Sulfur-containing monoglyceride derivatives with antimicrobial and antiviral properties

Abstract

This disclosure generally relates to novel sulfur-containing monoglyceride derivatives and methods for treating Gram-positive infections, Gram-negative infections, fungal infections, and enveloped viral infections in patients.

Description

[0001] Priority requirements

[0002] This patent application claims the benefit of priority to U.S. Application Serial No. 16 / 948,453, filed on September 18, 2020, which is incorporated herein by reference in its entirety. Technical Field

[0003] The teachings of this invention generally relate to novel sulfur-containing glycerol monoester derivatives and methods that can be used to treat infections. Background Technology

[0004] Microbial and viral infections remain a significant problem, including antibiotic resistance developed by microorganisms. Therefore, it is crucial to continue developing effective new therapeutic and / or prophylactic antimicrobial agents that are both inexpensive and logistically easy to deliver to suitable subjects.

[0005] Glycerol monolaureate (GML) has been widely shown to have antimicrobial activity against a wide range of organisms (see, for example, Table 1 in Schlievert and Peterson in PLoS ONE; July 2012, 7, e40350), excerpts of which are presented below.

[0006] Table 1. Antibacterial activity spectrum of GML (from Schlievert 2012).

[0007]

[0008]

[0009]

[0010] Although GML can treat Clostridium difficile and Bacillus (Schlievert et al., MSphere November / December 2018 Volume 3 Issue 6e00597-18), and kill all enveloped viruses (Patrick M. Schlievert et al.; ANTIMICROBIAL AGENTS AND CHEMOTHERAP Dec. 2008, p. 4448-4454), a more recent paper (Welch, Jennifer L. et al.; mBio: 2020 May 5; 11(3): e00686-20.) reported that GML is ineffective against Escherichia coli (e. coli).

[0011] Drug-resistant infections kill hundreds of thousands of people every year. There is a need for new antibiotics that can kill drug-resistant bacteria. Summary of the Invention

[0012] This disclosure relates to compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0013]

[0014] in:

[0015] R 1 Selected from alkyl, alkenyl, and ynyl groups;

[0016] R 2 and R 3 Independently selected from hydrogen, COR 4 -CON(H)R 4 -CO2R 4 or P(O)(OR) 4 )2; or, R 2 and R 3 Together with the carbon atoms they are attached to, they can form 3 to 5-membered aliphatic carbon rings;

[0017] R 4 It is H, alkyl, alkenyl, aryl, cycloalkyl, heterocyclic, or heteroaryl; and

[0018] X is either O or S.

[0019] This disclosure also provides pharmaceutical compositions comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier.

[0020] This disclosure also provides a method for treating an infection in an infected object, comprising administering a compound of formula (I) to the infected object.

[0021] These and other features, aspects, and advantages of this disclosure will be better understood by referring to the following figures, related descriptions, and claims. Attached Figure Description

[0022] Figures 1A to 1B The results are from culturing Staphylococcus aureus MN8 with different concentrations of GML, SGML and S2GML.

[0023] Figures 2A to 2B This is the result of the inhibition of TSST-1 by GML, SGML, and S2GML.

[0024] Figure 3 The results are from tests conducted using E. coli and GML, SGML, and S2GML.

[0025] Figure 4 These are photographs of the esterase activities of two Staphylococcus aureus strains treated with GML, SGML, and S2GML. Detailed Implementation

[0026] Although the concepts of this disclosure are shown and described in detail in the accompanying drawings and specification, the results in the drawings and their descriptions should be considered exemplary in nature and not restrictive; it should be understood that only some exemplary embodiments are shown and described, and protection is intended for all changes and modifications falling within the spirit of this disclosure.

[0027] Unless otherwise defined, scientific and technical terms have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0028] The entire contents of every patent publication, non-patent publication, and reference text cited herein are incorporated herein by reference, except in the event of any inconsistency in the disclosure or definitions herein, in which case the disclosure or definitions herein shall be deemed to have precedence.

[0029] In each of the foregoing and each of the following embodiments, it should be understood that the formula not only includes and represents all pharmaceutically acceptable salts of the conjugate formula, but also that in the various physical forms of the compound of formula (I), certain functional groups (e.g., hydroxyl groups) form complexes and / or coordination conjugates with water and / or various solvents. It should be understood that the formulas described throughout the disclosure include and represent hydrates and / or solvates of the compound of formula (I). It should also be understood that non-hydrates and / or non-solvents of the compound of formula (I) are described by such formulas as well as hydrates and / or solvates of the compound of formula (I).

[0030] definition

[0031] For convenience, some of the terms used in the specification, embodiments, and appended claims are summarized herein before further description of this disclosure. These definitions should be interpreted in light of the remainder of this disclosure and understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0032] To make this disclosure easier to understand, some terms and phrases are defined below and throughout the specification.

[0033] Nouns without quantifiers are used in this text to refer to one or more kinds (i.e., at least one kind). For example, "element" means one or more kinds of elements.

[0034] The phrase “and / or” as used herein in the specification and claims should be understood to mean “any one or both” of the elements so combined (i.e., elements present in some cases but not in others). Multiple elements listed with “and / or” should be interpreted in the same way, i.e., “one or more” of the elements so combined. Other elements may optionally be present in addition to those specifically identified by the “and / or” clause, whether related to or unrelated to those specifically identified. Thus, as a non-limiting example, when used in conjunction with open-ended language such as “comprising / including,” a reference to “A and / or B” may refer only to A in one embodiment (optionally including elements other than B); only to B in another embodiment (optionally including elements other than A); both A and B in yet another embodiment (optionally including other elements); and so on.

[0035] As used herein in the specification and claims, “or / or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or / or” or “and / or” should be interpreted as inclusive, i.e., including multiple elements or at least one of the elements in the list, but also including more than one, as well as optional additional items not listed. Only when the opposite terms are explicitly indicated, such as “only one of…” or “exact one of…”, or when used in the claims, “consisting of…”, will refer to the inclusion of multiple elements or exactly one of the elements in the list. In general, the term “or / or” as used herein, when preceded by an exclusive term such as “any,” “one of…,” “only one of…,” or “exact one of…”, should only be interpreted as indicating an exclusive alternative (i.e., “one or the other, but not both”). “Constitutes mainly of…” when used in the claims should have its ordinary meaning as used in the field of patent law.

[0036] As used herein in the specification and claims, the phrase “at least one” in relation to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list, but does not necessarily include at least one of each element specifically listed in the list, nor exclude any combination of elements in the list. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements referred to by the phrase “at least one,” whether related to or unrelated to those specifically identified elements. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or equivalently, “at least one of A and / or B”) in one embodiment may refer to at least one, optionally including more than one A, and without B (and optionally including elements other than B); in another embodiment may refer to at least one, optionally including more than one B, and without A (and optionally including elements other than A); in yet another embodiment may refer to at least one, optionally including more than one A, and at least one, optionally including more than one B (and optionally including other elements); and so on.

[0037] It should also be understood that, unless explicitly stated otherwise, in any method claimed herein that includes more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are recorded.

[0038] In the claims and in the foregoing description, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “constituting,” etc., should be understood as open-ended, meaning intended to include, but not limited to. As described in Section 2111.03 of the U.S. Patent Examination Procedure Manual, only the transitional phrases “constituting of” and “substantially consisting of” should be closed or semi-closed transitional phrases, respectively.

[0039] The various compounds included in the compositions of this disclosure may exist in specific geometric or stereoisomeric forms. Additionally, the polymers of this disclosure may also be optically active. This disclosure contemplates all such compounds, including cis and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, all of which fall within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, and mixtures thereof, are intended to be included in this disclosure.

[0040] For example, if a particular enantiomer of the compound of this disclosure is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary agent, wherein the resulting diastereomeric mixture is isolated and the auxiliary group is cleaved to provide a pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with a suitable optically active acid or base, followed by decomposition of the resulting diastereomeric mixture by fractional crystallization or chromatographic means known in the art, and then the pure enantiomer is recovered.

[0041] The structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, by replacing hydrogen with deuterium or tritium, or by using... 13 C- or 14 Compounds produced by C-enrichment of carbon substitutes for carbon are within the scope of this disclosure.

[0042] As used herein, the term "prodrug" encompasses compounds that are converted into therapeutically active agents under physiological conditions. A common method for preparing prodrugs involves selecting a portion that is hydrolyzed under physiological conditions to exhibit the desired molecule. Prodrugs can be converted by the enzymatic activity of a host animal. In other words, a "prodrug" is a compound that is converted in vivo to produce the disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of that compound. This conversion can occur through a variety of mechanisms, such as hydrolysis in the blood. For example, if the compound of the present invention or a pharmaceutically acceptable salt, hydrate, or solvate of that compound contains an alcohol functional group, a prodrug can be formed by replacing the hydrogen atom of the hydroxyl group with the desired group. Examples include: esters, oxygenated esters, oxaesters, polyethylene glycol esters, hydroxylated esters, alkyl esters, amino esters, alkylamino esters, dialkylamino esters, trialkylammonium esters, carbonates, alkyl carbonates, amino carbonates, alkylamino carbonates, dialkylamino carbonates, trialkylammonium carbonates, carbamates, alkyl carbamates, amino carbamates, alkylamino carbamates, dialkylamino carbamates, trialkylammonium carbamates, substituted phosphates, unsubstituted phosphates, unsubstituted diphosphates, substituted diphosphates, unsubstituted triphosphates, substituted triphosphates, phosphonates, substituted sulfates, unsubstituted sulfates, sulfonates, α-acyloxyalkyl, α-phosphonyloxyalkyl, or α-sulfonyloxyalkyl.

[0043] As used herein, the phrase “medicinal excipient” or “medicinal carrier” means a pharmaceutically usable material, composition, or carrier, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, relating to the carrying or transport of a subject chemical substance from one organ or site of the body to another organ or site of the body. Each carrier must be “usable” in the sense of being compatible with other components of the formulation, harmless to the patient, and substantially nonpyrogenic. Some examples of materials that can be used as pharmaceutically usable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and so on. Soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotropic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic and compatible substances used in pharmaceutical preparations. The pharmaceutical compositions of this disclosure may be pyrogen-free, i.e., they do not induce a significant increase in temperature when administered to a patient.

[0044] The term "pharmaceutical salt" refers to the relatively non-toxic inorganic and organic acid addition salt of a compound. These salts can be prepared in situ during the final separation and purification of the compound, or by reacting the purified compound, in its free base form, with a suitable organic or inorganic acid and then separating the resulting salt. Some representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, methanesulfonate, gluconate, lactobionate, and laurylsulfonate, etc. (e.g., see Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19.).

[0045] In other cases, compounds that can be used in the methods of this disclosure may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic base addition salt of the compound. These salts can also be prepared in situ during the final separation and purification of the compound, or by reacting the purified compound in its free acid form with a suitable base (e.g., a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation), with ammonia, or alone with a pharmaceutically acceptable primary, secondary, or tertiary organic amine. Some representative bases or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Some representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (see, for example, Berge et al., ibid.).

[0046] For therapeutic purposes, a “therapeutic effective amount” (or “effective amount”) of a compound refers to the amount of the compound in a formulation that, when administered as part of a desired dosing regimen (in mammals, such as humans), reduces symptoms, improves conditions, or slows the onset of disease symptoms, based on clinically acceptable criteria for the treatment of the disorder or condition or for cosmetic purposes, for example, with a reasonable benefit / risk ratio applicable to any medical treatment.

[0047] The term "preventive or therapeutic" treatment is recognized in the art and includes the administration of one or more compounds of this disclosure to a patient. A treatment is preventive (i.e., it protects the host from developing the undesirable condition) if administered before the clinical manifestation of an undesirable symptom (e.g., a disease or other undesirable state in the host animal), and therapeutic (i.e., it aims to reduce, alleviate, or stabilize the existing undesirable symptom or its side effects) if administered after the manifestation of the undesirable symptom.

[0048] The terms "patient" or "object" refer to a mammal requiring specific treatment. Patients or objects can be primates, dogs, felines, bovines, or equines. Patients or objects can be birds. Birds can be domesticated birds, such as chickens. Birds can be fowl. Patients or objects can be humans.

[0049] Aliphatic chains include the alkyl, alkenyl, and alkynyl categories as defined below. Straight aliphatic chains are limited to the unbranched carbon chain portion. As used herein, the term "aliphatic group" refers to a straight-chain, branched, or cyclic aliphatic hydrocarbon group and includes both saturated and unsaturated aliphatic groups, such as alkyl, alkenyl, or alkynyl groups.

[0050] "Alkyl" refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having a specified number of carbon atoms, or, if not specified, a maximum of 30 carbon atoms. For example, alkyl groups with 1 to 8 carbon atoms refer to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as those that are positional isomers of these moieties. Alkyl groups with 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, eicosyl, dodecyl, tridecyl, and tetradecyl. Straight-chain or branched alkyl groups may have 30 or fewer carbon atoms in their backbone (e.g., straight-chain C1-C1). 30 The branch is C3-C. 30 Alkyl groups have 20 or fewer carbon atoms. Alkyl groups can be substituted or unsubstituted.

[0051] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbon atoms (e.g., 2 to 12 carbon atoms) contained at two connection points on its longest carbon chain with the remainder of the compound. Some non-limiting examples of alkylenes include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylidene-(CH2CH(CH3))-, etc. Alkylenes can be cyclic or acyclic, branched or unbranched carbon chain portions, and may optionally be substituted with one or more substituents.

[0052] "Cycloalkyl" refers to a saturated carbocyclic ring, whether monocyclic, bicyclic, bridged, spirocyclic, or polycyclic, having 3 to 12 carbon atoms. Cycloalkyl groups can have 3 to 10 carbon atoms in their ring structure, or 3 to 6 carbon atoms. Cycloalkyl groups can be substituted or unsubstituted.

[0053] Unless otherwise specified, “lower alkyl” as used herein means an alkyl group as defined above but having 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms in its skeletal structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Substituents designated as alkyl groups herein may be lower alkyl groups.

[0054] "Alkenyl" refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having a specified number of carbon atoms, or, if no limit is specified, a maximum of 26 carbon atoms; and having one or more double bonds in the moiety. Examples of alkenyl groups with 6 to 26 carbon atoms include hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodeninyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosene, icosene, icosene, icosene, and icosene, in their various isomers, wherein the unsaturated bonds may be located anywhere in the moiety and may have (Z) or (E) configurations with respect to the double bonds.

[0055] "Alkyne" refers to a hydrocarbon moiety within the alkenyl group, but with one or more triple bonds in that moiety.

[0056] The term "alkylthio" refers to an alkyl group as defined above, having a sulfur moiety attached to it. The "alkylthio" moiety can be -(S)-alkyl, -(S)-alkenyl, -(S)-ynyl, or -(S)-(CH2). m -R 10 One of them represents m and R. 10 The definitions are as follows. Some representative alkyl thio groups include methyl thio, ethyl thio, etc. The term "alkoxy" or "alkoxy" as used herein refers to an alkyl group as defined below, having an oxygen moiety attached to it. Some representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc. An "ether" is two hydrocarbons covalently linked by oxygen. Therefore, the substituent of the alkyl group that makes it an ether is an alkoxy or similar alkoxy group, for example, it can be -O-alkyl, -O-alkenyl, -O-ynyl, -O-(CH2) m -R 10 One of them represents m and R. 10 As described below.

[0057] The terms "amine" and "amino" are recognized in the art and refer to both unsubstituted and substituted amines, for example, portions that can be represented by the following formula:

[0058]

[0059] Where R 11 and R 12 Each can independently represent hydrogen, alkyl, alkenyl, or -(CH2). m -R 10 , or R 11 and R 12Together with the N atoms they are attached to, they form heterocycles with 4 to 8 atoms in the ring structure; R 10 This indicates an alkenyl, aryl, cycloalkyl, cycloalkenyl, heterocyclic, or polycyclyl group; and m is an integer in the range of 0 or 1 to 8. In several embodiments, R 11 Or R 12 Only one of them can be a carbonyl group, such as R. 11 R 12 It does not form an imide with nitrogen. In several embodiments, R 11 and R 12 Each can independently represent hydrogen, alkyl, alkenyl, or -(CH2). m -R 10 Therefore, the term "alkylamine" as used herein refers to an amino group as defined above, which is attached to a substituted or unsubstituted alkyl group, i.e., R. 11 and R 12 At least one of them is an alkyl group. An amino or alkylamine can be basic, meaning it has a pK ratio. a Conjugate acids with a strength >7.00, i.e., the protonated forms of these functional groups, are pK. a pK relative to water a It is higher than approximately 7.00.

[0060] The term "amide" as used in this article refers to a group that:

[0061]

[0062] Each R 13 Independently representing a hydrogen or hydrocarbon group, or two Rs 13 Together with the N atom it is attached to, it forms a heterocycle with 4 to 8 atoms in the ring structure.

[0063] As used herein, the term "aryl" includes 3 to 12-membered substituted or unsubstituted monocyclic aromatic groups, wherein each atom of the ring is a carbon (i.e., carbocyclic aryl) or one or more atoms are heteroatoms (i.e., heteroaryl). Aryl groups can include 5 to 12-membered rings, 6 to 10-membered rings. The term "aryl" also includes polycyclic systems having two or more cyclic rings, wherein two or more carbons are common to two adjacent rings, and wherein at least one ring is aromatic; for example, the other rings can be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc. Heteroaryl groups include substituted or unsubstituted aromatic 3 to 12-membered ring structures, 5 to 12-membered rings, or 5 to 10-membered rings whose ring structures contain 1 to 4 heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, etc. Azides, thiazoles, triazoles, pyrazoles, pyridines, pyrazines, pyridazines, and pyrimidines, etc. Aryl and heteroaryl groups can be monocyclic, bicyclic, or polycyclic. Each instance of an aryl group can be independently and optionally substituted, i.e., unsubstituted (“unsubstituted aryl”) or substituted with one or more substituents, such as 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or only 1 substituent (“substituted aryl”). The aromatic ring can be substituted at one or more ring positions by one or more substituents, such as halogens, azides, alkyl, aryl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, mercapto, imino, amide, phosphonate, hypophosphonate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, etc. For example, the aryl group can be an unsubstituted C5-C. 12 Aryl groups may be substituted C5-C groups. 10 Aryl.

[0064] As used herein, the terms “halogenated,” “halide,” or “halogen” refer to halogens, and include, but are not limited to, fluorine, chlorine, bromine, iodine, etc., in both radioactive and non-radioactive forms. Halogenation may be selected from fluorine, chlorine, and bromine.

[0065] The term "heterocyclic group" or "heterocyclic group" refers to a 3- to 12-membered ring structure, a 5- to 12-membered ring, or a 5- to 10-membered ring, whose ring structure contains 1 to 4 heteroatoms. Heterocyclic rings can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclic groups include, for example, thiophene, thiathracene, furan, pyran, isobenzofuran, chromene, xanthene, and phenanthrene. Thiazole, pyrrole, imidazole, pyrazole, isothiazole, isothiazole Azole, pyridine, pyrazine, pyrimidine, pyridazine, indoleazine, isoindole, indole, indazole, purine, quinazine, isoquinoline, quinoline, phthalazine, naphthidine, quinoxaline, quinazoline, cinnazoline, pteridine, carbazole, caroline, phenanthridine, acridine, pyrimidine, phenanthroxaline, phenazine, phenanthridine, phenothiazine, furazine, phenanthridine Azides, pyrrolidines, oxolane, thiolane Zazoles, piperidines, piperazines, morpholines, lactones, lactams such as azacyclobutanone and pyrrolidone, sulopentaamides, sulopentalides, etc. The heterocycle may be substituted at one or more positions with substituents as described above, such as halogens, alkyl, aryl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, mercapto, imino, amide, phosphate esters, phosphonates, hypophosphonates, carbonyl, carboxyl, silyl, aminosulfonyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3, -CN, etc.

[0066] The term "carbonyl" is recognized in the art and includes a portion such as that which can be represented by the following formula:

[0067]

[0068] Where X' is a bond or represents oxygen, nitrogen, or sulfur, and R 14 Indicates hydrogen, alkyl, alkenyl, -(CH2) m -R 10 Or its medicinal salt, R 15 Indicates hydrogen, alkyl, alkenyl, or -(CH2). m -R 10 , where m and R 10 As defined above. Where X' is oxygen, and R 14 Or R 15 When it is not hydrogen, the formula represents "ester". Here, X' is oxygen, and R... 14 As defined above, this part is referred to as the carboxyl group in this paper, and especially when R 14 When the hydrogen is present, the formula represents "carboxylic acid". Here, X' is oxygen, and R... 15 When the oxygen atom is hydrogen, the formula represents "formate". Generally, when the oxygen atom in the above formula is replaced by sulfur, the formula represents "thiocarbonyl". Where X' is sulfur, and R... 14 Or R 15 When it is not hydrogen, this formula represents a "thioester" group. Where X' is sulfur, and R... 14 When the hydrogen is present, this formula represents a "thiocarboxylic acid" group. Where X' is sulfur, and R... 15 When X' is hydrogen, the formula represents a "thioformate" group. On the other hand, when X' is a bond and R... 14 When it is not hydrogen, the above formula represents a "ketone" group. Here, X' is a bond, and R... 14 When it is hydrogen, the above formula represents an "aldehyde" group.

[0069] As used herein, the term “nitro” means -NO2; the term “halogen” means -F, -Cl, -Br or -I; the term “mercapto” means -SH; the term “hydroxyl” means -OH; the term “sulfonyl” means -SO2-; the term “azide” means -N3; ​​the term “cyano” means -CN; the term “isocyanate” means -NCO; the term “thiocyanate” means -SCN; the term “isothiocyanate” means -NCS; and the term “cyanate” means -OCN.

[0070] The definition of each expression (e.g., alkyl, m, n, etc.) used herein, when it appears more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0071] The term "substituted" refers to a portion having a substituent that replaces hydrogen on one or more carbons of the skeleton. It should be understood that "substitution" or "replaced with..." includes the implicit condition that such substitution meets the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, which does not spontaneously undergo transformation (e.g., through rearrangement, cyclization, elimination, etc.). The term "substituted" as used herein is intended to include all permissible substituents in organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. For suitable organic compounds, permissible substituents may be one or more and may be the same or different. For the purposes of this disclosure, heteroatoms (e.g., nitrogen) may have hydrogen substituents and / or any permissible substituents of the organic compound described herein that satisfy the valence of that heteroatom. Substituents may include any substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetic acids, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate groups, phosphonates, hypophosphonates, amino groups, amide groups, amidine groups, imine groups, cyano groups, nitro groups, azide groups, mercapto groups, alkylthio groups, sulfate groups, sulfonates, aminosulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aryl groups, or aromatic or heteroaromatic moieties. Substituents on the substituted alkyl group may be selected from C10. 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, carbonyl, cyano, or hydroxyl groups. Substituents on the substituted alkyl group may be fluorine, carbonyl, cyano, or hydroxyl. Those skilled in the art will understand that the substituent itself may be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to the chemical part herein are understood to include substituted variants. For example, references to an “aryl” group or part of the term implicitly include both substituted and unsubstituted variants.

[0072] “GML” refers to glyceryl monolaurate.

[0073] “SGML” refers to glycerol thionomonolaureate (compound 2).

[0074] “S2GML” refers to dithionomonolaureate (compound 1), a dithioester.

[0075] For the purposes of this disclosure, chemical elements are determined according to the following: Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th edition, 1986-87, inside cover.

[0076] The compounds disclosed herein

[0077] This disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0078]

[0079] in:

[0080] R 1 Selected from alkyl, alkenyl, and ynyl groups;

[0081] R 2 and R 3 Independently selected from hydrogen, COR 4 -CON(H)R 4 -CO2R 4 or P(O)(OR) 4 )2;

[0082] Or, R 2 and R 3 Together with the carbon atoms they are attached to, they can form 3 to 5-membered aliphatic carbon rings;

[0083] R 4 It is H, alkyl, alkenyl, aryl, cycloalkyl, heterocyclic, or heteroaryl;

[0084] and

[0085] X is either O or S.

[0086] R 1 It can be an alkyl group. R 1 It can be a branched or unbranched (straight) alkyl group. R 1 It can be (C8-C) 20 )alkyl. R 1 It can be substituted (C8-C) 20 )alkyl. R 1 It can be unreplaced (C) 10 -C 16 )alkyl. R 1 It can be replaced (C) 10 -C 16 )alkyl. R 1 It can be C without replacement. 11 Alkyl group. R 1 It can be an unsubstituted linear C 11Alkyl group. R 1 It can be a substituted C 11 Alkyl group. R 1 It can be unreplaced (C) 10 -C 16 )alkenyl. R 1 It can be replaced (C) 10 -C 16 )alkenyl. R 1 It can be C without replacement. 11 Alkenyl. R 1 It can be a substituted C 11 Alkenyl. R 1 It can be unreplaced (C) 10 -C 16 ) ynyl group. R 1 It can be replaced (C) 10 -C 16 ) ynyl group. R 1 It can be C without replacement. 11 Alkynyl group. R 1 It can be a substituted C 11 Alkyne group.

[0087] R 2 It could be hydrogen. R 2 It can be a (C1-C4) alkyl group. R 2 It can be -COR 4 R 2 It can be -CON(H)R 4 R 2 It can be -CO2R 4 R 2 It can be P(O)(OR) 4 )2. R 2 It can be P(O)(OH)2.

[0088] R 3 It could be hydrogen. R 3 It can be a (C1-C4) alkyl group. R 3 It can be -COR 4 R 3 It can be -CON(H)R 4 R 3 It can be -CO2R 4 R 3 It can be P(O)(OR) 4 )2. R 3 It can be P(O)(OH)2.

[0089] R 2 and R 3 They can be the same. R 2 and R3 They can be different. R 2 and R 3 Both can be hydrogen.

[0090] R 2 and R 3 Together with the carbon atoms they are attached to, they can form 3 to 5-membered aliphatic carbon rings.

[0091] R 4 It can be H. R 4 It can be an alkyl group. R 4 It can be methyl. R 4 It can be ethyl. R 4 It can be n-propyl. R 4 It can be isopropyl. R 4 It can be n-butyl. R 4 It can be isobutyl. R 4 It can be tert-butyl. R 4 It can be a cycloalkyl group. R 4 It can be a heterocyclic group.

[0092] X can be O. X can be S.

[0093] R 1 R 2 R 3 and R 4 It can be substituted by at least one substituent selected from the following: halogen, alkyl, aryl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, mercapto, imino, amide, aminosulfonyl, sulfinyl, alkylthio, sulfonyl, ketone, heterocyclic, aromatic or heteroaromatic moiety, CHF2-CF3, -CN. If R 1 R 2 R 3 Or R 4 If a substance is replaced by two or more substituents, the substituents may be the same or different.

[0094] The compounds of the present invention may be

[0095]

[0096] The compounds of the present invention may be

[0097]

[0098] The compounds of the present invention may be

[0099]

[0100] The compounds of the present invention may be

[0101]

[0102] The compounds of the present invention may be

[0103]

[0104] The compounds of the present invention may be

[0105]

[0106] Treatment

[0107] This disclosure relates to a method of treating an infection, comprising the step of administering a therapeutically effective amount of any of the aforementioned compounds to an infected subject.

[0108] Viral infection

[0109] This disclosure relates to a method for treating viral infections, comprising the step of administering a therapeutically effective amount of any of the aforementioned compounds to a subject in need.

[0110] Viral infections can be respiratory infections, such as infections of the nose, throat, upper airways, and lungs. Infections can be upper respiratory tract infections, including sore throat, sinusitis, and the common cold. Other viral respiratory infections include influenza, pneumonia, and coronaviruses.

[0111] Infections can be inflammation of the upper and lower airways, such as laryngotracheobronchitis, or inflammation of the lower airways, such as bronchiolitis.

[0112] Viral infections can be gastrointestinal infections, such as gastroenteritis caused by viruses (e.g., norovirus and rotavirus).

[0113] Viral infections can cause liver infections, which can lead to hepatitis.

[0114] Viral infections can be infections of the nervous system. Some viruses (such as rabies virus and West Nile virus) infect the brain, causing encephalitis. Other infections cover the tissue layers of the brain and spinal cord (meninges), leading to meningitis or poliomyelitis.

[0115] Viral infections can be skin infections. Viral infections that only affect the skin sometimes cause warts or other blemishes. Many viruses that affect other parts of the body (such as chickenpox) also cause rashes.

[0116] Viral infections can affect both the placenta and the fetus. Some viruses (such as Zika virus, rubella virus, and cytomegalovirus) can infect the placenta and fetus of pregnant women.

[0117] Viral infections can be caused by enveloped viruses (such as SARS-CoV-2 or influenza viruses), large non-enveloped viruses, or small non-enveloped viruses.

[0118] fungal infection

[0119] This disclosure relates to a method for treating fungal infections, comprising the step of administering a therapeutically effective amount of any of the aforementioned compounds to a subject in need.

[0120] Fungal infections can be nail infections. Fungal infections can be tinea. Fungal infections can be yeast infections, such as vaginal candidiasis. Fungal infections can be candidiasis of the mouth, throat, or esophagus.

[0121] Fungal infections can be fungal diseases that affect people who live in or travel to certain areas, such as blastomycosis, coccidioidomycosis (Valley fever), Cryptococcus gattii infection, hispoplasmosis, or paracoccidioidomycosis.

[0122] Fungal infections can affect people with weakened immune systems, such as aspergillosis, candidiasis, auricularia auris infection, cryptococcal infection, invasive candidiasis, mycormycosis, Pneumocystis pneumonia (PCP), or talaromycosis.

[0123] Fungal infections can include ocular fungal infections, mycetoma, and sporotrichosis.

[0124] Bacterial infection

[0125] This disclosure relates to a method for treating bacterial infections, comprising the step of administering a therapeutically effective amount of any of the aforementioned compounds to a subject in need.

[0126] Bacterial infections can be skin infections involving only the skin or skin infections involving the subcutaneous soft tissue. Skin infections include: carbuncles, leg ulcers, erythritis, folliculitis, boils, impetigo, lymphadenitis, and small skin abscesses (pus-filled pockets in the skin). Other bacterial skin and skin structure infections include cellulitis, erysipelas, large skin abscesses, lymphangitis, necrotizing skin infections, staphylococcal scalded skin syndrome, and wound infections.

[0127] Bacterial infections can be ear or throat infections, such as streptococcal laryngitis.

[0128] Urinary tract infection (UTI)

[0129] Infections can be UTIs. UTIs can be lower UTs, such as bladder infections (cystitis). Lower UTIs can also be urethral infections (urethritis) or prostate infections (prostatitis).

[0130] UTIs can be upper UTIs, such as kidney infections (pyelonephritis).

[0131] UTIs can be caused by bacterial infections, such as bacterial infections of the lower urinary tract.

[0132] UTIs can be viral infections, such as those caused by the herpes simplex virus.

[0133] UTIs can be caused by fungal or yeast infections. UTIs can be vaginitis or candidiasis.

[0134] UTIs can be caused by parasites. UTIs can be trichomoniasis, schistosomiasis, or filariasis. Drug composition, route of administration, and dosage.

[0135] In some embodiments, this disclosure relates to pharmaceutical compositions comprising compounds of this disclosure and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises multiple compounds of this disclosure and a pharmaceutically acceptable carrier.

[0136] In some embodiments, the pharmaceutical compositions of this disclosure further comprise at least one additional pharmaceutically active agent besides the compounds disclosed herein. The at least one additional pharmaceutically active agent may be an agent that can be used to treat infections.

[0137] The pharmaceutical compositions of this disclosure can be prepared by combining one or more compounds of this disclosure with a pharmaceutically acceptable carrier and optionally one or more other pharmaceutically active agents.

[0138] As stated above, "effective amount" means any amount sufficient to achieve the desired biological effect. In conjunction with the teachings provided herein, effective prophylactic or therapeutic regimens can be planned that do not cause significant undesirable toxicity but are effective for treating a particular subject by selecting from a variety of active compounds and weighing factors such as potency, relative bioavailability, patient weight, severity of adverse side effects, and mode of administration. The effective amount for any particular application can vary depending on factors such as the disease or condition being treated, the specific compound of this disclosure being administered, the size of the subject, or the severity of the disease or condition. Those skilled in the art can empirically determine the effective amount of a particular compound and / or other therapeutic agent of this disclosure without excessive experimentation. A maximum dose can be used, i.e., the highest safe dose based on some medical judgment. Multiple daily doses can be considered to achieve appropriate systemic levels of the compound. Appropriate systemic levels can be determined, for example, by measuring the patient's peak or sustained plasma levels. "Dose" and "dosage" are used interchangeably herein.

[0139] Typically, for human subjects, the daily oral dose of the compound ranges from approximately 0.01 mg / kg / day to 1000 mg / kg / day. Oral doses of 0.5 to 50 mg / kg administered once or more daily can produce therapeutic results. Depending on the route of administration, the dose can be appropriately adjusted to achieve the desired local or systemic drug levels. For example, intravenous administration can range from lower doses of one to several orders of magnitude per day. If the response is insufficient at such doses, even higher doses (or more effective doses achieved through different, more localized delivery routes) can be used up to the extent tolerated by the patient. Multiple daily doses can be considered to achieve appropriate systemic levels of the compound.

[0140] For any of the compounds described herein, the therapeutically effective dose can be initially determined from animal models. The therapeutically effective dose can also be determined from human data of compounds that have been tested in humans and compounds known to exhibit similar pharmacological activity, such as other relevant active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the compound being administered. Adjusting the dose to achieve maximum potency based on the methods described above and others, as is known in the art, is entirely within the capabilities of a person skilled in the art.

[0141] For clinical use, any compound of this disclosure may be administered at an amount equal to or equivalent to 0.2 to 2000 mg of compound per kilogram of body weight per day. Compounds of this disclosure may be administered at a dose equal to or equivalent to 2 to 2000 mg of compound per kilogram of body weight per day. Compounds of this disclosure may be administered at a dose equal to or equivalent to 20 to 2000 mg of compound per kilogram of body weight per day. Compounds of this disclosure may be administered at a dose equal to or equivalent to 50 to 2000 mg of compound per kilogram of body weight per day. Compounds of this disclosure may be administered at a dose equal to or equivalent to 100 to 2000 mg of compound per kilogram of body weight per day. Compounds of this disclosure may be administered at a dose equal to or equivalent to 200 to 2000 mg of compound per kilogram of body weight per day. When a prodrug or prodrug of a compound of this disclosure is to be administered instead of the compound itself, it is administered at an amount equivalent to (i.e., sufficient to deliver) the amounts of the compounds of the present invention described above.

[0142] Formulations of the compounds disclosed herein can be administered to human subjects in therapeutically effective amounts, for example, in one or more unit dosage forms as described below. Typical dosage ranges are from about 0.01 micrograms / kg body weight / day to about 2 mg / kg body weight / day. The dosage of the drug to be administered may depend on variables such as the type and severity of the condition, the overall health status of the particular subject, the specific compound being administered, the excipients used to formulate the compound, and its route of administration. Routine experiments can be used to optimize the dosage and frequency of administration for any particular compound.

[0143] The compounds disclosed herein can be administered at concentrations ranging from about 0.001 μg / kg to greater than about 500 mg / kg. For example, concentrations may be 0.001 μg / kg, 0.01 μg / kg, 0.05 μg / kg, 0.1 μg / kg, 0.5 μg / kg, 1.0 μg / kg, 10.0 μg / kg, 50.0 μg / kg, 100.0 μg / kg, 500 μg / kg, 1.0 mg / kg, 5.0 mg / kg, 10.0 mg / kg, 15.0 mg / kg, 20.0 mg / kg, 25.0 mg / kg, 30.0 mg / kg, 35.0 mg / kg, etc. The values ​​are 40.0 mg / kg, 45.0 mg / kg, 50.0 mg / kg, 60.0 mg / kg, 70.0 mg / kg, 80.0 mg / kg, 90.0 mg / kg, 100.0 mg / kg, 150.0 mg / kg, 200.0 mg / kg, 250.0 mg / kg, 300.0 mg / kg, 350.0 mg / kg, 400.0 mg / kg, 450.0 mg / kg, up to greater than about 500.0 mg / kg or any increment thereof. It should be understood that all values ​​and ranges between these ranges are intended to be covered within the scope of this invention.

[0144] The compounds disclosed herein can be administered at doses ranging from about 0.2 mg / kg / day to greater than about 100 mg / kg / day. For example, doses may be 0.2 mg / kg / day to 100 mg / kg / day, 0.2 mg / kg / day to 50 mg / kg / day, 0.2 mg / kg / day to 25 mg / kg / day, 0.2 mg / kg / day to 10 mg / kg / day, 0.2 mg / kg / day to 7.5 mg / kg / day, 0.2 mg / kg / day to 5 mg / kg / day, 0.25 mg / kg / day to 100 mg / kg / day, 0.25 mg / kg / day to 50 mg / kg / day, 0.25 mg / kg / day to 25 mg / kg / day, 0.25 mg / kg / day... 0.25 mg / kg / day to 7.5 mg / kg / day, 0.25 mg / kg / day to 5 mg / kg / day, 0.5 mg / kg / day to 50 mg / kg / day, 0.5 mg / kg / day to 25 mg / kg / day, 0.5 mg / kg / day to 20 mg / kg / day, 0.5 mg / kg / day to 15 mg / kg / day, 0.5 mg / kg / day to 10 mg / kg / day, 0.5 mg / kg / day to 7.5 mg / kg / day, 0.5 mg / kg / day to 5 mg / kg / day, 0.75 mg / kg / day to 50mg / kg / day, 0.75mg / kg / day to 25mg / kg / day, 0.75mg / kg / day to 20mg / kg / day, 0.75mg / kg / day to 15mg / kg / day, 0.75mg / kg / day to 10mg / kg / day, 0.75mg / kg / day to 7.5mg / kg / day, 0.75mg / kg / day to 5mg / kg / day, 1.0mg / kg / day to 50mg / kg / day, 1.0mg / kg / day to 25mg / kg / day, 1.0mg / kg / day to 20mg / kg / day, 1.0m g / kg / day to 15 mg / kg / day, 1.0 mg / kg / day to 10 mg / kg / day, 1.0 mg / kg / day to 7.5 mg / kg / day, 1.0 mg / kg / day to 5 mg / kg / day, 2 mg / kg / day to 50 mg / kg / day, 2 mg / kg / day to 25 mg / kg / day, 2 mg / kg / day to 20 mg / kg / day, 2 mg / kg / day to 15 mg / kg / day, 2 mg / kg / day to 10 mg / kg / day, 2 mg / kg / day to 7.5 mg / kg / day, or 2 mg / kg / day to 5 mg / kg / day.

[0145] The compounds disclosed herein can be administered at doses of about 0.25 mg / kg / day to about 25 mg / kg / day. For example, doses may be 0.25 mg / kg / day, 0.5 mg / kg / day, 0.75 mg / kg / day, 1.0 mg / kg / day, 1.25 mg / kg / day, 1.5 mg / kg / day, 1.75 mg / kg / day, 2.0 mg / kg / day, 2.25 mg / kg / day, 2.5 mg / kg / day, 2.75 mg / kg / day, 3.0 mg / kg / day, 3.25 mg / kg / day, 3.5 mg / kg / day, 3.75 mg / kg / day, 4.0 mg / kg / day, etc. / kg / day, 4.25mg / kg / day, 4.5mg / kg / day, 4.75mg / kg / day, 5mg / kg / day, 5.5mg / kg / day, 6.0mg / kg / day, 6.5mg / kg / day, 7.0mg / kg / day, 7.5mg / kg / day, 8.0mg / kg / day, 8.5mg / kg / day, 9.0mg / kg / day, 9.5mg / kg / day, 10mg / kg / day, 11mg / kg / day, 12mg / kg / day, 13mg / kg / day, 14mg / kg / day, 15mg / kg / day, 16mg / kg / day, 17mg / kg / day, 18mg / kg / day, 19mg / kg / day, 20mg / kg / day, 21mg / kg / day, 22mg / kg / day, 23mg / kg / day, 24mg / kg / day, 25mg / kg / day, 26mg / kg / day, 27mg / kg / day, 28mg / kg / day, 29mg / kg / day, 30mg / kg / day, 31mg / kg / day, 32mg / kg / day g / kg / day, 33mg / kg / day, 34mg / kg / day, 35mg / kg / day, 36mg / kg / day, 37mg / kg / day, 38mg / kg / day, 39mg / kg / day, 40mg / kg / day, 41mg / kg / day, 42mg / kg / day, 43mg / kg / day, 44mg / kg / day, 45mg / kg / day, 46mg / kg / day, 47mg / kg / day, 48mg / kg / day, 49mg / kg / day, or 50mg / kg / day.

[0146] The compound or its precursor may be administered at concentrations from 0.01 μmol to greater than or equal to 500 μmol. For example, dosages may be 0.01 μmol, 0.02 μmol, 0.05 μmol, 0.1 μmol, 0.15 μmol, 0.2 μmol, 0.5 μmol, 0.7 μmol, 1.0 μmol, 3.0 μmol, 5.0 μmol, 7.0 μmol, 10.0 μmol, 15.0 μmol, 20.0 μmol, 25.0 μmol, 30.0 μmol, 35.0 μmol, 4... 0.0 μmol, 45.0 μmol, 50.0 μmol, 60.0 μmol, 70.0 μmol, 80.0 μmol, 90.0 μmol, 100.0 μmol, 150.0 μmol, 200.0 μmol, 250.0 μmol, 300.0 μmol, 350.0 μmol, 400.0 μmol, 450.0 μmol to greater than about 500.0 μmol or any increment thereof. It should be understood that all values ​​and ranges between these ranges are intended to be covered within the scope of this invention.

[0147] The compound or its precursor may be administered at concentrations ranging from 0.10 μg / mL to 500.0 μg / mL. For example, the concentration can be 0.10 μg / mL, 0.50 μg / mL, 1 μg / mL, 2.0 μg / mL, 5.0 μg / mL, 10.0 μg / mL, 20 μg / mL, 25 μg / mL, 30 μg / mL, 35 μg / mL, 40 μg / mL, 45 μg / mL, 50 μg / mL, 60.0 μg / mL, 70.0 μg / mL, 80.0 μg / mL, 90.0 μg / mL, 100.0 μg / mL, 150.0 μg / mL, 200.0 μg / mL, 250.0 μg / mL, 300.0 μg / mL, 350.0 μg / mL, 400.0 μg / mL, 450.0 μg / mL to greater than about 500.0 μg / mL or any increment thereof. It should be understood that all values ​​and ranges between these values ​​and ranges are intended to be covered in this invention.

[0148] The formulations disclosed herein can be administered as pharmaceutically acceptable solutions, which may conventionally contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, excipients, and optionally other therapeutic ingredients. For therapeutic use, an effective amount of the compound may be administered to the subject by any means of delivering the compound to a desired surface. The administration of the pharmaceutical composition may be achieved by any means known to a person skilled in the art. Routes of administration include, but are not limited to, intravenous, intramuscular, intraperitoneal, intravesical (bladder), oral, subcutaneous, direct injection (e.g., injection into a tumor or abscess), transmucosal (e.g., ocular surface), inhalation, and topical administration.

[0149] For intravenous and other parenteral administration routes, the compounds of this disclosure can be formulated into lyophilized formulations, lyophilized formulations of active compounds intercalated or encapsulated in liposomes, lipid complexes, or salt complexes in aqueous suspensions. Lyophilized formulations are typically reconstituted in a suitable aqueous solution, such as sterile water or saline, shortly before administration.

[0150] For oral administration, the compound can be readily formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art. Such a carrier enables the compounds of this disclosure to be formulated into tablets, pills, sugar-coated pills, capsules, liquids, gels, syrups, pastes, suspensions, etc., for oral ingestion by the intended recipient. Pharmaceutical formulations for oral use can be obtained as solid excipients, and optionally, after the addition of suitable excipients, the resulting mixture can be milled and processed into granular mixtures to obtain tablets or sugar-coated pill cores. Suitable excipients are particularly fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose formulations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinyl pyrrolidone (PVP). If desired, a disintegrant such as cross-linked polyvinylpyrrolidone, agar, or alginate or its salts, such as sodium alginate, may be added. Optionally, oral formulations may also be formulated in saline or buffer solutions (e.g., EDTA for neutralizing internal acidic conditions) or may be administered without any carrier.

[0151] Oral dosage forms of the compounds of this disclosure are also considered. The compounds of this disclosure can be chemically modified to make oral delivery of the derivatives effective. Typically, the chemical modifications considered are the attachment of at least one part of the compound itself, wherein said part allows (a) inhibition of acid hydrolysis; and (b) uptake from the stomach or intestine into the bloodstream. Increased overall stability of the compound and increased in vivo circulation time are also desired. Some examples of such parts include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts,” In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, NY, pp. 367-383 (1981); Newmark et al., JAppl Biochem 4: 185-9 (1982). Other polymers that can be used are poly-1,3-dioxane-pentane and poly-1,3,6-trioxane-octane. For pharmaceutical applications, as indicated above, the polyethylene glycol portion is suitable.

[0152] The site of release of the compound disclosed herein may be the stomach, small intestine (duodenum, jejunum, or ileum), or large intestine. Those skilled in the art will obtain formulations that do not dissolve in the stomach but release material in the duodenum or other locations in the intestine. Release can avoid the harmful effects of the gastric environment by protecting the compound disclosed herein or by releasing the compound outside the gastric environment (e.g., in the intestine).

[0153] To ensure complete gastric resistance, an impermeable coating at at least pH 5.0 is necessary. Some examples of common inert ingredients used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings can be used as blended membranes.

[0154] Coatings or coating mixtures may also be used on tablets, not necessarily intended to provide protection against the stomach. This may include sugar coatings or coatings that make the tablets easier to swallow. Capsules may consist of a hard shell (e.g., gelatin) for delivering dry therapeutic agents (e.g., powders); for liquid forms, a soft gelatin shell may be used. The shell material for caches may be thick starch paper or other edible paper. For pills, lozenges, molded tablets, or tablet triturates, wet massing techniques may be used.

[0155] Therapeutic agents can be contained in formulations as finely fragmented, multi-particle granules or pellets with a particle size of about 1 mm or smaller (i.e., nanoparticles). Formulations for materials used in capsule administration can also be in the form of powders, lightly compressed chewables, or even tablets. Therapeutic agents can be prepared by compression.

[0156] Colorants and flavoring agents may both be included. For example, the compounds disclosed herein may be formulated (e.g., encapsulated via liposomes or microspheres) and subsequently further included in edible products, such as chilled beverages containing colorants and flavoring agents.

[0157] Therapeutic agents can be diluted or increased in volume using inert materials. These diluents may include carbohydrates, particularly mannitol, alpha-lactose, anhydrous lactose, cellulose, sucrose, modified dextran, and starch. Certain inorganic salts may also be used as fillers, including calcium triphosphate, magnesium carbonate, and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress, and Avicell.

[0158] Disintegrants can be included in the formulation of therapeutic agents into solid dosage forms. Materials used as disintegrants include, but are not limited to, starch, including the commercially available starch-based disintegrant Explotab. Sodium glycolate starch, amberlite, sodium carboxymethyl cellulose, ultrabranched starch, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponges, and bentonite are all possible applications. Another form of disintegrant is an insoluble cation exchange resin. Powdered gum can be used as both a disintegrant and a binder, and these may include powdered gums such as agar, ark tartar gum, or tragacanth gum. Alginic acid and its sodium salts can also be used as disintegrants.

[0159] Adhesives can be used to hold therapeutic agents together to form hard tablets and include materials derived from natural products such as gum arabic, tragacanth gum, starch, and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC), and carboxymethyl cellulose (CMC). Both polyvinylpyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) can be used in alcoholic solutions to granulate therapeutic agents.

[0160] Anti-friction agents may be included in the formulation of the therapeutic agent to prevent sticking during formulation. Lubricants may be used as a layer between the therapeutic agent and the mold wall, and these may include, but are not limited to: stearic acid (including its magnesium and calcium salts), polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils, and waxes. Soluble lubricants may also be used, such as sodium dodecyl sulfate, magnesium dodecyl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000, and 6000.

[0161] A flow aid may be added to improve drug flow properties during formulation and to aid rearrangement during compression. Flow aids may include starch, talc, thermally induced silica, and hydrated aluminosilicates.

[0162] To aid in the dissolution of the therapeutic agent in an aqueous environment, a surfactant may be added as a wetting agent. Surfactants may include anionic detergents such as sodium dodecyl sulfate, dioctyl sodium sulfosuccinate, and dioctyl sodium sulfonate. Cationic detergents may be used, and these may include benzalkonium chloride and benzyl chloride. Potential nonionic detergents that may be included in formulations as surfactants include polidocanol 400; polyoxyethylene 40 stearate; polyoxyethylene hydrogenated castor oil 10, 50, and 60; glyceryl monostearate; polysorbate 40, 60, 65, and 80; sucrose fatty acid esters; methylcellulose; and carboxymethylcellulose. These surfactants may be present, alone or in mixtures in varying proportions, in formulations of the compounds or derivatives disclosed herein.

[0163] Pharmaceutical formulations that can be administered orally in unit dosage forms include push-fit capsules made of gelatin and soft-sealable capsules made of gelatin and plasticizers (such as glycerin or sorbitol). Push-fit capsules may contain a mixture of the active ingredient and fillers (such as lactose), binders (such as starch), and / or lubricants (such as talc or magnesium stearate), and optionally stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres are well defined in the art. All formulations intended for oral administration should be at doses suitable for such administration.

[0164] For buccal administration, the composition may be in the form of tablets or lozenges formulated in a conventional manner.

[0165] For surface application, compounds can be formulated as solutions, gels, ointments, creams, suspensions, etc., as is known in the art. Systemic formulations include those designed for administration by injection (e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection), as well as those designed for transdermal, transmucosal, oral, or transpulmonary administration.

[0166] For administration by inhalation, the compounds used according to this disclosure may be conveniently delivered as aerosols from a pressurized package or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In the case of pressurized aerosols, the dosage unit can be determined by providing a valve to deliver the measured amount. Capsules and cartridges (e.g., gelatin) for inhalers or blowpipes may be formulated as powder mixtures containing the compound with a suitable powder matrix (e.g., lactose or starch).

[0167] This article also considers pulmonary delivery of the disclosed compounds (or salts thereof). The compounds are delivered to the lungs of mammals upon inhalation and cross the epithelial lining into the bloodstream. Other reports on inhaled molecules include: Adjei et al., Pharm Res 7: 565-569 (1990); Adjei et al., Int J Pharmaceutics 63: 135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13 (suppl. 5): 143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3: 206-212 (1989) (α1-antitrypsin); Smith et al., 1989, J Clin Invest 84: 1145-1146 (α-1-protease); Oswein et al., 1990, "Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (Recombinant Human Growth Hormone); Debset et al., 1988, J Immunol 140:3482-3488 (Interferon-γ and Tumor Necrosis Factor α); and Platz et al., US Patent No. 5,284,656 (Granocyte Colony-Stimulating Factor; incorporated by reference). Methods and compositions for pulmonary delivery of drugs to achieve systemic effects are described in US Patent No. 5,451,569 (incorporated by reference), issued to Wong et al. on September 19, 1995.

[0168] Considerable for use in the practice of this disclosure are a variety of mechanical devices designed for lung delivery therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.

[0169] Nasal delivery of the pharmaceutical compositions of this disclosure is also considered. Nasal delivery allows the pharmaceutical compositions of this disclosure to enter the bloodstream directly after the therapeutic product is applied to the nose, without requiring deposition of the product in the lungs. Nasal-delivered formulations include those containing dextran or cyclodextrin.

[0170] When systemic delivery of a compound is desired, it can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Formulations for injection may be present in unit dosage forms (e.g., in ampoules or in multi-dose containers) with the addition of preservatives. The composition may take the form of a suspension, solution, or emulsion, for example, in an oily or aqueous carrier, and may contain formulations such as suspending agents, stabilizers, and / or dispersants.

[0171] Pharmaceutical formulations intended for parenteral administration include aqueous solutions of the active compound in a water-soluble form. Alternatively, suspensions of the active compound can be prepared as suitable oily injectable suspensions. Suitable lipophilic solvents or carriers include fatty oils (e.g., sesame oil), synthetic fatty acid esters (e.g., ethyl oleate or triglycerides), or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that improve the solubility of the compound to allow for the preparation of highly concentrated solutions.

[0172] Alternatively, the active compound can be in powder form for use with a suitable carrier (e.g., sterile, pyrogen-free water) prior to use.

[0173] The compound can also be formulated into rectal or vaginal compositions, such as suppositories or retention enemas, for example, containing a conventional suppository base, such as cocoa butter or other glycerides.

[0174] In addition to the formulations described above, compounds can also be formulated into depot preparations. Such long-acting preparations can be formulated using suitable polymers or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or as sparingly soluble derivatives, such as sparingly soluble salts.

[0175] The pharmaceutical composition may also contain a suitable solid or gel phase carrier or excipient. Some examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0176] Suitable liquid or solid pharmaceutical formulations include, for example, aqueous or saline solutions for inhalation; microencapsulated, encochleated, microscopic gold particle-coated, liposome-containing, nebulized aerosols; and pellets for implantation into the skin or drying onto a sharp object for insertion into the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or formulations with a prolonged release of the active compound, in which the aforementioned excipients and additives and / or excipients, such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners, or solubilizers, are conventionally used. Pharmaceutical compositions are suitable for a variety of drug delivery systems. For a brief overview of drug delivery methods, see Langer, R, Science 249:1527-33 (1990).

[0177] The compounds and optionally other therapeutic agents disclosed herein may be administered either in their pure (neat) form or as pharmaceutically acceptable salts. When used in a pharmaceutical context, the salts should be pharmaceutically acceptable, but non-pharmaceutical salts may be conveniently used to prepare their pharmaceutically acceptable form. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Similarly, such salts may be prepared as alkali metal or alkaline earth salts, such as sodium, potassium, or calcium salts of a carboxylic acid group.

[0178] Suitable buffers include: acetic acid and its salt (1% to 2% w / v); citric acid and its salt (1% to 3% w / v); boric acid and its salt (0.5% to 2.5% w / v); and phosphoric acid and its salt (0.8% to 2% w / v). Suitable preservatives include benzalkonium chloride (0.003% to 0.03% w / v); chlorobutanol (0.3% to 0.9% w / v); parabens (0.01% to 0.25% w / v); and thimerosal (0.004% to 0.02% w / v).

[0179] The pharmaceutical compositions of this disclosure contain an effective amount of the compounds as described herein and optionally a therapeutic agent contained in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers, diluents, or encapsulating substances suitable for administration to humans or other vertebrates. The term "carrier" refers to a natural or synthetic organic or inorganic component with which the active ingredient is combined to facilitate application. The components of the pharmaceutical composition are also miscible with the compounds of this disclosure, and with each other, in a manner that prevents interactions that would significantly impair the desired pharmaceutical efficacy.

[0180] Therapeutic agents (specifically, including but not limited to, the compounds of this disclosure) may be provided in the form of particles. As used herein, particles refer to nanoparticles or microparticles (or, in some cases, larger particles) that may consist wholly or partially of the compounds of this disclosure or other therapeutic agents as described herein. The particles may contain the therapeutic agent within a core surrounded by a coating (including, but not limited to, enteric coating). The therapeutic agent may also be dispersed throughout the particle. The therapeutic agent may also be adsorbed into the particle. The particles may have any level of release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof. In addition to therapeutic agents, the particles may also contain any of those materials conventionally used in the pharmaceutical and medical fields, including but not limited to erosive, non-erosive, biodegradable, or non-biodegradable materials, or combinations thereof. The particles may be microcapsules containing the compounds of this disclosure in a solution or semi-solid state. The particles may virtually be of any shape.

[0181] Both non-biodegradable and biodegradable polymeric materials can be used to manufacture particles for delivering therapeutic agents. Such polymers can be natural or synthetic. The polymer is selected based on the desired release time period. Of particular interest are bioadhesive polymers including bio-erosive hydrogels described in Sawhney HS et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein by reference. These include polyhyaluronic acid, casein, gelatin, gelatin protein, polyanhydride, polyacrylic acid, alginate, chitosan, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(laurate methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).

[0182] Therapeutic agents may be included in controlled-release systems. The term “controlled release” is intended to refer to any formulation containing a drug in which the manner and spectrum of drug release from the formulation are controlled. This refers to immediately released formulations and non-immediately released formulations, wherein non-immediately released formulations include, but are not limited to, sustained-release and delayed-release formulations. The term “sustainable release” (also known as “extended release”) is used in its conventional sense to refer to a pharmaceutical formulation that provides a gradual release of the drug over an extended period of time and may result in a substantially constant blood level of the drug over the extended period of time. The term “delayed release” is used in its conventional sense to refer to a pharmaceutical formulation in which there is a time delay between formulation administration and the release of the drug therefrom. “Delayed release” may or may not involve a gradual release of the drug over an extended period of time, and therefore may or may not be “sustained release”.

[0183] The use of long-term sustained-release implants is particularly suitable for the treatment of chronic conditions. As used herein, “long-term” release means that the implant is constructed and positioned to deliver therapeutic levels of active ingredient for at least 7 days and up to 30 to 60 days. Long-term sustained-release implants are well known to those skilled in the art and include some of the aforementioned release systems.

[0184] Those skilled in the art will understand that, given the information known to them, other suitable modifications and adaptations to the compositions and methods described herein will readily emerge from the description of the disclosure contained herein and may be made without departing from the scope of this disclosure or any embodiment thereof. Now that this disclosure has been described in detail, it will become clearer to them by referring to the following examples, which are included herein for illustrative purposes only and are not intended to limit the scope of this disclosure.

[0185] Example

[0186] The invention will now be described in general terms, and will be more readily understood by referring to the following embodiments, which are included only for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0187] Materials and methods

[0188] General Chemical Synthesis

[0189] This document describes several methods for the chemical synthesis of exemplary compounds. These and / or other known methods can be modified and / or adapted in known ways to synthesize other compounds described herein.

[0190] General Plan

[0191]

[0192] In one method, certain compounds described herein can be conveniently prepared by reacting a suitably substituted carboxylic acid G1 with a reagent such as G2 to give intermediate G3. Other sulfiding reagents, such as Lawstson's reagent, P4S10, Davy's reagent, and other similar compounds, can also be used after methylation. Alternatively, G3 can be prepared by deprotonating G1 with a strong base (e.g., lithium diisopropylamino) followed by reaction with carbon disulfide and then with a methylating reagent MeY (e.g., iodomethane). Intermediate G3 can be further modified with an alcohol or thiol G4, where R2 and R3 are protecting groups or variable substituents. If R2 and R3 are variable substituents, then compound G5 will be the final example. In the case where R2 and R3 are protecting groups, or in the case of a single diol protecting group forming a cyclic diether, deprotection of intermediate G5 will provide G6, which can be the final example or intermediate. In the case where R2 and R3 are cyclic diether protecting groups, deprotection can be conveniently performed with an aqueous acid. R2 and R3 have many other possibilities as protecting groups, such as ethers, silyl ethers, or esters, which can be different or combined into a single group including both R2 and R3. If intermediate G6 can be further modified with R2 and R3 groups to give compound G7 with suitable reagents R2Y and R3Y, where Y is a leaving group such as a halogen, carboxyl, or sulfonyl group, intermediate G4 can be achiral, racemic, or a single enantiomer.

[0193] Chemical reaction

[0194]

[0195] Example 1 (SGML)

[0196] Methyl dodecanedithioate (12): Compound 11 (1.00 g, 5 mmol) was added to O,O-dimethyl S-hydrogen dithiophosphate (5.0 mL) under N2. The reaction mixture was heated to 130 °C for 1.5 h. It was then cooled to room temperature. Diethyl ether (50 mL) was added, and the mixture was washed with saturated NaHCO3 (25 mL × 3) and saturated sodium chloride (30 mL × 1), and dried over Na2SO4. The mixture was concentrated by vacuum evaporation. The residue was purified by silica gel column chromatography (petroleum ether) to give compound 12 (0.57 g, 46%).

[0197] 1 H NMR (300MHz, CDCl3) δ3.04 (m, J=7.5Hz 2H), 2.62 (s, 3H), 1.85-1.78 (m, 2H), 1.37-1.26 (m, 16H), 0.88 (t, J=7.2Hz, 3H).

[0198] O-((2,2-dimethyl-1,3-dioxolane-4-yl)methyl)dodecanethioate (13): (2,2-dimethyl-1,3-dioxolane-4-yl)methanol (0.45 mL, 3.60 mmol) was dissolved in dichloromethane (11 mL) containing sodium methoxide (0.19 g, 3.60 mmol). Compound 12 (0.59 g, 2.40 mmol) was added, and the solution was stirred at room temperature for 0.5 h. It was concentrated by vacuum evaporation. It was added to diethyl ether (60 mL), washed with water (15 mL) and saturated sodium chloride (20 mL × 2), and dried over Na2SO4. It was concentrated by vacuum evaporation. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 90:1 to 60:1) to give compound 13 (115 mg, 14%) and compound 12 (110 mg).

[0199] 1 H NMR (300MHz, CD3OD) δ4.51-4.11(m, 3H), 4.15-4.10(m, 1H), 3.82-3.77(m, 1H), 2.75(t, J=7. 5Hz, 2H), 1.80-1.70 (m, 2H), 1.41 (s, 3H), 1.35 (s, 3H), 1.30 (m, 16H), 0.90 (t, J=6.9Hz, 3H).

[0200] SGML: Under N2, an aqueous solution of acetic acid (8.18 mL, 60%) was added to a solution of compound 13 (0.382 g, 1.15 mmol) in tetrahydrofuran (6.5 mL). The reaction mixture was heated to 120 °C for 1.5 h. It was then cooled to room temperature. Diethyl ether (100 mL) was added, and the mixture was washed with water (30 mL × 2), saturated NaHCO3 (30 mL × 3), and saturated sodium chloride (20 mL × 2), and dried over MgSO4. The mixture was concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:2) to give compound 2 (SGML) (100 mg, 29.8%).

[0201] 1 H NMR (300MHz, CD3OD) δ3.83-3.79 (m, 1H), 3.57-3.50 (m, 3H), 3.26 (d, J=7.5Hz, 1H), 3 .03 (t, J=7.2Hz, 2H), 1.88-1.78 (m, 2H), 1.39-1.29 (m, 16H), 0.90 (t, J=6.6Hz, 3H).

[0202] Example 2 (S2GML)

[0203] 1-Thioglycerol (0.26 mL, 2.95 mmol; dissolved in anhydrous methanol (19.4 mL) containing a catalytic amount of sodium methoxide (16 mg, 0.30 mmol) after water removal by azeotropic distillation with toluene). Compound 12 (0.87 g, 3.54 mmol) was added, and the solution was stirred at room temperature for 1.5 h. Diethyl ether (100 mL) was added, and the solution was washed with water (20 mL) and saturated sodium chloride (40 mL) and dried over MgSO4. The solution was concentrated by vacuum evaporation. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:2) to give compound 2 (S2 GML) (89 mg, 19%).

[0204] 1 H NMR (300MHz, CD3OD) δ3.83-3.79 (m, 1H), 3.57-3.50 (m, 3H), 3.26 (d, J=7.5Hz, 1H), 3 .03 (t, J=7.2Hz, 2H), 1.88-1, 78 (m, 2H), 1.39-1.29 (m, 16H), 0.90 (t, J=6.6Hz, 3H).

[0205] Option 2

[0206]

[0207] Example 3: ((R)-SGML))

[0208] (R)-SGML was prepared from (S)-(2,2-dimethyl-1,3-dioxolane-4-yl)methanol in a manner similar to that of Example 1.

[0209] Example 4: ((S)-SGML)

[0210] ((S)-SGML) was prepared from (R)-(2,2-dimethyl-1,3-dioxolane-4-yl)methanol in a manner similar to that of Example 1.

[0211] Example 5: ((R)-S2GML)

[0212] [(4R)-2,2-Dimethyl-1,3-dioxolane-4-yl]methanethiol ((R)-14): A solution of toluene p-sulfonyl chloride (5.2 g, 27.2 mmol) in anhydrous CH2Cl2 (30 mL) was added at 0 °C to a solution of (S)-(2,2-dimethyl-1,3-dioxolane-4-yl)methanol (3 g, 22.7 mmol), DMAP (0.01 equivalent, 28 mg, 0.23 mmol), and triethylamine (7.3 mL, 52.2 mmol) in anhydrous CH2Cl2 (50 mL). The flask was stored in a refrigerator for 2 days. After dilution with CH2Cl2 (225 mL), the solution was washed twice with water (45 mL). After evaporation of the solvent, the residue was dissolved in diethyl ether (75 mL), and the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Crude tosylate was dissolved in acetone (120 mL), and potassium thioacetate (2.95 g, 25.8 mmol) was added. The resulting solution was refluxed for 24 hours. After filtration and concentration, the residue was treated with water (20 mL) and extracted with diethyl ether (2 × 100 mL). The organic layer was dried over MgSO4, filtered, and concentrated to give thioacetate dissolved in EtOH (3 mL), and 5N NaOH (5.5 mL, 27.7 mmol) was added. The resulting solution was stirred at 20 °C for 9 hours. The reaction was carefully neutralized with acetic acid, and the EtOH was evaporated. After extraction with diethyl ether (3 × 10 mL), the combined organic layers were washed with saturated NaHCO3 solution, dried over MgSO4, and concentrated. The residue was finally subjected to rapid column chromatography (C5H500). １2 The solution was purified by (Et2O, 24:1) to obtain (R)-14.

[0213] (R)-(2,2-Dimethyl-1,3-dioxolane-4-yl)dodecanedithioate methyl ester ((R)-15): (R)-14 (0.30 g, 2.0 mmol) was dissolved in anhydrous methanol (19.4 mL) containing a catalytic amount of sodium methoxide (16 mg, 0.30 mmol). Compound 12 (0.58 g, 2.4 mmol) was added, and the solution was stirred at room temperature for 1.5 h. Diethyl ether (100 mL) was added, and the mixture was washed with water (20 mL) and saturated sodium chloride (40 mL) and dried over MgSO4. The mixture was concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:2) to give the title compound (140 mg, 20%).

[0214] (R)-S2GML: Under N2, an aqueous solution of acetic acid (5 mL, 60%) was added to a solution of compound (R)-15 (0.10 g, 0.29 mmol) in tetrahydrofuran (5 mL). The reaction mixture was heated to 120 °C for 1.5 hours. It was then cooled to room temperature. Diethyl ether (50 mL) was added, and the mixture was washed with water (25 mL × 2), saturated NaHCO3 (25 mL × 3), and saturated sodium chloride (20 mL × 2), and dried over MgSO4. The mixture was concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:2) to give Example 5 ((R)-S2GML) (44 mg, 50%).

[0215] 1 H NMR (300MHz, CD3OD) δ3.83-3.79 (m, 1H), 3.57-3.50 (m, 3H), 3.26 (d, J=7.5Hz, 1H), 3 .03 (t, J=7.2Hz, 2H), 1.88-1.78 (m, 2H), 1.39-1.29 (m, 16H), 0.90 (t, J=6.6Hz, 3H).

[0216] Example 6: ((S)-S2GML)

[0217] ((S)-S2GML) was prepared from (R)-(2,2-dimethyl-1,3-dioxolane-4-yl)methanol in a manner similar to that of Example 5.

[0218] Example 7

[0219]

[0220] Under continuous stirring, LDA (lithium diisopropylamino) (2M, 330mmol in tetrahydrofuran) was added dropwise to a solution of dodecanoic acid (30g, 150mmol) in anhydrous THF (1000mL) at 0°C. After complete addition, the reaction was heated to 35°C for 30 minutes, forming a thick brown slurry. The reaction was cooled to -30°C, and CS2 (12.6g, 165mmol) was added dropwise. The reaction mixture was stirred for another 15 minutes and cooled to -50°C. MeI (21.3g, 150mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes. The reaction mixture was quenched by pouring into ice-cold 1M HCl (1000mL). The aqueous layer was extracted with pentane, the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by rapid column chromatography using pentane as the eluent to give 17 (13.4 g, 54.37 mmol, 36%) as a yellow oil.

[0221]

[0222] Sodium methoxide (402 mg, 7.44 mmol) was added to a solution of 1-thioglycerol (4.02 g, 37.2 mmol) in methanol (450 mL). The reaction mixture was stirred for 5 minutes, followed by the addition of 17 (11 g, 44.6 mmol). The reaction mixture was stirred for 2 hours, diluted with water (750 mL), and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by FCC (3:2PE:EA) and then recrystallized from cyclohexane to give 2 (1.06 g, 3.46 mmol, 9.3%) as a yellow crystalline solid.

[0223] 1 H NMR (400MHz, DMSO-d6) δ5.12 (d, J=5.5Hz, 1H), 4.74 (t, J=5.7Hz, 1H), 3.73-3.63 (m, 1H), 3.47 (dd, J=13.3, 4.3Hz, 1H), 3.39 (dt, J =10.8, 5.4Hz, 1H), 3.17 (dd, J=13.3, 7.9Hz, 1H), 3.00 (t, J=7.5Hz, 2H), 1.74 (p, J=7.3Hz, 2H), 1.24 (s, 16H), 0.85 (iJ=6.7Hz, 3H).

[0224] Example 8

[0225]

[0226] NaOMe (3.03 g, 56.0 mmol) was added to a solution of (2,2-dimethyl-1,3-dioxolane-4-yl)methanol (7.40 g, 56.0 mmol) in dichloromethane (DCM 500 mL) to form a suspension. 17 (9.2 g, 37.3 mmol) was added and the reaction mixture was stirred for 1 hour. The reaction mixture was diluted with water (500 mL) and extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude product was purified by FCC (2% EA / PE) to give 19 (4.4 g, 12.70 mmol, 34%) as a colorless oil.

[0227]

[0228] A solution of 19 (4.4 g, 12.70 mmol) in acetic acid (10 mL), THF (5 mL), and water (5 mL) was heated to 90 °C for 30 min. The reaction mixture was quenched by carefully pouring it into ice-cold NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by FCC and then recrystallized from cyclohexane to give 1,740 mg (2.55 mmol, 20%) as a colorless needle-like substance.

[0229] 1 H NMR (400MHz, DMSO-d6) δ5.02 (br s, J=5.3Hz, 1H), 4.71 (br s, 1H), 4.43 (dd, J=11.4, 3.8Hz, 1H), 4.29 (dd, J=11.4, 6.5Hz, 1H), 3.83 (br s, J=6.9Hz, 1H), 3.46-3.38 (m, 2H), 2.72 (t, J=7.5Hz, 2H), 1.67 (p, J=7.3Hz, 2H), 1.34-1.18 (m, 16H), 0.86 (t, J=6.8Hz, 3H).

[0230] Antibacterial activity - results

[0231] The following examples illustrate SGML and S2GML compounds that perform at least as well as, if not better than, natural GML.

[0232] Example 9

[0233] Staphylococcus aureus (including strains exhibiting toxic shock syndrome) is one of the most resistant bacteria to glyceryl monolaurate (GML). All tested Staphylococcus aureus strains remain sensitive to ≤500 μg / ml. For most Staphylococcus aureus strains, GML is bactericidal at 250 μg / ml. At the time of examination, other Gram-positive bacteria and Gram-negative bacteria with incomplete lipopolysaccharides (referred to as lipooligosaccharides in their case) are killed by GML at concentrations of approximately 25 to 50 μg / ml. Gram-negative bacteria with complete lipopolysaccharides (e.g., Escherichia coli) are completely resistant to GML unless an accelerator is added to enhance activity. Such accelerators would include low pH and the addition of EDTA to remove calcium and magnesium from the lipopolysaccharide layer. Under these conditions, GML is capable of killing such Gram-negative bacteria at 25 to 50 μg / ml.

[0234] The reason why Staphylococcus aureus strains exhibit some resistance to GML is that these bacteria produce glycerol ester hydrolases (lipases), which can degrade GML into lauric acid and glycerol, and subsequently use the products as a nutrient source. Our experience is that lipases cannot be produced at a GML concentration of approximately 300 μg / ml.

[0235] The following schemes were developed to test GML plus SGML and S2GML, in which a sulfur group was inserted to replace the oxygen in the GML molecule.

[0236] The *Staphylococcus aureus* strain MN8, which produces TSS toxin-1 (TSST-1), was cultured overnight in 125 ml Erlenmeyer flasks in Difco, Detroit, MI Todd Hewitt broth to ensure it reached the stationary phase. For this experiment, all cultures were aerobic at 37°C with shaking at 150 RPM. The stationary phase for this microorganism had a concentration of 1.0 × 10¹⁰ colony-forming units (CFU) / ml.

[0237] The following morning, the culture was diluted in a 5ml polystyrene tube with 1ml of Todd Hewitt broth to approximately 5×10⁻⁶. 6 / ml. This tube contains sequentially double-diluted glyceryl monolaurate, SGML, or S2GML. The control tube does not contain GML or SGML and S2GML compounds. Test the compound in triplicate. Dissolve GML, SGML, and S2GML in anhydrous ethanol at 100 mg / ml. The control tube contains the highest volume of ethanol used to deliver the compound to each 1 ml tube.

[0238] After 24 hours of incubation, plate counts were performed for each tube using serially 10-fold dilutions, with plates inoculated onto Todd Hewitt 1.5% agar plates. Following inoculation, the plates were aerobically incubated at 37°C for 24 hours. Counts were then performed to determine CFU / ml.

[0239] Logarithmically transform the CFU / ml and determine the mean ± SD.

[0240] The tubes grown 24 hours prior were treated with 4 volumes of anhydrous ethanol. After TSST-1 precipitation for 12 hours, the precipitate was collected by centrifugation at 4000×g for 10 minutes and the supernatant was discarded. The precipitate was dried in a laminar flow hood for 30 minutes to remove ethanol. The precipitate was then diluted with water to 0.1 ml to obtain a 10× concentration of TSST-1. TSST-1 was serially diluted twice in distilled water. In a standard double immunodiffusion assay, each dilution was set to 20 μL. The central well contained a hyperimmune polyclonal antibody against TSST-1. The diluted toxin preparation was added in a hexagonal pattern around the outer perimeter, 4 mm from the antibody. The slide was incubated at 37°C for exactly 4 hours, and then checked for visible precipitin arcs. Positive control, purified TSST-1 was visible at 6 μg / ml. Therefore, the lower limit of detection for TSST-1 in the test sample was 0.6 μg / ml at a 10× concentration.

[0241] Read each slide and determine TSST = 1 μg / ml. Because the sensitivity of this assay is limited by a factor of two, there is an average value, but no standard deviation. Data are recorded only as averages.

[0242] Using the standard MIC and MBC of Staphylococcus aureus strain MN8, SGML and S2GML were tested against GML.

[0243] Figure 1A and 1B The logarithmic values ​​of CFU / mL for Staphylococcus aureus MN8 cultured with different concentrations of GML, SGML, and S2GML are shown. SGML and S2GML can be easily distinguished by color. SGML is clear in ethanol, while S2GML is yellow. The yellow (S2GML) clearly has higher activity, although both are more active than GML. CFUs are logarithmically transformed, so small variations in the data do not introduce error. All data points below zero added compound are statistically significant. Generally, a 3-log decrease is considered bactericidal. There is a small standard deviation on the logarithmic CFU / mL.

[0244] A second study was conducted, in which the toxic shock syndrome superantigen (TSST-1) was measured.

[0245] Figure 2A and 2B The results of each compound reducing TSST-1 are shown. TSST-1 was already turned off before it affected growth.

[0246] Example 10

[0247] The same MIC and MBC tests were performed on E. coli, and SGML was found to be more effective than S2GML than GML, at least in this assay, S2GML performed similarly to GML. Figure 3 ).

[0248] The test conditions were the same as those described in the previous example using Staphylococcus aureus MN8. The Escherichia coli strain was a laboratory strain derived from a patient with a confirmed urinary tract infection. This strain was maintained in the laboratory at -80°C.

[0249] In the determination of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Staphylococcus aureus strain MN8, both SGML and S2GML showed higher activity than the parental compound GML. Both were more effective than GML, with MICs and MBCs of 250 μg / mL and 125 μg / mL respectively. SGML had a MIC of 125 μg / mL and a MBC of 125 μg / mL, while S2GML had a MIC of 31.125 μg / mL and a MBC of 63.5 μg / mL. Furthermore, using the same Staphylococcus aureus strain MN8, both SGML and S2GML showed significant reductions in TSST-1 toxin, with GML showing inhibition at 16 μg / mL, SGML at 8 μg / mL, and S2GML showing <4 μg / mL inhibition of TSST-1.

[0250] E. coli

[0251]

[0252] Example 11. Esterase resistance of SGML and S2GML compounds.

[0253] Lipase (glycerol ester hydrolase) assay protocol:

[0254] 1. Prepare two separate samples with lipase concentration of 25 μg / ml.

[0255] 2. Microscopic slides were prepared from 500 μg / ml of GML, SGML, or S2ML compounds. These slides contained 0.85% agarose (Difco) thermally dissolved in PBS (0.005 M NaPO4 pH 7.2; 0.15 M NaCl).

[0256] 3. The mixture contained compounds exceeding their solubility limits, so it was vortexed and 4.5 ml of the turbid mixture was spread onto a microscope slide.

[0257] 4. Keep the slide at room temperature for 1 hour to allow the agarose to solidify.

[0258] 5. Punch 4mm wells in the agarose gel twice per slide.

[0259] 6. Add 20 μL of lipase to each well.

[0260] 7. Incubate the slide at 37°C for 24 hours.

[0261] 8. Figure 4 The document provides a photograph of each slide.

[0262] 9. The square of their respective diameters was determined. This allows for the determination of the hydrolysis of the compounds.

[0263] GML: 15mm; 15mm diameter (diameter squared = 225mm)

[0264] SGML: 12mm; 13mm diameter (diameter squared = 144mm and 169mm, average 156.5mm)

[0265] S2GML: 0mm; 0mm diameter (diameter squared = 0)

[0266] 10. Using the square of the diameter to determine, it will be a straight line and a standard curve.

[0267] Set GML to 100%

[0268] 11. SGML is 70% of GML.

[0269] 12. S2GML is 0% of GML.

[0270] These figures are related to the fact that SGML is slightly more effective at killing Staphylococcus aureus than GML, and that S2GML is even more effective at killing it.

[0271] Example 12

[0272]

[0273]

[0274] Candida auris is a newly emerging yeast (fungus) that causes skin and bloodstream infections in humans. It readily develops resistance to antifungal agents, thus necessitating the development of new therapeutic agents. This organism is associated with Candida albicans and other Candida species. The MIC and MBC values ​​in the table above show that both SGML and S2GML exhibit very good activity against this organism.

[0275] Bacillus subtilis (aerobic spore-former) was incubated at 37°C with shaking at 200 RPM. This strain is a recent clinical isolate from the University of Iowa and has been shown to be resistant to standard antifungal agents.

[0276] Streptococcus pyogenes (Group A Streptococcus) 594 is a standard scarlet fever strain that has been widely published. This strain was incubated statically at 37°C in 5% CO2.

[0277] All solutions used in the MBC and MIC studies were prepared from stock solutions of GML, SGML, or S2GML in anhydrous ethanol at a concentration of 100 mg / ml.

[0278] By incorporating via reference

[0279] All U.S. patents, U.S. patent application publications, and non-patent publications cited in this document are incorporated herein by reference.

[0280] Equivalent scheme

[0281] Those skilled in the art will recognize or be able to determine numerous equivalents of the various embodiments of the present disclosure described herein using only conventional experiments. Such equivalents are covered in the appended claims.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof. in: R 1 It is C 11 alkyl; R 2 and R 3 Each is hydrogen; and X is either O or S.

2. The compound of claim 1, wherein X is O.

3. The compound of claim 1, wherein X is S.

4. The compound of claim 1, wherein the compound is 5. The compound of claim 1, wherein the compound is 6. A pharmaceutical composition comprising the compound of claim 1 or a salt thereof and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising the compound of claim 2 or a salt thereof and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition comprising the compound of claim 3 or a salt thereof and a pharmaceutically acceptable carrier.

9. Use of the compound of claim 1 in the preparation of a medicament for treating viral infections.

10. Use of the compound of claim 1 in the preparation of a medicament for treating bacterial infections.

11. Use of the compound of claim 1 in the preparation of a medicament for treating fungal infections.

12. The use according to claim 10, wherein the infection is a UTI.

13. The use according to claim 11, wherein the infection is a UTI.

14. The use of claim 10, wherein the infection is caused by Bacillus subtilis.

15. The use according to claim 10, wherein the infection is caused by Streptococcus pyogenes.

16. The use according to claim 11, wherein the infection is caused by Candida auris.

17. The use according to claim 10, wherein the infection is caused by Escherichia coli (E. coli).

Images