyl group of a haloalkylphenyl can contain, for example, 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms. A cycloalkyl can contain, for example, 3 to 6 carbon atoms or 3 to 4 carbon atoms. A cycloalkyl can be, for example, cyclopropyl. A heterocyclyl can contain, for example, 3 to 6 carbon atoms and 1 or 2 heteroatoms (e.g., oxygen or sulfur). A heterocyclyl can contain, for example, 4 or 5 carbon atoms and 1 heteroatom (e.g., oxygen or sulfur). The heterocyclyl can be, for example, furan or thiophene.

[0046] R1 can be, for example, phenyl, substituted phenyl, cycloalkyl, or heterocyclyl. R1 can be, for example, phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, cycloalkyl, or heterocyclyl. R1 can be, for example, phenyl or substituted phenyl, for example, phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, or alkylphenylsulfone. For example, R1 can be phenyl or cycloalkyl. For example, R1 can be substituted phenyl or cycloalkyl, for example, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, or cycloalkyl. For example, R1 can be phenyl. For example, R1 can be substituted phenyl. For example, R1 can be cycloalkyl. For example, R1 can be substituted cycloalkyl. For example, R1 can be heterocyclyl. For example, R1 can be substituted heterocyclyl. The alkyl group of haloalkylphenyl can contain, for example, 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms. The cycloalkyl or cycloalkyl moiety of a substituted cycloalkyl can contain, for example, 3 to 6 carbon atoms or 3 to 4 carbon atoms. The cycloalkyl or substituted cycloalkyl can be, for example, cyclopropyl or substituted cycloalkyl. The heterocyclyl or heterocyclyl moiety of a substituted heterocyclyl can contain, for example, 3 to 6 carbon atoms and 1 or 2 heteroatoms (e.g., oxygen or sulfur). For example, the heterocyclyl or heterocyclyl moiety of a substituted heterocyclyl can contain, for example, 4 or 5 carbon atoms and 1 heteroatom (e.g., oxygen or sulfur). The heterocyclyl or substituted heterocyclyl can be, for example, furan, thiophene, substituted furan, or substituted thiophene.

[0047] R2 can be selected from, for example, phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, substituted cycloalkyl, and alkenyl. For example, R2 can be selected from phenyl, halomethylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, substituted cycloalkyl, and alkenyl. For example, R2 can be selected from phenyl, trifluoromethylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, substituted cycloalkyl, and alkenyl. The alkyl groups of haloalkylphenyl, alkyl benzoate, and alkoxyphenyl can each contain, for example, 1 to 4 carbon atoms, e.g., 1 or 2 carbon atoms. The cycloalkyl can each contain, for example, 3 to 6 carbon atoms or 3 to 4 carbon atoms. The cycloalkyl can be, for example, cyclopropyl. The alkenyl can contain, for example, 2 to 4 carbon atoms and 1 double bond, e.g., 2 to 3 carbon atoms and 1 double bond. The alkenyl can be, for example, ethenyl. R2 can be selected from, for example, phenyl, substituted phenyl, cycloalkyl, and alkenyl. R2 can be selected from, for example, phenyl, substituted phenyl, cyclopropyl, and alkenyl. For example, R2 can be selected from phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cyclopropyl, and alkenyl. For example, R2 can be selected from phenyl, halomethylphenyl, alkyl benzoate, alkoxyphenyl, cyclopropyl, and alkenyl. For example, R2 can be selected from phenyl, trifluoromethylphenyl, alkyl benzoate, alkoxyphenyl, cyclopropyl, and alkenyl. The alkyl groups of haloalkylphenyl, alkyl benzoate, and alkoxyphenyl can each contain, for example, 1 to 4 carbon atoms, e.g., 1 or 2 carbon atoms. The cycloalkyl group can contain, for example, 3 to 6 carbon atoms or 3 to 4 carbon atoms. The cycloalkyl group can be, for example, cyclopropyl. The alkenyl group can contain, for example, 2 to 4 carbon atoms and 1 double bond, e.g., 2 to 3 carbon atoms and 1 double bond. An alkenil can be, for example, an etenyl.

[0048] R2 can be selected from, for example, phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, and ethenyl. For example, R2 can be selected from phenyl, substituted phenyl, cycloalkyl, and ethenyl. For example, R2 can be selected from phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, and ethenyl. For example, R2 can be selected from phenyl, halomethylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, and ethenyl. For example, R2 can be selected from phenyl, trifluoromethylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, and ethenyl. The alkyl groups of haloalkylphenyl, alkyl benzoate, and alkoxyphenyl can each contain, for example, 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms. The cycloalkyl can contain, for example, 3 to 6 carbon atoms or 3 to 4 carbon atoms. The cycloalkyl can be, for example, cyclopropyl.

[0049] R2 can be selected from, for example, phenyl, substituted phenyl, cyclopropyl, and ethenyl. R2 can be selected from, for example, phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, and ethenyl. R2 can be selected from, for example, phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cyclopropyl, and ethenyl. The alkyl groups of haloalkylphenyl, alkyl benzoate, and alkoxyphenyl can each contain, for example, 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms. The cycloalkyl can contain, for example, 3 to 6 carbon atoms or 3 to 4 carbon atoms. The cycloalkyl can be, for example, cyclopropyl.

[0050] In certain embodiments, R1 is phenyl, substituted phenyl, or cycloalkyl, and R2 is phenyl, substituted phenyl, cycloalkyl, or alkenyl. In certain embodiments, R1 is phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, or cycloalkyl, and R2 is phenyl, substituted phenyl, cycloalkyl, or alkenyl. In certain embodiments, R1 is phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, or cycloalkyl, and R2 is phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, or alkenyl. In certain embodiments, R1 is phenyl, haloalkylphenyl, or cycloalkyl, and R2 is phenyl, substituted phenyl, cycloalkyl, or alkenyl. In certain embodiments, R1 is phenyl, haloalkylphenyl, or cycloalkyl, and R2 is phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, or alkenyl. In certain embodiments, R1 is phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenyl sulfone, or cycloalkyl, and R2 is phenyl, substituted phenyl, cycloalkyl, or alkenyl, and when R1 is haloalkylphenyl, alkoxyphenyl, or alkylphenyl sulfone, the alkyl group contains 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms.

[0051] In certain embodiments, R1 is phenyl, substituted phenyl, cycloalkyl, or heterocyclyl, and R2 is phenyl, substituted phenyl, cycloalkyl, or alkenyl. In certain embodiments, R1 is phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, cycloalkyl, or heterocyclyl, and R2 is phenyl, substituted phenyl, cycloalkyl, or alkenyl. In certain embodiments, R1 is phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, cycloalkyl, or heterocyclyl, and R2 is phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, or alkenyl. In certain embodiments, R1 is phenyl, haloalkylphenyl, cycloalkyl, or heterocyclyl, and R2 is phenyl, substituted phenyl, cycloalkyl, or alkenyl. In certain embodiments, R1 is phenyl, haloalkylphenyl, cycloalkyl, or heterocyclyl, and R2 is phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, or alkenyl. In certain embodiments, R1 is phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, cycloalkyl, or heterocyclyl, and R2 is phenyl, substituted phenyl, cycloalkyl, or alkenyl, and when R1 is haloalkylphenyl, alkoxyphenyl, or alkylphenylsulfone, the alkyl group contains 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms. In certain embodiments, R1 is phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, cycloalkyl, or heterocyclyl, and R2 is phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, or alkenyl, and when R1 and / or R2 are haloalkylphenyl, alkyl benzoate, alkoxyphenyl, or alkylphenylsulfone, the alkyl group contains 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms.

[0052] In certain embodiments, R1 is phenyl, substituted phenyl, or cycloalkyl, and R2 is phenyl, substituted phenyl, cycloalkyl, or alkenyl, and when R1 and / or R2 are cycloalkyl, the cycloalkyl contains 3 to 6 carbon atoms, for example 3 or 4 carbon atoms, for example 3 carbon atoms. In certain embodiments, R1 is phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, or cycloalkyl, and R2 is phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, or alkenyl, and when R1 and / or R2 are cycloalkyl, the cycloalkyl contains 3 to 6 carbon atoms, for example 3 or 4 carbon atoms. In certain embodiments, R1 is phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenyl sulfone, or cycloalkyl, and R2 is phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, or alkenyl, and when R1 and / or R2 are cycloalkyl, the cycloalkyl contains 3 to 6 carbon atoms, for example, 3 or 4 carbon atoms, and when R1 and / or R2 are haloalkylphenyl, alkyl benzoate, alkoxyphenyl, or alkylphenyl sulfone, the alkyl contains 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms. In certain embodiments, R1 is phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, or cycloalkyl, and R2 is phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, or alkenyl, and when R1 and / or R2 are cycloalkyl, the cycloalkyl contains 3 to 6 carbon atoms, for example 3 or 4 carbon atoms, and when R2 is alkenyl, the alkenyl contains 1 double bond and 2 to 6 carbon atoms, for example 2 or 3 carbon atoms.In certain embodiments, R1 is phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenyl sulfone, or cycloalkyl, and R2 is phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, or alkenyl, and when R1 and / or R2 are cycloalkyl, the cycloalkyl contains 3 to 6 carbon atoms, for example 3 or 4 carbon atoms, and when R2 is alkenyl, the alkenyl contains 1 double bond and 2 to 6 carbon atoms, for example 2 or 3 carbon atoms, and when R1 and / or R2 are haloalkylphenyl, alkylbenzoate, alkoxyphenyl, or alkylphenyl sulfone, the haloalkyl or alkyl contains 1 to 4 carbon atoms, for example 1 or 2 carbon atoms.

[0053] In certain embodiments, R1 is phenyl, substituted phenyl, cycloalkyl, or heterocyclyl, and R2 is phenyl, substituted phenyl, cycloalkyl, or alkenyl, and when R1 and / or R2 are cycloalkyl, the cycloalkyl comprises 3 to 6 carbon atoms, e.g., 3 or 4 carbon atoms, e.g., 3 carbon atoms, and / or when R1 is heterocyclyl, the heterocyclyl comprises 3 to 6 carbon atoms and 1 or 2 heteroatoms (e.g., oxygen or sulfur), e.g., 4 or 5 carbon atoms and 1 heteroatom (e.g., oxygen or sulfur), e.g., the heterocyclyl is furan or thiophene. In certain embodiments, R1 is phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, cycloalkyl, or heterocyclyl, and R2 is phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, or alkenyl, and when R1 and / or R2 are cycloalkyl, the cycloalkyl comprises 3 to 6 carbon atoms, for example 3 or 4 carbon atoms, and / or when R1 is heterocyclyl, the heterocyclyl comprises 3 to 6 carbon atoms and 1 or 2 heteroatoms (e.g., oxygen or sulfur), for example 4 or 5 carbon atoms and 1 heteroatom (e.g., oxygen or sulfur), for example, the heterocyclyl is furan or thiophene.

[0054] In certain embodiments, R1 is phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, cycloalkyl, or heterocyclyl, and R2 is phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, or alkenyl, and when R1 and / or R2 are cycloalkyl, the cycloalkyl contains 3 to 6 carbon atoms, for example 3 or 4 carbon atoms, and when R1 and / or R2 are haloalkylphenyl, alkyl benzoate, alkoxyphenyl, or alkylphenylsulfone, the alkyl contains 1 to 4 carbon atoms, for example 1 or 2 carbon atoms, and / or when R1 is heterocyclyl, the heterocyclyl contains 3 to 6 carbon atoms and 1 or 2 heteroatoms (e.g., oxygen or sulfur), for example 4 or 5 carbon atoms and 1 heteroatom (e.g., oxygen or sulfur), and for example, the heterocyclyl is furan or thiophene.

[0055] In certain embodiments, R1 is phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, cycloalkyl, or heterocyclyl, and R2 is phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl, or alkenyl, and when R1 and / or R2 are cycloalkyl, the cycloalkyl contains 3 to 6 carbon atoms, for example 3 or 4 carbon atoms, and / or when R2 is alkenyl, the alkenyl contains one double bond and 2 to 6 carbon atoms, for example 2 or 3 carbon atoms, and / or when R1 is heterocyclyl, the heterocyclyl contains 3 to 6 carbon atoms and 1 or 2 heteroatoms (e.g., oxygen or sulfur), for example 4 or 5 carbon atoms and 1 heteroatom (e.g., oxygen or sulfur), and for example, the heterocyclyl is furan or thiophene. In certain embodiments, R1 is phenyl, halophenyl, haloalkylphenyl, alkoxyphenyl, alkylphenylsulfone, cycloalkyl or heterocyclyl, and R2 is phenyl, haloalkylphenyl, alkyl benzoate, alkoxyphenyl, cycloalkyl or alkenyl, and when R1 and / or R2 are cycloalkyl, the cycloalkyl contains 3 to 6 carbon atoms, for example 3 or 4 carbon atoms, and when R2 is alkenyl, the alkenyl contains 1 double bond and 2 to 6 carbon atoms, for example 2 or When a compound contains three carbon atoms and R1 and / or R2 is a haloalkylphenyl, alkyl benzoate, alkoxyphenyl, or alkylphenyl sulfone, the haloalkyl or alkyl group contains 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms, and / or when R1 is a heterocyclyl, the heterocyclyl contains 3 to 6 carbon atoms and 1 or 2 heteroatoms (e.g., oxygen or sulfur), for example, 4 or 5 carbon atoms and 1 heteroatom (e.g., oxygen or sulfur), for example, the heterocyclyl is furan or thiophene.

[0056] In certain embodiments, R1 is phenyl, fluorophenyl, trifluoromethylphenyl, methoxyphenyl, methylphenyl sulfone, or cyclopropyl, and R2 is phenyl, trifluoromethylphenyl, methyl benzoate, methoxyphenyl, cyclopropyl, or ethenyl. In certain embodiments, R1 is phenyl, fluorophenyl, trifluoromethylphenyl, methoxyphenyl, or methylphenyl sulfone, and R2 is phenyl, trifluoromethylphenyl, methyl benzoate, methoxyphenyl, or ethenyl. In certain embodiments, R1 is phenyl or trifluoromethylphenyl, and R2 is phenyl, trifluoromethylphenyl, methyl benzoate, methoxyphenyl, or ethenyl.

[0057] In certain embodiments, R1 is phenyl, fluorophenyl, trifluoromethylphenyl, methoxyphenyl, methylphenylsulfone, cyclopropyl, furan, or thiophene, and R2 is phenyl, trifluoromethylphenyl, methyl benzoate, methoxyphenyl, cyclopropyl, or ethenyl. In certain embodiments, R1 is phenyl, fluorophenyl, trifluoromethylphenyl, methoxyphenyl, methylphenylsulfone, furan, or thiophene, and R2 is phenyl, trifluoromethylphenyl, methyl benzoate, methoxyphenyl, or ethenyl. In certain embodiments, R1 is phenyl, trifluoromethylphenyl, furan, or thiophene, and R2 is phenyl, trifluoromethylphenyl, methyl benzoate, methoxyphenyl, or ethenyl.

[0058] The carbon-carbon double bond between the sulfone group and the disulfide group of the compound of formula (I) can have either E or Z stereochemistry. Therefore, formula (I) encompasses both E and Z stereoisomers.

[0059] In certain embodiments, the method for producing the compound of formula (I) is stereospecific such that one stereoisomer is preferentially formed over the other, for example, so that only one stereoisomer is formed. In certain embodiments, the E and / or Z stereoisomers can be separated from a mixture of the E and Z isomers. Thus, in certain embodiments, the compound of formula (I) has the E configuration. In alternative embodiments, the compound of formula (I) has the Z configuration.

[0060] In certain embodiments, a method for producing a compound of formula (I) produces a mixture of stereoisomers, for example, approximately equal amounts of E and Z stereoisomers (e.g., E:Z in ratios of about 10:90 to about 90:10, or about 30:70 to about 70:30, or about 40:60 to about 60:40, or about 45:55 to about 55:45, or about 50:50). Thus, the pharmaceutical compositions described herein may, for example, include a mixture of E and Z stereoisomers of formula (I).

[0061] In certain embodiments, the compound of formula (I) is one of the following compounds. These compounds may have an E configuration or a Z configuration. Compositions and pharmaceutical compositions comprising one of the following compounds may, for example, include mixtures of the E and Z stereoisomers of that compound.

[0062] [ka] 1-Methoxy-4-{[3-(prop-2-ene-1-yldisulfanyl)prop-2-ene-1-sulfonyl]methylbenzene NMR: δ H(400 MHz,CDCl3) 7.32-7.27 (2H, m), 6.93-6.88 (2H, m), Z-isomer: 6.56 (0.77H, dt, J = 9.5, 1.1 Hz), E-isomer: 6.33 (0.23H, br t, J = 14.8 Hz), 5.93-5.74 (1.23H, m), Z-isomer: 5.69 (0.77H, dt, J = 9.5, 7.7 Hz), 5.21-5.12 (2H, m), 4.13 (2H, s), E-isomer: 3.80 (s) Overlapping Z-isomer: 3.80 (s) (total 3H), Z-isomer: 3.72 (1.54H, br d, J = 8.2), E-isomer: 3.59 (0.46H, d, J = 7.6 Hz)

[0063] [ka] 1-Methanesulfonyl-4-{[3-(prop-2-ene-1-yldisulfanyl)prop-2-ene-1-sulfonyl]methylbenzene NMR: δH (400 MHz, CDCl3) 7.99-7.94 (2H, m), 7.63-7.58 (2H, m), Z-isomer: 6.62 (0.66H, unseparated triplet doublet, J = 9.5 Hz), E-isomer: 6.41 (0.34H, br d, J = 14.8 Hz), E-isomer: 5.90 (0.34H, dt, J = 14.8 Hz) 5.87-5.75 (1H, m) Overlapping Z-isomer: 5.73 (0.66H, dt, J = 9.5, 7.8 Hz), 5.21-5.13 (2H, m), 4.26 (2H, s), Z-isomer: 3.84 (1.32H, br d, J = 8.4 Hz), E-isomer: 3.72 (0.68H, br d, J = 7.9 Hz), Z-isomer: 3.38 (1.32H, br d, J = 7.4 Hz) Overlapping E-isomer: 3.35 (0.68H, br d, J = 7.4 Hz), E-isomer: 3.06 (s) Overlapping Z-isomer: 3.05 (s) (Total 3H)

[0064] [ka] 1-Fluoro-4-{[3-(prop-2-ene-1-yldisulfanyl)prop-2-ene-1-sulfonyl]methylbenzene NMR: δH (400 MHz,CDCl3) 7.40-7.33 (2H, m), 7.13-7.04 (2H, m), Z-isomer: 6.58 (0.71H, dt, J = 9.5, 1.1 Hz), E-isomer: 6.35 (0.29H, doublet of non-separated triplets, J = 14.8 Hz), E-isomer: 5.89 (dt, J = 14.8, 7.6 Hz) overlapping 5.86-7.74 (m) total (1.29H), Z-isomer: 5.70 (0.71H, dt, J = 9.5, 7.7 Hz), 5.21-5.12 (2H, m), 4.15 (2H, s), Z-isomer: 3.76 (1.42H, br d, J = 7.7 Hz), E-isomer: 3.62 (0.58H, br d, J = 7.6 Hz), 3.38-3.33 (2H, m)

[0065] [ka] {[(3-phenylmethanesulfonylprop-1-en-1-yl)disulfanyl]methylbenzene NMR: δ H (400 MHz, CDCl3) 7.42-7.21 (10H, m) Overlapping residual CHCl3 signal, Z-isomer: 6.21 (0.68H, dt, J = 9.5, 1.1 Hz), E-isomer: 6.12 (0.32H, unseparated triplet doublet, J = 14.8 Hz), E-isomer: 5.78 (0.32H, dt, J = 14.9, 7.6 Hz), Z-isomer: 5.55 (0.68H, dt, J = 9.5, 7.7 Hz), Z-isomer: 4.14 (1.36H, s), E-isomer: 4.13 (0.64H, s), Z-isomer: 3.92 (1.36H, s), E-isomer: 3.91 (0.64H, s), Z-isomer: 3.67 (1.36H, d, J = 7.8 Hz), E-isomer: 3.49 (0.64H, d, J = 7.6Hz)

[0066] [ka] 1-Methoxy-3-{[(3-phenylmethanesulfonylprop-1-en-1-yl)disulfanyl]methylbenzene NMR: δH (400 MHz, CDCl3) 7.42-7.33 (5H, m), 7.28-7.15 (2H, m), 6.89-6.83 (2H, m), Z-isomer: 6.26 (0.7H, unseparated triplet doublet, J = 9.5 Hz), E-isomer: 6.15 (0.3H, unseparated triplet doublet, J = 14.8 Hz), E-isomer: 5.82 (0.3H, dt, J = 14.8, 7.6 Hz), Z-isomer: 5.56 (0.7H, dt, J = 9.54, 7.70 Hz), Z-isomer: 4.15 (1.4H, s), E-isomer: 4.12 (0.6H, s), Z-isomer: 3.97 (1.4H, s), E-isomer: 3.95 (0.6H, s), E-isomer: 3.86 (0.9H, s), Z-isomer: 3.83 (2.1H, s), Z-isomer: 3.69 (1.4H, d, J = 8.2 Hz), E-isomer: 3.49 (0.6H, d, J = 7.6 Hz)

[0067] [ka] 1-Methoxy-3-({[-3-{[4-(trifluoromethyl)phenyl]methanesulfonyl}prop-1-en-1-yl]disulfanyl}methyl)benzene NMR: 1H-nmr ​​(600Hz, CDCl3): 3.77 (d, J.= 7.8 Hz, 2H, CH2-CH=), 3.81 (s, 3H, OCH3), 3.95 (s, 2H, CH2-SS), 4.22(s, 2H, CH2SO2), 5.60 - 5.65 (m, 1H, CH2-CH=), 6.31 (d, J.= 9.6 Hz, 2H, =CH-SS), 6.85 (d, J = 7.2 Hz, 1H, CH-Ar), 6.91 (d, J = 7.2 Hz, 1H, CH-Ar), 7.25 (t, J = 7.8 Hz, 2H, CH-Ar), 7.54 (d, J = 7.8 Hz, 2H, CH-Ar), 7.69 (d, J = 7.8 Hz, 2H, CH-Ar)

[0068] [ka] 1-Methoxy-2-{[(3-phenylmethanesulfonylprop-1-en-1-yl)disulfanyl]methylbenzene NMR: δH (400 MHz, CDCl3) 7.42-7.33 (5H, m), 7.28-7.15 (2H, m), 6.89-6.83 (2H, m), Z-isomer: 6.26 (0.7H, unseparated triplet doublet, J = 9.5 Hz), E-isomer: 6.15 (0.3H, unseparated triplet doublet, J = 14.8 Hz), E-isomer: 5.82 (0.3H, dt, J = 14.8, 7.6 Hz), Z-isomer: 5.56 (0.7H, dt, J = 9.54, 7.70 Hz), Z-isomer: 4.15 (1.4H, s), E-isomer: 4.12 (0.6H, s), Z-isomer: 3.97 (1.4H, s), E-isomer: 3.95 (0.6H, s), E-isomer: 3.86 (0.9H, s), Z-isomer: 3.83 (2.1H, s), Z-isomer: 3.69 (1.4H, d, J = 8.2 Hz), E-isomer: 3.49 (0.6H, d, J = 7.6 Hz)

[0069] [ka] 1-Methoxy-4-{[(3-phenylmethanesulfonylprop-1-en-1-yl)disulfanyl]methylbenzene NMR: δH (400 MHz,CDCl3) 7.41-7.33 (5H, m), 7.24-7.16 (2H, m), 6.85-6.79 (2H, m), Z-isomer: 6.25 (0.6H, dt, J= 9.5, 1.1 Hz), E-isomer: (0.4H, doublet of non-separable triplets, J = 14.9Hz), E-isomer: 5.79 (0.4H, dt, J = 14.8, 7.7 Hz), Z-isomer: 5.58 (0.6H, dt, J = 9.5, 7.7 Hz), Z-isomer: 4.15 (1.2H, s),E-isomer: 4.13 (0.8H, s), Z-isomer: 3.89 (1.2H, s), E-isomer: 3.87 (0.8H, s), Z-isomer: 3.77 (1.8H, s), E-isomer: 3.74 (1.2H, s), Z-isomer 3.69 (1.2H, d, J = 8.2 Hz), E-isomer: 3.51 (0.8H, d, J = 7.6 Hz)

[0070] [ka] {[3-(prop-2-en-1-yldisulfanyl)prop-2-en-1-sulfonyl]methylbenzene NMR: δH (400 MHz,CDCl3) 7.40-7.38 (5H, m), Z-isomer: 6.57 (0.72H, dt, J = 9.5, 1.1 Hz), E-isomer: 6.34 (0.28H doublet of non-separable triplets, J = 14.9 Hz), E-isomer: 5.88 (0.28H, dt, J = 14.8, 7.7Hz) overlapping 5.85-5.74 (1H, m), Z-isomer: 5.70 (0.72H, dt, J = 9.5, 7.7Hz), 5.22-5.12 (2H, m), 4.19 (2H, s), E-isomer: 3.74 (1.54H, dd, J = 7.7, 0.5Hz), Z-isomer: 3.60 (0.54H, d, 7.6 Hz), 3.38-3.33 (2H, m)

[0071] [ka] 1-Methoxy-4-({[-3-{[4-(trifluoromethyl)phenyl]methanesulfonyl}prop-1-en-1-yl]disulfanyl}methyl)benzene NMR: 1 H-nmr ​​(600Hz, CDCl3): 3.59 (d, J.= 7.8 Hz, 2H, CH2-SO2), 3.78 (s, 3H, OCH3), 3.92 (s, 2H, CH2-SS), 4.20 (s, 2H, CH2-C-Ar), 5.78-5.88 (m, 1H, CH=), 6.21 (d, J = 15 Hz, 1H, CH-SS), 6.87 (d, J= 8.4 Hz, 2H, CH-Ar), 7.26 (d, J = 8.4 Hz, 2H, CH-Ar), 7.53 (d, J = 7.8 Hz, 2H, CH-Ar), 7.70 (d, J = 7.8Hz, 2H, CH-Ar)

[0072] [ka] Methyl-4-({[-3-{[4-(trifluoromethyl)phenyl]methanesulfonyl}prop-1-en-1-yl]disulfanyl}methyl)benzoate NMR: δ H (400 MHz,CDCl3) 7.97 (2H, AA'BB'), 7.68-7.61 (2H, m), 7.52-7.45 (2H, m), 7.39-7.32 (2H, m), 6.14 (0.16H, dt, J = 14.9, 1.1 Hz), 5.77 (0.16H, dt, J = 14.9, 7.7 Hz), 4.15 (0.32H, s), 3.93 (0.32H, s), 3.86 (0.48H, s), 3.53 (0.32H, d, J = 7.5 Hz)

[0073] [ka] 1-{[-3-(prop-2-ene-1-yldisulfanyl)prop-2-ene-1-sulfonyl]methyl}4-(trifluoromethyl)benzene NMR: 1 H-nmr ​​(600Hz, CDCl3): 3.39 (d, J.= 7.2 Hz, 2H, CH2-SS), 3.70 (d, J.= 7.8 Hz, 2H, CH2-CH=), 4.28 (s, 2H, CH2), 5.22 (dd, J.= 9, 15 Hz, 2H, CH2=), 5.86 - 5.96 (m, 2H, -CH=), 6.42 (d, J = 15 Hz, 1H, =CHS-S), 7.57 (d, J = 7.8 Hz, 2H, CH-Ar), 7.71 (d, J = 7.8 Hz, 2H, CH-Ar)

[0074] [ka] 1-Methoxy-2-{[(3-{[4-(trifluoromethyl)phenyl]methanesulfonyl}prop-1-en-1-yl)disulfanyl]methyl}benzene NMR: δH (400 MHz,CDCl3) 7.64 (2H, d, J = 8.1 Hz), 7.52-7.46 (2H, m), 7.29-7.15 (2H, m) overlapping CHCl3 signal, 6.89-6.83 (2H, m), Z-isomer: 6.27 (0.58H, dt, J = 8.4, 1.1 Hz), E-isomer: 6.17 (0.42H, dt, J = 14.8, 1.1 Hz), E-isomer: 5.82 (0.42H, dt, J =14.8, 7.6 Hz), Z-isomer: 5.57 (0.58H, dt, J = 9.5, 7.8 Hz), Z-isomer: 4.18 (1.16H, s), E-isomer: 4.14 (0.84H, s), Z-isomer: 3.98 (1.16H, s), E-isomer: 3.96 (0.84H, s), E-isomer: 3.86 (1.26H, s), Z-isomer: 3.83 (1.74H, s), Z-isomer: 3.74 (1.16H, dd, J = 7.8, 0.7 Hz), E-isomer: 3.53 (0.84H, d, J = 7.5 Hz)

[0075] [ka] 1-(trifluoromethyl)-4-{[(3-{[4-(trifluoromethyl)phenyl]methanesulfonyl}prop-1-en-1-yl)disulfanyl]methyl}benzene NMR: δH (400 MHz,CDCl3) 7.68-7.62 (2H, m), 7.56 (2H, d, J = 8.0 Hz), 7.49 (2H, d, J = 8.1 Hz), 7.43-7.37 (2H, m), Z-isomer: 6.25 (0.72H, d, J = 9.5 Hz), E-isomer: 6.13 (0.28H, d, J = 14.9 Hz),E-isomer: 5.75 (0.28H, dt, J = 14.9, 7.5 Hz), Z-isomer: 5.58 (0.72H, dt, J = 9.5, 7.8 Hz), 4.19 (2H, s), Z-isomer: 3.96 (1.44H, s), Z-isomer: 3.92 (0.56H, s), Z-isomer: 3.70 (1.44H, d, J = 7.9 Hz), E-isomer: 3.52 (0.56H, d, J = 7.7 Hz)

[0076] [ka] {[3-(prop-2-en-1-yldisulfanyl)prop-2-en-1-sulfonyl]methyl}cyclopropane NMR: δH (400 MHz,CDCl3) Z-isomer: 6.56 (0.58H, dt, J = 9.5, 1.2 Hz), E-isomer: 6.40 (0.42H, dt, J = 14.8, 1.0 Hz), E-isomer: 5.92 (0.42H, dt, J = 14.9, 7.6 Hz), 5.87-5.75 (1H, m) Overlapping Z-isomer: 5.72 (0.58H, dt, J = 9.5, 7.8 Hz), 5.21-5.13 (2H, m), Z-isomer: 3.88 (1.16H, d, J = 7.8 Hz), E-isomer: 3.79 (0.84H, d, J = 7.6 Hz), Z-isomer: 3.37 (1.16H, d, J = 7.3), overlapping E-isomer: 3.34 (0.84H, d, J = 7.4 Hz), Z-isomer: 2.87 (1.16H, d, J = 7.2 Hz) overlapping E-isomer: 2.87 (0.84H, d, J = 7.2 Hz), 1.23-1.10 (1H, m), 0.79-0.72 (2H, m), 0.43-0.35 (2H, m)

[0077] [ka] {[(3-cyclopropylmethanesulfonylprop-1-en-1-yl)disulfanyl]methyl}cyclopropane NMR: δH (400 MHz,CDCl3) Z-isomer: 6.65 (0.62H, dt, J = 9.5, 1.1 Hz), E-isomer: 6.47 (0.38H, dt, J = 14.8, 1.1 Hz), E-isomer: 5.96 (0.38H, dt, J = 14.8, 7.7 Hz), Z-isomer: 5.72 (0.62H, dt, J = 9.5, 7.8 Hz), Z-isomer: 3.88 (1.24H, d, J = 7.7 Hz), E-isomer: 3.80 (0.76H, d, J = 7.6 Hz), 2.90-2.84 (2H, overlapping doublet), Z-isomer: 2.70 (1.24H, d, J = 7.2 Hz), E-isomer: 2.67 (0.76H, d, J = 7.2 Hz), 1.23-1.00 (2H, m), 0.78-0.72 (2H, m), 0.64-0.57 (2H, m), 0.43-0.35 (2H, m), 0.30-0.24 (2H, m)

[0078] [ka] 2-{[3-(prop-2-ene-1-yldisulfanyl)prop-2-ene-1-sulfonyl]methyl}furan NMR: δ H (400 MHz, CDCl3): 7.41-7.42 (1H, m), 6.55 (0.64 H, dt, J = 9.5, 1.1 Hz), 6.48 (0.64 H, dd, J = 3.3, 0.7 Hz), 6.47 (0.34 Hz, dd, J = 3.4, 0.6 Hz), 6.36-6.40 (1.34 H, m), 5.64 (0.66 H, dt, J = 9.5, 7.7 Hz), 5.08-5.16 (2 H, m), 4.23 (d, 2H, J = 7.5 Hz), 3.79 (1.28 H, d, J = 7.8 Hz), 3.64 (0.68 H, d, J = 7.8 Hz), 3.32, 3.30 (4H, unseparated doublet pair)

[0079] [ka] 2-{[3-(prop-2-ene-1-yldisulfanyl)prop-2-ene-1-sulfonyl]methylthiophene NMR: δ H (400 MHz, CDCl3): 7.37 (1H, dd, J = 5.2, 1.2 Hz), 7.14-7.18 (1H m), 7.05 (1H, dt, J = 5.2, 3.6 Hz), 6.58 (0.56 H, dt, J = 9.5, 1.1 Hz), 6.39 (0.34 H, dt, J = 14.8, 0.5 Hz), 5.95-5.74 (1.34 H, m), 5.68 (0.56 H, dt, J = 9.5, 7.8 Hz), 5.19 (0.68 H, dq, J = 8.9, 1.3 Hz), 5.15 (1.32 H, dt, J = 8.7, 0.9 Hz), 4.40 (2H, d, J = 5.4 Hz), 3.80 (1H, d, J = 7.8 Hz), 3.36 (1.22 H, d, J = 7.3 Hz), 3.34 (0.68 H, d, J = 7.4 Hz)

[0080] In a particular embodiment, the compound of formula (I) is one of the following compounds having an E configuration (compound according to formula (IA)). [ka] [ka]

[0081] In certain embodiments, the compound of formula (I) is one of the following compounds having a Z configuration (compound according to formula (IB)). [ka]

[0082] In a particular embodiment, the compound of formula (I) is [ka] This compound may have an E configuration or a Z configuration. A composition or pharmaceutical composition containing this compound may, for example, include a mixture of the E and Z stereoisomers of this compound.

[0083] Pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier and / or excipient and / or diluent are further provided herein. In relation to the present invention, the terms “pharmaceutical composition” or “pharmaceutical” mean a composition comprising a compound of formula (I) (in a pharmaceutically effective amount), and one or more pharmaceutically acceptable carriers and / or excipients and / or diluents.

[0084] Depending on the mode of administration and the properties of the dosage form, the pharmaceutical composition may further contain components selected from, for example, adjuvants, vehicles, preservatives, fillers, binders, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, lubricants, coating agents, encapsulating agents, aerosolizing agents, and dispersants.

[0085] Pharmaceutical compositions can take the form of solid formulations, such as tablets, capsules, caplets, sugar-coated tablets, lozenges, granules, powders, pellets, beads, dressings, bandages, patches, surgical patches, catheters, pastes, and cachets; semi-solid formulations, such as gels, balms, creams, ointments, gums, foams, topical agents, adhesives, and lotions; liquid formulations, such as elixirs, syrups, suspensions, sprays, emulsions, lotions, soaps, shakes, collodions, paints, detergents, perfuming agents, and solutions; solutions; aqueous systems; suspension or dispersion systems; foam systems; and / or aerosol formulations utilizing liquefied gas propellants, compressed gases, dry powders, and sprays. The techniques and formulations are generally described in Remington, The Science and Practice of Pharmacy, Mack Publishing Co., Easton, PA, latest edition.

[0086] Pharmaceutical compositions (pharmaceuticals) may be suitable for, for example, oral, nasal, topical, suppository, intravenous, or intradermal administration. Alternatively, the composition may be a nutritional supplement composition, such as a food, food supplement, dietary supplement, health supplement, meal replacement product, beverage, beverage supplement, food additive, animal feed, or feed additive.

[0087] Compounds of formula (I) can be administered, for example, in combination with one or more other biologically active agents. Therefore, a pharmaceutical composition may contain one or more other biologically active agents. One or more biologically active agents may include, for example, debridement agents, soaps, antibiotics, such as penicillins (e.g., penicillin, amoxicillin), cephalosporins (e.g., cephalexin), macrolids (e.g., erythromycin, clarithromycin, azithromycin), fluoroquinolones (e.g., ciprofloxacin, levoflavin, ofloxacin), sulfonamides (e.g., cotrimoxazole, trimethoprim), tetracyclines (e.g., tetracycline, doxycycline), and amino acids. Glycosides (e.g., gentamicin, tobramycin), preservatives (e.g., tauroridine, potassium permanganate, boric acid), surfactants (e.g., octenidine dihydrochloride, octenidine dihydrochloride / phenoxyethanol), alcohols (e.g., ethanol, isopropyl alcohol, n-propanol), anilides (e.g., triclocarban), biguanides (e.g., chlorhexidine, polyhexazine, polyhexamethylene, polyhexanide), bisphenols (e.g., diphenyl ether-tri Closan (chlorinated phenol-hexachlorophene), chlorine compounds (e.g., sodium hypochlorite), halophenols (e.g., chloroxylenol), iodine compounds (e.g., Lugol's solution, iodine tincture, iodophores containing polyvinylpyrrolidone iodine, povidone iodine, cadexomer-iodine), silver compounds (e.g., silver sulfadiazine, silver nitrate, (silver released from solutions, creams, ointments, or nanocrystalline silver, regardless of the source)), peroxygen (e.g., hydrogen peroxide), and oxygen treatment (in the form of radical oxygen species). and gaseous O2 (e.g., high-pressure chambers, nitrox / natrox), anti-inflammatory agents (e.g., non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and naproxen), antithrombotic agents such as anticoagulants (e.g., heparin or warfarin), antiplatelet agents (e.g., aspirin) and thrombolytic agents (e.g., streptokinase), antimicrobial light sources in the ultraviolet, visible, violet, blue, green, yellow, red, and infrared regions (one or a combination thereof), wound healing devices and photodynamic therapy sources, for example,Deep tissue light therapy and low-level light / laser therapy can be selected from light sources such as lasers, wide-range or short-range polarized and unpolarized light sources, and incoherent light sources, such as those using light-emitting diodes (LEDs).

[0088] The compound of formula (I) can be administered in combination with one or more other biologically active agents used, for example, to treat cystic fibrosis. Therefore, the pharmaceutical composition may contain one or more other biologically active agents used to treat cystic fibrosis. Examples of biologically active agents used to treat cystic fibrosis include, for example, cystic fibrosis membrane conductance regulator (CFTR) modulators (e.g., ibacaftol, lumacaftol, tezacaftol), antibiotics, mucolytics (e.g., dormase alfa, hypertonic sodium chloride, mannitol), immunomodulators (e.g., azithromycin), bronchodilators, and steroids.

[0089] In a particular embodiment, one or more other biologically active agents are present in the composition or pharmaceutical composition in an amount ranging from about 0.00001 wt% to about 99 wt% based on the total mass of the composition, for example, about 0.0001 wt% to about 80 wt%, or about 0.001 wt% to about 50 wt%, or about 0.1 wt% to about 15 wt%, or about 0.5 wt% to about 10 wt%, or about 0.5 wt% to about This is 5 wt%, or approximately 0.1 wt% to 3 wt%, or approximately 0.1 wt% to 2 wt%, or approximately 0.1 wt% to 1 wt%, or approximately 0.001 wt% to 5 wt%, or approximately 0.001 wt% to 2 wt%, or approximately 0.001 wt% to 1 wt%, or approximately 0.001 wt% to 0.5 wt%, or approximately 0.001 wt% to 0.1 wt%, or approximately 0.001 wt% to 0.01 wt%.

[0090] In solid dosage forms for oral administration, the compound of formula (I) may be mixed with one or more pharmaceutically acceptable carriers such as dicalcium phosphate or macrolides, and / or any of the following: diluents, fillers or expanders, e.g., starch, silicon lactose, sucrose, glucose, mannitol, microcrystalline cellulose and / or silicic acid; binders, e.g., hydroxypropyl cellulose, hypromellose, hydroxypropyl methylcellulose, carboxymethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl acetate, sucrose and B and / or acacia, disintegrants, e.g., starch, e.g., potato or tapioca starch, starch derivatives such as sodium starch glycolate, crospolyvinylpyrrolidone, calcium carbonate, croscarmellose sodium, alginic acid and certain silicates, lubricants, e.g., talc, calcium stearate, magnesium stearate, stearic acid, sodium sulfate, stearyl fumarate, solid polyethylene glycol, solubilizers, e.g., sodium lauryl sulfate, ammonium dodecyl sulfate and sodium dodecyl sulfate, surfactants, For example, nonionic surfactants, e.g., polyglycerol alkyl ethers, glucosyl dialkyl ethers, crown ethers; ester-bonded surfactants, e.g., polyoxyethylene alkyl ethers, Brij, Spans (sorbitan esters), and Tweens (polysorbates); anionic surfactants, e.g., sulfonates, phosphates, sulfates, and carboxylates; alkyl carboxylates (soaps), e.g., sodium stearate, sodium dioctyl sulfosuccinate, perfluorooctanesulfonate, linear alkylbenzene sulfonate (LAB), and perfluorobutanesulfonate; alkylaryl ether phosphates, sodium lauroyl sarcosinate, and carboxylate-based fluorosurfactants, e.g., perfluorononanoate and perfluorooctanoate; cationic surfactants, e.g., benzalkonium chloride, cetylpyridinium chloride, and benzethonium chloride; alkyltrimethylammonium salts, e.g., cetyltrimethylammonium bromide (CTAB) and cetyltrimethylammonium chloride (CTAC); zwitterionic surfactants, e.g.,Sulfonates, sultaines, CHAPS (3-[(3-coramidopropyl)dimethylammonio]-1-propanesulfonate), betaines, such as cocamidopropyl betaine, flavorings and colorants, and mixtures thereof.

[0091] Tablets and other solid dosage forms of pharmaceutical compositions may be prepared using coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation technology. They may also be formulated to provide sustained or controlled release of the active ingredient, using, for example, natural and synthetic polymers, such as hydroxypropyl methylcellulose methacrylate, methacrylic acid copolymers (e.g., methyl methacrylate-methacrylic acid copolymer and methyl methacrylate-methacrylic acid copolymer), shellac, ethylcellulose, cellulose phthalate acetate, cellulose trimellitic acetate, polyvinyl phthalate acetate, cellulose succinate acetate, hydroxypropyl methylcellulose succinate acetate, sodium alginate, waxes, fatty acids, and zein, each in various proportions to provide a desired release profile, and other polymer matrices, liposomes and / or microspheres may also be used. These compositions may also optionally contain colorants and / or opacifiers, and they may be compositions that release only the active ingredient, or preferentially, in a delayed manner in a specific part of the gastrointestinal tract.

[0092] The pharmaceutical composition may contain pharmaceutically acceptable carriers and / or excipients and / or diluents in an amount of about 50% w / w or less, for example, pharmaceutically acceptable carriers and / or excipients and / or diluents in an amount of about 45% w / w or less, or pharmaceutically acceptable carriers and / or excipients and / or diluents in an amount of about 40% w / w or less, or pharmaceutically acceptable carriers and / or excipients and / or diluents in an amount of about 35% w / w or less. For example, the pharmaceutical composition may contain at least about 1% w / w, or at least about 10% w / w, or at least about 15% w / w, or at least about 20% w / w, or about 25% w / w, or at least about 30% w / w of pharmaceutically acceptable carriers and / or excipients and / or diluents.

[0093] Liquid formulations include solutions, suspensions, and emulsions, such as water or water-propylene glycol solutions for oral administration. Liquid formulations can also be formulated as solutions in aqueous polyethylene glycol solutions. In certain embodiments, the compound of formula (I) can be mixed with water and / or one or more pharmaceutically acceptable carriers, such as polyethylene glycol, solvents such as alcohol, humectants such as glycerol, sweeteners such as liquid glucose, corn syrup, and sucrose, artificial sweeteners such as aspartame, stevia, and sucralose, preservatives such as benzoates and parabens, viscosity modifiers / thickeners such as gums and alginates, buffers, flavoring agents, and colorants.

[0094] This also includes solid formulations such as tablets, capsules, granules, and powders, which are intended to be converted into liquid formulations for oral administration immediately before use. Such liquid forms include solutions, suspensions, and emulsions. These particular solid formulations are most conveniently provided in unit dose forms and are used to provide a single liquid dosage unit themselves. Alternatively, by measuring a predetermined volume of the solid formulation using a spoon or other measuring device, sufficient solid material can be provided to reconstitute multiple individual liquid doses as needed. Solid formulations intended to be converted into liquids may contain, in addition to the active ingredient, flavorings, colorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like. Liquids used to prepare liquid formulations may include water, isotonic water, juice, milk, ethanol, and mixtures thereof.

[0095] The ingredients mentioned above and below are selected in particular from those listed in pharmacopoeias, such as the United States Pharmacopeia National Prescriptions, the European Pharmacopoeia, the Helvetica Pharmacopoeia, the British Pharmacopoeia, the German Pharmacopoeia, the Chinese Pharmacopoeia, the Japanese Pharmacopoeia, or appendices of regulations, etc.

[0096] Use of the compound of formula (I) and pharmaceutical composition The compounds and pharmaceutical compositions described herein can be used in a variety of therapeutic and non-therapeutic applications. For example, the compounds and pharmaceutical compositions described herein can be used to provide one or more beneficial effects to a patient. For example, the compounds and pharmaceutical compositions described herein can be used in a variety of cosmetic applications. For example, the compounds and pharmaceutical compositions described herein can be used in an in vitro or in vivo manner. This method may include administering the compounds or pharmaceutical compositions described herein to a target.

[0097] The terms “treatment procedure” or “treatment method” also include, but are not cosmetic treatments, the prevention and alleviation of symptoms of disease and / or disorder in the subject.

[0098] As used herein, the expression “treatment or prevention” and similar terms refer to any form of healthcare aimed at eliminating or avoiding a disease and / or disability by common medical practice, or alleviating its symptoms, including preventive and curative care, as determined according to any available trials. Interventions that aim with a reasonable expectation of achieving a particular outcome, but not always, are included in the expression “treatment or prevention.” Interventions that succeed in slowing or halting the progression of a disease and / or disability are included in the expression “treatment or prevention.”

[0099] In certain embodiments, the subject is human. In other embodiments, the subject is mammals other than humans, such as non-human primates (e.g., apes, monkeys and lemurs), companion animals such as cats or dogs, working animals and sporting animals such as dogs, horses and ponies, animals such as pigs, sheep, goats, deer, cattle and livestock, and experimental animals such as rodents (rabbits, rats, mice, hamsters, garbills, guinea pigs, etc.).

[0100] The amount of compound or pharmaceutical composition administered may be varied depending on the target or requirements of use. For both therapeutic and non-therapeutic uses, the amount of compound or pharmaceutical composition administered may be varied depending on the desired outcome, the requirements of the target, and the severity of the condition being treated. Determining the appropriate amount / dosage for a particular situation is within the scope of the art of the field. For example, for therapeutic uses, a physician or veterinarian skilled in the art can easily determine and prescribe the effective amount of the required compound or pharmaceutical composition. If necessary, the total daily amount / dosage may be divided and administered in installments throughout the day.

[0101] Generally, a suitable daily dosage of the active agent (i.e., the compound of formula (I)) is an amount that is the lowest dosage effective to produce the desired effect, such as a therapeutic effect. Due to the non-toxic nature of the composition, it is contemplated that a wide range of dosages can be used. Those skilled in the art will understand that the appropriate dosage or dosing regimen will typically vary for each subject and will depend on factors such as the severity of the subject's health condition at the start of administration. For example, the dosage of the active agent in the composition can be up to 15 g per day, such as up to about 10 g per day, or up to about 5 g per day.

[0102] In certain embodiments, the dosage of the active agent ranges from 100 mg to about 3 g per day, which can be administered as two or more secondary dosages, optionally in unit dosage forms, at appropriate intervals throughout the day. In certain embodiments, the dosage of the active agent in the composition can be about 200 mg to about 3 g of the compound per day, such as about 500 mg to about 3 g of the compound per day, or about 750 mg to about 2.5 g of the compound per day, or about 1000 mg to about 2000 mg of the compound per day. In certain embodiments, the active agent can be administered two or three times a day. In certain embodiments, each dosage of the active agent is about 5 g or less, such as about 3 g or less, such as about 2.5 g or less. Each dosage of the active agent can be combined with other conventional agents for the desired effect. When the composition is for topical administration, the concentration of the compound is about 0.01 g to about 0.5 g per 1 cm of skin, 2 or about 0.1 g to about 0.4 g per 1 cm of skin, 2 or about 0.2 g to about 0.3 g.

[0103] The compounds and pharmaceutical compositions described herein may be used, for example, to treat microbial infections, and / or inflammation, and / or to reduce blood clot formation, and / or to treat wounds, and / or to treat cystic fibrosis, and / or to treat epidermolysis bullosa. The compounds and pharmaceutical compositions described herein may be used to treat wounds in subjects with epidermolysis bullosa. These uses may be, for example, therapeutic or non-therapeutic.

[0104] The compounds and pharmaceutical compositions described herein can be used as antimicrobial agents. As used herein, the term “antimicrobial agent” means that the compositions and pharmaceutical compositions described herein can be used to kill microorganisms, inhibit bacterial motility, e.g., swarming, aerotropy or convulsion, and / or inhibit microbial growth and / or reduce microbial growth.

[0105] The compounds and pharmaceutical compositions described herein can be used to inhibit and / or eradicate bacterial biofilm formation. Inhibition and / or eradication of bacterial biofilm formation can be achieved, for example, by inhibiting bacterial signaling, e.g., quorum sensing; inhibiting the formation or dispersion of bacterial biofilms; inhibiting or stimulating global regulatory systems (e.g., those dependent on intracellular levels of cyclic dimer guanosine monophosphate); and inhibiting the formation of functional bacterial cell surfaces and excretory proteins.

[0106] In certain embodiments, microorganisms may be selected from bacteria, fungi, and protozoa. Bacterial strains may be selected from, for example, Gram-positive bacteria, Gram-negative bacteria, and atypical bacteria. Gram-positive bacteria may be selected from, for example, one or more of the following genera: Clostridium perfringens, Listeria monocytogenes, Bacillus cereus, Enterococcus faecalis, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Clostridium, and Peptostreptococcus. Gram-negative bacteria may be selected from, for example, Salmonella tiphyllum, Vibrio parahaemolyticus, and one or more of the following intestinal bacteria: Escherichia coli, Klebsiella pneumoniae, Enterobacter, Proteus, Citrobacter, Morgan bacilli, Pseudomonas aeruginosa, Acinetobacter baumanni, Campylobacter jejunum, Bacteroides, Prevotella, Helicobacter pylori, and Porphyromonas. Atypical bacteria may be selected from, for example, one or more of the following: Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila, and Mycobacteria. Fungal strains may be selected from, for example, one or more of the following: Candida albicans, Candida glabrata, and Aspergillus fumigatus.

[0107] The bacterial strain may be a biofilm-forming bacterium and / or a bacterium capable of forming a biofilm. Examples of biofilm-forming bacteria and / or bacters capable of forming a biofilm include Bacillus species, Listeria monocytogenes, Staphylococcus aureus, Lactobacillus plantarum, Lactococcus lactis, Vibriofis, Aeromonas hydrophylla, Aeromonas salmonicida, Agrobacterium tumefaciens, Burgholderia cepacia, Chromobacterium violaceum, Enterobacter agglomerans, soft rot bacteria, black leg bacteria, Erwinia stewatii The following can be selected: Stewartii), Escherichia coli, Helicobacter pylori, Pseudomonas aureofasciens, Pseudomonas aeruginosa, Bacillus subtilis, Rhizobium etri, Rhizobium regminosalum, Rhodobacter spheroides, Salmonella tiphyllum, Serratia lycfaciens, Sinorhizobium melilotii, Vibrio angilarum, Vibrio harveyi, Yersinia enterocolitica, and Mycobacterium pseudotuberculosis.

[0108] For example, the compounds and pharmaceutical compositions described herein may be administered to a subject to treat and / or prevent microbial infections in that subject. For example, the compounds and pharmaceutical compositions described herein can be used to promote the healing of damaged wounds on the skin. For example, the compounds and pharmaceutical compositions described herein can be used to prevent microbial infections of damaged skin. For example, the compounds and pharmaceutical compositions described herein can be used to treat or prevent microbial infections in the digestive system. For example, the compounds and pharmaceutical compositions described herein can be used to treat or prevent microbial infections in the nasal cavity or ear cavity of a subject. For example, the compounds and pharmaceutical compositions described herein can be used to treat or prevent microbial infections in the respiratory tract of a subject. For example, the compounds and pharmaceutical compositions described herein can be used to treat or prevent microbial infections in the respiratory tract of patients with cystic fibrosis. For example, the compounds and pharmaceutical compositions described herein can be used as a urinary tract rinse or bladder rinse for, for example, urinary tract implants, indwelling urinary catheters and patients undergoing renal dialysis.

[0109] Accordingly, therapeutic use of the compounds or pharmaceutical compositions described herein as antimicrobial agents is provided herein. Compounds or pharmaceutical compositions described herein for use as antimicrobial agents are also provided herein. Use of the compositions or pharmaceutical compositions described herein in the manufacture of antimicrobial agents is further provided herein. Therapeutic methods for treating and / or preventing microbial infections in a subject are further provided herein, and these methods include administering the compounds or pharmaceutical compositions described herein to the subject.

[0110] In certain embodiments, the compounds and pharmaceutical compositions disclosed herein are used for non-therapeutic purposes.

[0111] For example, the compounds described herein can be used as antimicrobial agents on non-living surfaces (e.g., as disinfectants). For example, the compounds and pharmaceutical compositions disclosed herein can be used in cosmetic applications, for example, as antimicrobial agents on living surfaces (e.g., skin). For example, the compounds and pharmaceutical compositions disclosed herein can be used as antimicrobial agents in cosmetic skincare compositions or makeup compositions.

[0112] For example, the compounds described herein may be used as antimicrobial agents on industrial non-biological surfaces, for example, to remove or prevent biofilm formation in piping used in the water or petroleum industries, as cleaning agents for water tanks (e.g., in fisheries), and as anti-fowling agents in industrial processes (e.g., fisheries).

[0113] For example, the compounds described herein can be used as food and / or water additives for protection and / or prevention of disease transmission. For example, the compounds described herein can be used for washing plants, fresh fruits and vegetables. The compounds described herein can reduce surface bacteria, extend shelf life, and / or protect surfaces from pest infestation of live crops or agricultural products.

[0114] For example, the compounds described herein can be used as antimicrobial agents for medical devices or medical compositions, such as cements for bone or dental implants, implants, wound dressings, stitches, or threads.

[0115] For example, the compounds described herein can be used as antimicrobial agents on biological surfaces. For example, the compounds described herein can be applied to the skin to kill microorganisms or inhibit their growth for hygienic reasons (e.g., to prevent the spread of disease). For example, the compounds described herein can be applied to the hands as hand sanitizers. For example, the compounds described herein can be used as mouthwash to treat or prevent bad breath. For example, the compounds described herein can be used as dental care products to treat or prevent tooth decay and disease.

[0116] For example, the compounds described herein can be used in agricultural applications. For example, the compounds described herein can be used to treat or prevent infection of micro-wounds in plants, or to reduce surface pathogens on plants. For example, the compounds described herein can be used as biosecurity disinfectants for animal farm facilities. For example, the compounds described herein can be used for sterilization of animal feed.

[0117] The compounds and pharmaceutical compositions described herein can be used as anti-inflammatory agents. As used herein, the term “anti-inflammatory” means that inflammation or swelling can be reduced by using the compositions and pharmaceutical compositions described herein.

[0118] For example, the compounds and pharmaceutical compositions described herein can be administered to a subject to treat and / or prevent inflammation of that subject. Therefore, the therapeutic use of the compounds or pharmaceutical compositions described herein as anti-inflammatory agents is provided herein. The compounds or pharmaceutical compositions described herein for use as anti-inflammatory agents are also provided herein. The use of the compositions or pharmaceutical compositions described herein in the manufacture of anti-inflammatory drugs is further provided herein. Further therapeutic methods for treating and / or preventing inflammation of a subject are provided herein, these methods include administering the compounds or pharmaceutical compositions described herein to a subject.

[0119] Accordingly, the compounds and pharmaceutical compositions described herein can be used to treat or prevent inflammatory diseases or disorders. Examples of inflammatory diseases or disorders include, for example, allergies, cancer, atherosclerosis, ischemic heart disease, acne vulgaris, asthma, autoimmune diseases, autoinflammatory diseases, abdominal diseases, chronic prostatitis, colitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivity, inflammatory bowel disease, interstitial cystitis, lichen planus, mast cell activation syndrome, mastocytosis, otitis, pelvic inflammatory disease, reperfusion injury, rheumatic fever, rheumatoid arthritis, rhinitis, sarcoidosis, transplant rejection, and vasculitis.

[0120] Treatment of inflammation can be determined by measuring the expression levels of one or more inflammatory markers, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Decreased CRP and ESR expression indicates reduced inflammation.

[0121] The compounds and pharmaceutical compositions described herein can be used as antithrombotic agents. As used herein, the term “antithrombotic” means that the compositions and pharmaceutical compositions described herein can be used, for example, to reduce the formation of blood clots by inhibiting platelet aggregation. Therefore, antithrombotic agents can be used to increase blood flow in a given area.

[0122] For example, the compounds and pharmaceutical compositions described herein may be administered to a subject to reduce the formation of blood clots in that subject. Therefore, the therapeutic use of the compounds or pharmaceutical compositions described herein as antithrombotic agents is provided herein. The compounds or pharmaceutical compositions described herein for use as antithrombotic agents are also provided herein. The use of the compositions or pharmaceutical compositions described herein in the manufacture of antithrombotic agents is further provided herein. Further, a therapeutic method for reducing the formation of blood clots in a subject is provided herein, the method comprising administering the compounds or pharmaceutical compositions described herein to the subject.

[0123] Therefore, the compounds and pharmaceutical compositions described herein can be used to treat or prevent disorders related to blood flow in a subject. The compounds and pharmaceutical compositions disclosed herein can be used to improve (e.g., increase) blood flow in a subject, for example, a subject having blood flow levels outside the range considered normal or healthy. For example, the compounds and pharmaceutical compositions disclosed herein can be used to treat or prevent any disease or disorder related to blood flow (e.g., the circulatory system) in a subject. For example, a subject may be susceptible to one or more diseases or disorders related to blood flow.

[0124] Diseases and disorders related to blood flow and / or platelet aggregation include, for example, cardiovascular diseases, cerebrovascular or brain diseases, immune disorders, bone, joint and / or muscle diseases, and fatigue disorders.

[0125] Cardiovascular diseases and disorders include, for example, coronary artery disease, coronary heart disease, angina, myocardial infarction, hypertensive heart disease, heart failure, pulmonary heart disease, cardiac arrhythmias, inflammatory heart disease, rheumatic heart disease, cardiomyopathy, atrial myopathy, congenital heart disease, endocarditis, inflammatory cardiac hypertrophy, myocarditis, valvular heart disease, aortic aneurysm, venous thrombosis, rheumatic vasculitis, atherosclerosis, peripheral artery disease, and renal artery stenosis.

[0126] Examples of cerebrovascular and brain diseases include stroke (e.g., mini-stroke, hemorrhagic stroke, ischemic stroke), transient ischemic attack (TIA), subarachnoid hemorrhage, and vascular dementia.

[0127] Immune disorders and immune deficiencies include, for example, any disease in which the immune response of a subject is lower than that of a normal, healthy individual, such as immunodeficiency disorders (e.g., primary, secondary, humoral, T-cell, neutropenia, asplenia, and complement deficiency), and hypoimmune responses in subjects with impaired immune systems (e.g., subjects undergoing chemotherapy and / or radiotherapy, subjects infected with HIV, subjects lacking one or more organs related to immune function such as the spleen, tonsils, or lymph nodes). Examples of immune disorders include ataxia-telangiectasia, Chediak-Higashi syndrome, combined immunodeficiency, complement deficiency, DiGeorge syndrome, hypogammaglobulinemia, Job syndrome, leukocyte adhesion disorders, panhypogammaglobulinemia, Bruton's disease, congenital agammaglobulinemia, selective IgA deficiency, Wiscott-Aldrich syndrome, and severe combined immunodeficiency (SCID). For example, infections or symptoms related to immune health include upper and lower respiratory tract infections, hay fever, sinusitis, and pharyngitis.

[0128] Joint diseases and disorders include, for example, any disease relating to the health of the joints, mobility, muscles, and bones, such as arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriatic arthritis, septic arthritis), bursitis, osteonecrosis, dislocation, Perthes disease, and Paget's disease of bone.

[0129] Fatigue-related illnesses and disorders include, for example, simple fatigue and / or any illness in which fatigue is a symptom. Examples of fatigue-related illnesses and disorders include chronic fatigue syndrome, anemia, depression, iron deficiency (without anemia), sleep disorders, hypothyroidism, hyperthyroidism, Addison's disease, anorexia nervosa or other eating disorders, autoimmune diseases such as lupus, diabetes mellitus, fibromyalgia, kidney disease, liver disease, and malnutrition.

[0130] In certain embodiments, the compounds or pharmaceutical compositions described herein may be used to maintain and / or improve the overall health of the cardiovascular system, for example, to treat, reduce or prevent the onset of one or more cardiovascular-related diseases or disorders, and / or to provide beneficial effects on the metabolic system through maintaining or improving healthy blood flow.

[0131] The compounds and pharmaceutical compositions described herein can be used in a variety of non-therapeutic applications.

[0132] For example, compounds and pharmaceutical compositions can be used in a manner that maintains the blood flow of a subject. For example, if a subject is healthy or has normal blood flow levels and is not at any particular risk of developing, for example, a blood flow-related disease, the subject may consume the compositions disclosed herein to maintain normal blood flow levels. For example, if a subject is healthy and is not at any particular risk of developing, for example, a blood flow and / or platelet aggregation-related disease, the subject may consume the compositions disclosed herein as part of a healthy lifestyle.

[0133] The antithrombotic activity of a compound can be measured, for example, by determining the degree of platelet aggregation using an optical agglutinator.

[0134] The compounds and pharmaceutical compositions described herein can be used as agents for promoting wound healing (for example, for inducing or accelerating wound healing).

[0135] For example, the compounds and pharmaceutical compositions described herein can be administered to a subject as wound treatment agents. Therefore, therapeutic uses of the compounds or pharmaceutical compositions described herein for treating wounds are provided herein. Compounds or pharmaceutical compositions described herein for use as wound treatment agents are also provided herein. The use of the compositions or pharmaceutical compositions described herein in the manufacture of wound treatment agents is further provided herein. Further, a therapeutic method for healing a wound in a subject is provided herein, the method comprising administering the compounds or pharmaceutical compositions described herein to the subject.

[0136] Accordingly, the compounds and pharmaceutical compositions described herein can be used to treat or prevent wound-related disorders in a subject. The compounds and pharmaceutical compositions disclosed herein can be used to improve (e.g., enhance) wound healing in a subject, for example, a subject that has an increased number and / or severity of wounds compared to a healthy individual, or a subject whose wound healing is delayed, incomplete, or atypical compared to a healthy individual. For example, the compounds and pharmaceutical compositions disclosed herein can be used to treat or prevent any disease or disorder related to wound healing in a subject. For example, the compounds and pharmaceutical compositions disclosed herein can be used to treat or prevent wounds in a subject that has a disease or disorder in which wound healing is delayed, incomplete, or atypical. For example, a subject may be susceptible to one or more diseases or disorders related to wound healing.

[0137] Diseases and disorders that are associated with, or result in delayed, incomplete, or atypical wound healing in the subjects include, for example, epidermolysis bullosa, diabetes mellitus (type 1 or type 2), anemia, circulatory disorders, Ehlers-Danlos syndrome (EDS), eczema, and skin ulcers.

[0138] The compounds and pharmaceutical compositions described herein can be used as anticancer agents. Therefore, the compounds and pharmaceutical compositions described herein can be used to treat or prevent cancer.

[0139] Method for producing the compound of formula (I) Compounds of formula (I) and pharmaceutical compositions containing compounds of formula (I) can be manufactured by any suitable method.

[0140] In certain embodiments, a pharmaceutical composition is prepared by combining a compound of formula (I) with a pharmaceutically acceptable carrier and / or excipient and / or diluent. The components are combined in appropriate amounts to obtain a composition having a desired amount and concentration of each component. Each component can be combined with one or more other components in any order and combination suitable for obtaining the desired product. For example, each component can be combined by mixing. Such methods are well known in the art, for example, methods known in the pharmaceutical industry. The pharmaceutical composition can be prepared in a dry solid form, for example, in powder form, and can be subjected to further processing steps depending on the type of formulation for the intended final product. This method involves processing the mixture into a certain shape (e.g., a bar, ball, pellet, cluster, tablet) by molding, pressing, spray drying or other methods, preferably into a shape having dimensions and / or texture suitable for consumption by humans or other mammals of the type described herein.

[0141] In a particular embodiment, a method for producing the compound of formula (I) can be carried out via the following reaction scheme. [ka]

[0142] In a particular embodiment, step 1 is [ka] The process involves reacting with a compound containing propargyl. For example, step 1 is [ka] This involves reacting with a halogenated propargyl. For example, step 1 is [ka] This involves reacting with propargyl bromide.

[0143] The reaction in step 1 can occur in the presence of a hydroxide and an alcohol. The hydroxide can be, for example, potassium hydroxide. The alcohol can be, for example, an organic alcohol such as methanol.

[0144] Step 1 may include, for example, bubbling nitrogen through the reaction mixture. The reaction mixture in Step 1 may have a temperature of, for example, about 20°C or less, for example, about 10°C or less, for example, about 5°C.

[0145] The reaction in step 1 may, for example, form a precipitate product. The reaction mixture may be warmed to room temperature, for example, before the product is purified.

[0146] Purification of the product from step 1 may include, for example, removing the solvent under vacuum. The residue can then be partitioned between water and an organic compound such as tert-butyl methyl ether. The aqueous layer can then be extracted a second time using more organic compounds, such as tert-butyl methyl ether. The organic layer can then be washed with water and brine (e.g., sodium chloride), dried (e.g., with sodium sulfate), filtered, and then concentrated (e.g., under reduced pressure).

[0147] In a particular embodiment, step 2 is [ka] This involves reacting with thioacetic acid. Thioacetic acid can be present in organic solvents such as toluene.

[0148] The product of step 1 may be present in an organic solvent such as toluene. This can be degassed, for example, with nitrogen. 2,2'-Azobis(2-methylpropionitrile) or 1,1'-Azobis(cyanocyclohexane) (ACHN) can be used as a radical initiator in step 2.

[0149] The reaction mixture in step 2 may have a temperature of, for example, about 50°C or higher, or about 60°C or higher. For example, the reaction mixture in step 2 may have a temperature in the range of about 50°C to about 100°C, for example, about 60°C to about 90°C, for example, about 70°C to about 80°C.

[0150] After the product of step 2 is produced, the reaction mixture can be cooled to room temperature before the product is purified.

[0151] Purification of the product in step 2 may include, for example, removing the solvent under vacuum. The crude residue can be purified (e.g., twice) by silica gel flash column chromatography using, for example, a heptane:ethyl acetate 10% solvent system.

[0152] In a particular embodiment, step 3 is [ka] This involves reacting with R2-tosylate or R2-mesylate. The R2-tosylate can be present in an organic solvent such as methanol and / or tetrahydrofuran.

[0153] The product of step 2 can be present in an organic solvent, such as methanol. The reaction of step 1 can proceed in the presence of a hydroxide and an alcohol. The hydroxide can be, for example, potassium hydroxide. The alcohol can be, for example, an organic alcohol such as methanol.

[0154] The temperature of the reaction mixture in step 3 can be, for example, below 0°C, for example below -10°C, below -20°C, below -30°C, or below -40°C, for example between approximately -80°C and approximately -20°C, or between approximately -60°C and approximately -30°C, or between approximately -50°C and approximately -30°C.

[0155] After the product of step 3 is produced, the reaction mixture can be warmed to room temperature before the product is purified.

[0156] The purification of the product in step 2 may include, for example, adding an aqueous solution of ammonium chloride to the reaction mixture. The product in step 3 can then be extracted using an organic solvent such as ethyl acetate. The organic layer can then be washed with water and brine (e.g., sodium chloride), dried (e.g., with sodium sulfate), filtered, and then concentrated (e.g., under reduced pressure). The product can then be purified by silica gel flash column chromatography, for example, using a heptane:ethyl acetate 2-3% solvent system.

[0157] In a particular embodiment, step 4 is [ka] This involves reacting it with 3-chloroperbenzoic acid or another oxidizing agent.

[0158] The product of step 3 can be present in an organic solvent, such as dichloromethane.

[0159] The temperature of the reaction mixture in step 4 can be, for example, about -20°C or lower, for example, about -30°C or lower, for example, about -40°C or lower, for example, about -50°C or lower. For example, the temperature of the reaction mixture in step 4 can be about -80°C to about -20°C, or about -70°C to about -40°C, or about -70°C to about -50°C.

[0160] The reaction mixture can be warmed to room temperature, for example, before the product is purified.

[0161] The purification of the product in step 4 may include, for example, partitioning the reaction mixture between a semi-saturated aqueous solution of a weak base, such as sodium bicarbonate, and dichloromethane. The aqueous layer can be further extracted using an organic solvent, such as dichloromethane. The organic layer can then be dried (e.g., on magnesium sulfate), filtered, and concentrated (e.g., under vacuum). The product can then be purified by silica gel flash column chromatography, for example, using dichloromethane:ethyl acetate 0-5% as the solvent system.

[0162] In a particular embodiment, step 5 is: [ka] This involves reacting with a permanganate such as potassium permanganate or another oxidizing agent. Permanganates can be present in organic solvents such as acetone.

[0163] The reaction mixture may contain an organic solvent, such as acetone. The reaction mixture may also contain a drying agent, such as magnesium sulfate.

[0164] The temperature of the reaction mixture in step 5 can be, for example, below 0°C, below -10°C, below -20°C, below -30°C, or below -40°C, and can be in the range of, for example, between approximately -80°C and approximately -20°C, between approximately -60°C and approximately -30°C, or between approximately -50°C and approximately -30°C.

[0165] The reaction mixture can be filtered (e.g., through a Celite pad) and washed with an organic solvent (e.g., acetone). The filtrate can be concentrated under reduced pressure. The product can be purified, for example, by silica gel flash column chromatography, using a solvent system of hexane:ethyl acetate 10-30%. [Examples]

[0166] Examples Example 1 - Method for preparing 1-allyl-2-(3-((4-(trifluoromethyl)benzyl)sulfonyl)prop-1-en-1-yl)disulfan

[0167] [ka]

[0168] Step 1 - Preparation of prop-2-in-1-yl(4-(trifluoromethyl)benzyl)sulfane A solution of potassium hydroxide (7.02 g, 125.00 mmol) in methanol (240 mL) was stirred in a three-necked round-bottom flask while bubbling nitrogen for 20 minutes, and the solution was cooled to 5°C in an ice salt bath. Next, (4-(trifluoromethyl)phenyl)methanethiol (20.02 g, 104.30 mmol) was added dropwise over 15 minutes using a pressure-equalizing dropping funnel, and the resulting reaction mixture was stirred for a further 20 minutes. Then, propargyl bromide (17.4 mL, 156.00 mmol) was added dropwise to the mixture via syringe over 20 minutes, and the precipitate was observed. The reaction mixture was warmed to room temperature and stirred for a further 2 hours.

[0169] The solvent was removed under reduced pressure, and the residue was partitioned between water (300 mL) and tert-butyl methyl ether (200 mL). The aqueous layer was further extracted with tert-butyl methyl ether (2 x 200 mL). The organic layers were combined, washed with water (2 x 200 mL) and brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the desired product, prop-2-in-1-yl(4-(trifluoromethyl)benzyl)sulfan, as a pale yellow oil (23.09 g, 96% yield).

[0170] Step 2 - Preparation of S-(3-((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)ethanethioate A solution of prop-2-in-1-yl(4-(trifluoromethyl)benzyl)sulfan (23.09 g, 100.40 mmol) in toluene (400 mL) was degassed under nitrogen for 20 minutes. 2,2'-azobis(2-methylpropionitrile) (824 mg, 5.02 mmol) was added to the previous solution, and degassing was continued while heating the reaction mixture to 75°C (internal temperature). Next, a solution of thioacetic acid (7.6 mL, 105.70 mmol) in toluene (100 mL) was added dropwise to the reaction mixture over 2 hours. The mixture was stirred under these conditions for 18 hours.

[0171] The reaction mixture was cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified twice by silica gel flash column chromatography using a heptane:ethyl acetate 10% solvent system to obtain the desired product, S-(3-((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)ethanethioate (6.4 g).

[0172] Step 3 - Preparation of 1-allyl-2-(3-((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)disulfane A solution of S-(3-((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)ethanethioate (3.16 g, 10.33 mmol) in methanol (60 mL) was cooled to -30°C under nitrogen in an acetonitrile / dry ice bath. A solution of 1 M potassium hydroxide in methanol (12.4 mL, 12.40 mmol) was added dropwise to the previous solution over 15 minutes. The reaction mixture was stirred for 30 minutes. Next, the mixture was further cooled to -65°C and stirred for 15 minutes, followed by the addition of a solution of S-allyl tosylate (2.83 g, 12.4 mmol) in methanol (40 mL) dropwise over 30 minutes. The mixture was stirred for a further 1.5 hours. LC-MS analysis indicated that the reaction was complete.

[0173] A saturated aqueous solution of ammonium chloride (10 mL) was added dropwise to the reaction mixture and the mixture was heated to room temperature. The mixture was poured into a saturated aqueous solution of ammonium chloride (400 mL) and extracted with ethyl acetate (3 x 200 mL). The organic layers were combined, washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography using a heptane:ethyl acetate solvent system of 2-5% to obtain the desired product, 1-allyl-2-(3-((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)disulfane (3.1 g).

[0174] Step 4 - Preparation of 1-allyl-2-(3-((4-(trifluoromethyl)benzyl)sulfinyl)prop-1-en-1-yl)disulfan 3-Chloroperbenzoic acid (77%) (2.17 g, 9.67 mmol) was added in four portions at -78°C to a stirred solution of 1-allyl-2-(3-(((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)disulfan (3.10 g, 9.21 mmol) in dichloromethane (75 mL). The reaction mixture was slowly warmed to -20°C over 1.5 hours, stirred at this temperature for 1 hour, and then at room temperature for another 1 hour. LC-MS analysis indicated that the reaction had reached completion.

[0175] The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with dichloromethane (3 x 100 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography using a solvent system of 50% heptane:dichloromethane and 5% heptane:ethyl acetate to obtain the desired product, 1-allyl-2-(3-((4-(trifluoromethyl)benzyl)sulfinyl)prop-1-en-1-yl)disulfan (2.67 g).

[0176] Step 5 - Preparation of 1-allyl-2-(3-((4-(trifluoromethyl)benzyl)sulfonyl)prop-1-en-1-yl)disulfan 1-Allyl-2-(3-((4-(trifluoromethyl)benzyl)sulfinyl)prop-1-en-1-yl)disulfan (2.65 g, 7.52 mmol) was dissolved in acetone (75 mL) at room temperature in a three-necked round-bottom flask equipped with a thermometer and a nitrogen inlet. Magnesium sulfate (9.96 g, 8.27 mmol) was added to the above solution and cooled to -40°C. Potassium permanganate (2.67 g, 16.92 mmol) in acetone (100 mL) was added dropwise over 50 minutes, maintaining the temperature at -30°C. The mixture was washed with undissolved potassium permanganate using an additional acetone (25 mL). The reaction mixture was stirred overnight at -25°C.

[0177] LC-MS analysis indicated that the reaction was complete. The reaction mixture was warmed to room temperature, filtered through a Celite pad, and washed several times with acetone. The filtrate was concentrated under reduced pressure to provide 1.9 g of crude material. Due to a slightly low recovery rate, the Celite pad was washed several more times with acetone and then with dichloromethane, but this did not yield a significant amount of product. The previously isolated crude material was purified by silica gel flash column chromatography using hexane:ethyl acetate 20% as the solvent system to obtain the desired product, 1-allyl-2-(3-((4-(trifluoromethyl)benzyl)sulfonyl)prop-1-en-1-yl)disulfan, as a white solid content of (66:34)(Z:E) ratio (1.50 g).

[0178] Example 2 - Preparation method for 1-(4-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)sulfonyl)prop-1-en-1-yl)disulfan

[0179] [ka]

[0180] Step 1 - Preparation of prop-2-in-1-yl(4-(trifluoromethyl)benzyl)sulfane A solution of potassium hydroxide (7.02 g, 125.00 mmol) in methanol (240 mL) was stirred in a three-necked round-bottom flask while bubbling nitrogen for 20 minutes, and the solution was cooled to 5°C in an ice / salt bath. Next, (4-(trifluoromethyl)phenyl)methanethiol (20.02 g, 104.30 mmol) was added dropwise over 15 minutes using a pressure-equalizing dropping funnel, and the resulting reaction mixture was stirred for a further 20 minutes. Then, propargyl bromide (17.4 mL, 156.00 mmol) was added dropwise to the mixture via syringe over 20 minutes, and the precipitate was observed. The reaction mixture was warmed to room temperature and stirred for a further 2 hours.

[0181] The solvent was removed under reduced pressure, and the residue was partitioned between water (300 mL) and tert-butyl methyl ether (200 mL). The aqueous layer was further extracted with tert-butyl methyl ether (2 x 200 mL). The organic layers were combined, washed with water (2 x 200 mL) and brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the desired product, prop-2-in-1-yl(4-(trifluoromethyl)benzyl)sulfan, as a pale yellow oil (23.09 g, 96% yield).

[0182] Step 2 - Preparation of S-(3-((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)ethanethioate A solution of prop-2-in-1-yl(4-(trifluoromethyl)benzyl)sulfan (23.09 g, 100.40 mmol) in toluene (400 mL) was degassed with nitrogen for 20 minutes. 2,2'-azobis(2-methylpropionitrile) (824 mg, 5.02 mmol) was added to the previous solution, and degassing was continued while heating the reaction mixture to 75°C (internal temperature). Then, a solution of thioacetic acid (7.6 mL, 105.70 mmol) in toluene (100 mL) was added dropwise to the reaction mixture over 2 hours. The mixture was stirred under these conditions for 18 hours.

[0183] The reaction mixture was cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified twice by silica gel flash column chromatography using a heptane:ethyl acetate 10% solvent system to obtain the desired product, S-(3-((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)ethanethioate (6.4 g).

[0184] Step 3-1-(4-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)disulfan preparation A solution of S-(3-((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)ethanethioate (3.06 g, 10.00 mmol) in methanol (100 mL) was cooled to -44°C under nitrogen in an acetonitrile / dry ice bath. A 1 M solution of potassium hydroxide in methanol (12 mL, 12.00 mmol) was added dropwise to the previous solution while maintaining the internal temperature at -37°C. The reaction mixture was stirred for 30 minutes. Next, the mixture was further cooled to -70°C in an acetone / dry ice bath. A solution of S-(4-methoxybenzyl)4-methylbenzenesulfonothioate (4.63 g, 15.00 mmol) in tetrahydrofuran (100 mL) was added dropwise using a dropping funnel while maintaining the temperature below -65°C. The mixture was stirred at that temperature for a further 2 hours, and then at room temperature for a further 2 hours.

[0185] The reaction mixture was partitioned between tert-butyl methyl ether (500 mL) and a semi-saturated aqueous solution of ammonium chloride (500 mL). The aqueous layer was further extracted with tert-butyl methyl ether (2 x 200 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography using hexane:ethyl acetate 2% as the solvent system to obtain the desired product, 1-(4-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)disulfan (4.02 g).

[0186] Step 4 - Preparation of 1-(4-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)sulfinyl)prop-1-en-1-yl)disulfan 3-Chloroperbenzoic acid (77%) (2.67 g, 11.50 mmol) was added in multiple steps to a stirred solution of 1-(4-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)disulfan (4.02 g, 9.60 mmol) in dichloromethane (60 mL) at -70°C. The temperature rose by 5°C. The reaction mixture was slowly warmed to room temperature overnight.

[0187] The reaction mixture was partitioned between dichloromethane (50 mL) and a semi-saturated aqueous solution of sodium bicarbonate (100 mL). The aqueous layer was further extracted with dichloromethane (2 x 50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography using dichloromethane:ethyl acetate 3-5% as the solvent system to provide the desired product, 1-(4-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)sulfinyl)prop-1-en-1-yl)disulfan (4.05 g).

[0188] Step 5 - Preparation of 1-(4-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)sulfonyl)prop-1-en-1-yl)disulfan 1-(4-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)sulfinyl)prop-1-en-1-yl)disulfan (4.05 g, 9.36 mmol) was dissolved in acetone (35 mL) at room temperature in a three-necked round-bottom flask equipped with a thermometer and a nitrogen inlet. Magnesium sulfate (12.61 g, 105.00 mmol) was added to the previous solution and cooled to -35°C. A solution of potassium permanganate (3.35 g, 21.20 mmol) in acetone (350 mL) was added dropwise over 40 minutes using a dropping funnel, while maintaining the internal temperature below -25°C. The reaction mixture was stirred overnight at -24°C.

[0189] The reaction mixture was warmed to room temperature, filtered through a Celite pad, and washed several times with acetone (500 mL). The filtrate was concentrated under reduced pressure. The crude material was loaded onto a column using toluene (40 mL) and a small amount of dichloromethane, and purified by silica gel flash column chromatography (using a 120 g cartridge) with hexane:ethyl acetate 10-20% as the solvent, to obtain the desired product, 1-(4-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)sulfonyl)prop-1-en-1-yl)disulfan, as a colorless solids content (3:1) (Z:E) ratio (1.70 g).

[0190] Example 3 - Preparation method for 1-(3-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)sulfonyl)prop-1-en-1-yl)disulfan

[0191] [ka]

[0192] Preparation of step 1-prop-2-in-1-yl(4-(trifluoromethyl)benzyl)sulfane A solution of potassium hydroxide (7.02 g, 125.00 mmol) in methanol (240 mL) was stirred in a three-necked round-bottom flask while bubbling nitrogen for 20 minutes, and the solution was cooled to 5°C in an ice / salt bath. Next, (4-(triphenylmethyl)phenyl)methanethiol (20.02 g, 104.30 mmol) was added dropwise over 15 minutes using a pressure-equalizing dropping funnel, and the resulting reaction mixture was stirred for a further 20 minutes. Then, propargyl bromide (17.4 mL, 156.00 mmol) was added dropwise to the mixture via syringe over 20 minutes, and the precipitate was observed. The reaction mixture was warmed to room temperature and stirred for a further 2 hours.

[0193] The solvent was removed under vacuum, and the residue was partitioned between water (300 mL) and tert-butyl methyl ether (200 mL). The aqueous layer was further extracted with tert-butyl methyl ether (2 x 200 mL). The organic layers were combined, washed with water (2 x 200 mL) and brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the desired product, prop-2-in-1-yl(4-(trifluoromethyl)benzyl)sulfan, as a pale yellow oil (23.09 g, 96% yield).

[0194] Step 2 - Preparation of S-(3-((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)ethanethioate A solution of prop-2-in-1-yl(4-(trifluoromethyl)benzyl)sulfan (23.09 g, 100.40 mmol) in toluene (400 mL) was degassed with nitrogen for 20 minutes. 2,2'-azobis(2-methylpropionitrile) (824 mg, 5.02 mmol) was added to the previous solution, and degassing was continued while the reaction mixture was heated to 75°C (internal temperature). A solution of thioacetic acid (7.6 mL, 105.70 mmol) in toluene (100 mL) was then added dropwise to the reaction mixture over 2 hours. The mixture was stirred under these conditions for 18 hours.

[0195] The reaction mixture was cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified twice by silica gel flash column chromatography using a heptane:ethyl acetate 10% solvent system to obtain the desired product, S-(3-((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)ethanethioate (6.4 g, 21% yield).

[0196] Step 3 - Preparation of 1-(3-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)disulfane A solution of S-(3-((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)ethanethioate (1.32 g, 4.31 mmol) in methanol (40 mL) was cooled to -40°C (internal temperature) in an acetonitrile / dry ice bath. A solution of 1 M potassium hydroxide in methanol (5.2 mL, 5.17 mmol) was added dropwise over 10 minutes, and the temperature was maintained at -40°C. The resulting mixture was stirred at this temperature for a further 30 minutes, and then cooled to -70°C using an acetone / dry ice bath. A solution of m-methoxybenzyl mercaptotosylate (1.59 g, 5.17 mmol) in methanol (20 mL) and tetrahydrofuran (4 mL) was added to the previous solution, and the temperature was maintained at -65°C. The mixture was maintained at this temperature for 30 minutes, and then warmed to room temperature and stirred for 1 hour.

[0197] A saturated aqueous solution of ammonium chloride (20 mL) was carefully added to the reaction mixture until turbidity persisted. Next, the mixture was poured into a saturated aqueous solution of ammonium chloride (230 mL) and extracted with ethyl acetate (3 x 100 mL). The organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a pale yellow oil. The crude oil was purified by silica gel flash column chromatography using a heptane:ethyl acetate 2-3% solvent system to obtain the desired product, 1-(3-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)disulfan (1.57 g, 87% yield), as a colorless oil.

[0198] Step 4 - Preparation of 1-(3-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)sulfinyl)prop-1-en-1-yl)disulfan The solution of 1-(3-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)thio)prop-1-en-1-yl)disulfan (1.57 g, 3.77 mmol) was cooled to -65°C in dichloromethane (50 mL). 3-chloroperbenzoic acid (1.01 g, 4.52 mmol) was added, and the resulting reaction mixture was stirred at -65°C for 15 minutes and then at room temperature for 3 hours.

[0199] The reaction mixture was partitioned between a semi-saturated aqueous solution of sodium bicarbonate (50 mL) and dichloromethane. The aqueous layer was further extracted with dichloromethane (2 x 25 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel flash column chromatography using an 80 g silica cartridge with a solvent system of dichloromethane:ethyl acetate 0-5% to obtain the desired product, 1-(3-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)sulfinyl)prop-1-en-1-yl)disulfan, as off-white solids in Z:E 71:29 (1.43 g, 88% yield).

[0200] Step 5 - Preparation of 1-(3-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)sulfonyl)prop-1-en-1-yl)disulfan

[0201] A solution of potassium permanganate (1.17 g, 7.40 mmol) in acetone (100 mL) was added dropwise over 15 minutes via a dropping funnel to a mixture of 1-(3-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)sulfinyl)prop-1-en-1-yl)disulfan (1.41 g, 3.26 mmol) and magnesium sulfate (4.40 g, 36.60 mmol) in acetone (100 mL), which had been pre-cooled to -45°C, while maintaining the temperature below -25°C. Further acetone (50 mL) was used to dissolve any remaining potassium permanganate. The resulting mixture was stirred overnight at -28°C.

[0202] The reaction mixture was filtered through a Celite pad and washed with acetone (3 x 70 mL). The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel flash column chromatography using an 80 g silica cartridge with hexane:ethyl acetate 10-30% as the solvent system to obtain the desired product, 1-(3-methoxybenzyl)-2-(3-((4-(trifluoromethyl)benzyl)sulfonyl)prop-1-en-1-yl)disulfan, as a colorless solid at Z:E 86:14 (753 mg, 51% yield).

[0203] Example 4 - Minimum biofilm inhibitory concentration (MBIC) of 1-(trifluoromethyl)-4-{((3-{(4-(trifluoromethyl)phenyl]methanesulfonyl}prop-1-en-1-yl)disulfanyl]methyl}benzene

[0204] The inhibitory activity of the compound of formula (I) below against Staphylococcus aureus and Pseudomonas aeruginosa was compared with that of ajoene and DMSO (dimethyl sulfoxide).

[0205] [ka] Test compound 1

[0206] The compounds were assayed for their ability to inhibit biofilm formation in Staphylococcus aureus or Pseudomonas aeruginosa as follows: All compounds were prepared as 30 mM stocks in DMSO and diluted to 48 μM (Staphylococcus aureus) or 144 μM (Pseudomonas aeruginosa) in TSB. The compounds were further serially diluted 2-fold from 48 μM to 0.75 μM (Staphylococcus aureus) or 144 μM to 2.3 μM (Pseudomonas aeruginosa) and added to a 96-well plate at 100 μl per well. The bacterial overnight cultures were osmothered in fresh TSB. 600 The bacterial culture was diluted to 0.07 and 100 μl of the diluted culture was added to the compound-containing well. The bacteria were incubated overnight at 37°C in the presence of the compound. After incubation, the planktonic bacteria were removed by three washes with H2O, and the remaining biofilm was stained with crystal violet.570 It was quantitatively determined photometrically. The absorbance corresponding to the biofilm mass was plotted against the compound concentration, and the IC 50 values were calculated. Literature: O’Toole GA. Microtiter Dish Biofilm Formation Assay. J. Vis. Exp. (2011).

[0207] The results are shown in Figures 1 and 2. It was surprisingly found that the compound of formula (I) (test compound 1) had a lower IC50 against Staphylococcus aureus and Pseudomonas aeruginosa than ajoene.

[0208] Example 5 - Minimum Biofilm Inhibitory Concentration (MBIC) Assay with Reference to Ajoene Control The MBIC assay of the compound is performed together with ajoene for reference and normalization. The IC50 of ajoene against Staphylococcus aureus and Pseudomonas aeruginosa is clear and reproducible, and ajoene can be used as a valid control for the experiment. Therefore, the IC50 calculated for the tested compounds is expressed as % ajoene because it is compared with the IC50 of ajoene in all experiments.

[0209] In a given experiment, if the IC50 of the compound is 100% ajoene, this compound has an effect equivalent to ajoene. If the IC50 of the compound is less than 100% ajoene, this compound is more effective than ajoene. If the IC50 of the compound is more than 100% ajoene, this compound is less effective than ajoene.

[0210] Table 1 below shows the MBIC results of representative compounds having the structure of formula (I).

[0211]

Table 1

[0212]

Table 2

[0213]

Table 3

[0214] Comparison of the inhibitory activity of Example 6-1-{[-3-(prop-2-en-1-yldisulfanyl)prop-2-en-1-sulfonyl]methyl}-4-(trifluoromethyl)benzene with other biofilm inhibitors The inhibitory activities of the following compounds against Staphylococcus aureus and Pseudomonas aeruginosa were compared with other biofilm inhibitors, namely, ajoene, cysteamine, gallium nitrate, HDMF, and C-30.

[0215]

Chemical formula

[0216] The structures of HDMF, cysteamine, gallium nitrate, and C-30 are shown below.

[0217]

Chemical formula

[0218] The compounds and other biofilm inhibitors were assayed for inhibitory activity using the MBIC method described in Example 4. The absorbance corresponding to the biofilm mass was plotted against the concentrations of the compounds and other biofilm inhibitors.

[0219] The results are shown in Figures 3 and 4. Surprisingly, the compound of formula (I) (test compound 2) was found to have improved inhibitory activity compared to ajoene, cysteamine, gallium nitrate, HDMF, and C-30.

[0220] Example 7 - Scratch closure test HaCaT cells (aneuploid immortal keratinocyte cell line) were seeded at 5x10 per well in a 96-well plate 4Cells were seeded at cell density and incubated overnight at 37°C, 5% CO2, and 95% humidity. Test and control compounds were prepared in 1% DMSO and diluted to a concentration of 5 μM in preheated HaCaT cell medium. Cells were washed with preheated PBS, the monolayer was mechanically damaged by introducing a vertical cell-free area into each well, and washed again. Test and control compounds were added, and all wells were imaged with a microscope at time 0. Cells were incubated as described above and imaged after 20 hours. All conditions were tested in 4 repetitions of N. Scratch closures were analyzed using ImageJ software, and the standard deviation was calculated. The reduction of scratch closure areas was plotted using GraphPrism 8 software.

[0221] The compound of formula (I) that was tested had the following structure: [ka] Test compound 3

[0222] The comparative compounds were E-ajoene, sulforaphane (SFN), 1% DMSO (vehicle control), epidermal growth factor (EGF) (positive control (pos)), and BAY 61-3606 hydrochloride hydrate (negative control (neg)). The results are shown in Figures 5 and 6. All 5 μM test compounds 3, E-ajoene, and sulforaphane showed improved scratch closure compared to the vehicle control (P<0.0001), and complete scratch closure was observed at 20 hours, consistent with the epidermal growth factor (EGF)-positive control.

[0223] The above broadly describes specific embodiments of the present invention without limitation. Modifications and changes that would be readily apparent to those skilled in the art are intended to fall within the scope of the present invention as defined in the appended claims.

Claims

1. Equation (I) 【Chemistry 1】 Equation (I) (In the above formula, R １ These are phenyl, methoxyphenyl, trifluoromethylphenyl, fluorophenyl, methylsulfonylphenyl, cyclopropyl, furan, or thiophene, and, R ２ The compound is phenyl, ethenyl, methoxyphenyl, methyl benzoate, trifluoromethylphenyl, or cyclopropyl.

2. The compound according to claim 1, wherein R1 is methoxyphenyl and R2 is ethenyl.

3. The compound according to claim 1, wherein R1 is methylsulfonylphenyl and R2 is ethenyl.

4. The compound according to claim 1, wherein R1 is fluorophenyl and R2 is ethenyl.

5. The compound according to claim 1, wherein R1 is phenyl and R2 is selected from the group consisting of phenyl, methoxyphenyl, and ethenyl.

6. The compound according to claim 1, wherein R1 is trifluoromethylphenyl, and R2 is selected from the group consisting of methoxyphenyl, methyl benzoate, ethenyl, and trifluoromethylphenyl.

7. The compound according to claim 1, wherein R1 is cyclopropyl and R2 is ethenyl or cyclopropyl.

8. The compound according to claim 1, wherein R1 is furan and R2 is ethenyl.

9. The compound according to claim 1, wherein R1 is thiophene and R2 is ethenyl.

10. The aforementioned compound, 【Chemistry 2】 The compound according to claim 1.

11. The aforementioned compound, 【Transformation 3】 The compound according to claim 1.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable excipient and / or carrier and / or diluent.

13. The pharmaceutical composition according to claim 12, for use in a therapeutic method for treating microbial infections, and / or inflammation, and / or reducing the formation of blood clots, and / or treating epidermolysis bullosa.

14. Use of the compound according to claim 1 in the manufacture of a drug for treating microbial infections, and / or inflammation, and / or reducing blood clot formation, and / or treating epidermolysis bullosa.

15. Non-therapeutic use of the compound according to claim 1 as an antibacterial agent and / or an anti-inflammatory agent and / or an antithrombotic agent.

16. A pharmaceutical composition according to claim 12 for treating wounds.

17. The pharmaceutical composition according to claim 12 for treating epidermolysis bullosa.

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