WO2019126568A1 - Analogues de nifuroxazide et leurs utilisations thérapeutiques - Google Patents

Analogues de nifuroxazide et leurs utilisations thérapeutiques Download PDF

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WO2019126568A1
WO2019126568A1 PCT/US2018/066921 US2018066921W WO2019126568A1 WO 2019126568 A1 WO2019126568 A1 WO 2019126568A1 US 2018066921 W US2018066921 W US 2018066921W WO 2019126568 A1 WO2019126568 A1 WO 2019126568A1
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group
alkyl
haloalkyl
compound
aryl
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PCT/US2018/066921
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Brett Hall
Kesavan Nair PRAVEEN
Bart Decorte
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Asellus Therapeutics, L.L.C.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present disclosure relates to the fields of chemistry and medicine. More particularly, the present disclosure relates to nifuroxazide analogs, compositions, their preparation, and their use as therapeutic agents. Description of the Related Art
  • STAT3 Signal transduce and activator of transcription 3
  • STAT3 is a transcription factor that mediates the expression of a variety of genes in response to cell stimuli and plays a key role in many cellular processes.
  • Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma, melanoma, colorectal cancer, and breast cancer. Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers.
  • Nifuroxazide is a broad spectrum nitrofuran antibiotic that is useful in the treatment of colitis and diarrhea in humans and animals. Nifuroxazide is an effective inhibitor of STAT3 function and has demonstrated unique antitumor activity. In particular, nifuroxazide decreases the viability of three breast cancer cell lines and induce apoptosis of cancer cells in a dose-dependent manner. Moreover, nifuroxazide demonstrated markedly blocked cancer cell migration and invasion, and reduced phosphorylated-STAT3(Tyr705), matrix metalloproteinase (MMP) MMP-2 and MMP-9 expression. It is believed that nifuroxazide preferentially targets tumor cell metabolism and moderates paracrine induction of STAT3.
  • MMP matrix metalloproteinase
  • R 1 is selected from the group consisting of unsubstituted C6-10 aryl; substituted C6-10 aryl; unsubstituted five- to ten-membered heteroaryl having 1-4 atoms selected from the group consisting of O, N, and S; and substituted five- to ten-membered heteroaryl having 1-4 atoms selected from the group consisting of O, N, and S.
  • a moiety indicated as substituted is substituted with one or more Q.
  • each Q is independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-10 heterocycloalkyl, C 6-10 aryl, C 6-10 arylalkyl, C 3-10 heteroaryl, C 3-10 heteroarylalkyl, halo, oxo, -OH, -O-(C 1-4 alkyl), -O-(C 1-4 haloalkyl), -SH, -S-(C 1-4 alkyl), -S-(C 1-4 haloalkyl), -S(O)2-(C 1-4 alkyl), -S(O)2-(C 1-4 haloalkyl), -S(O) 2 NR a R a , -NR a R a , -NO 2 -CN, -C(
  • each R a is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.
  • R A , R B , and R C are each independently selected from hydrogen and–NO 2 , wherein one of R A , R B , and R C is–NO 2 .
  • R 1 is not unsubstituted phenyl.
  • R 1 is not (Z)-5-((4-nitrocyclopenta-1,3-dien-1- yl)methylene)-3-phenylthiazolidine-2,4-dione.
  • R A is–NO2. In some embodiments, R B is–NO2. In some embodiments, R C is–NO 2 .
  • R 1 represents a double bond.
  • R 1 is unsubstituted C 6-10 aryl. In some embodiments, R 1 is substituted C6-10 aryl. In some embodiments, R 1 is unsubstituted five- to ten-membered heteroaryl having 1-4 atoms selected from the group consisting of O, N, and S. In some embodiments, R 1 is substituted five- to ten-membered heteroaryl having 1-4 atoms selected from the group consisting of O, N, and S.
  • the compound of Formula I has the structure depicted in Formula Ia [0016] In some embodiments, represents a single bond or a double bond.
  • each Q is selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-10 heterocycloalkyl, C 6-10 aryl, C 6-10 arylalkyl, C 3-10 heteroaryl, C3-10 heteroarylalkyl, halo, oxo, -OH, -O-(C 1-4 alkyl), -O-(C 1-4 haloalkyl), -SH, -S- (C 1-4 alkyl), -S-(C 1-4 haloalkyl), -S(O) 2 -(C 1-4 alkyl), -S(O) 2 -(C 1-4 haloalkyl), -S(O) 2 NR a R a , - NR a R a , -NO 2 -CN, -C(O)NR a R a , and–NR a C(O) 2 NR a R
  • n is 1, 2, 3, 4, or 5.
  • n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
  • the compound of Formula I has the structure depicted in Formula 1b [0022] In some embodiments, represents a single bond or a double bond.
  • hAr is five- to ten-membered heteroaryl having 1-4 atoms selected from the group consisting of O, N, and S.
  • each Q is selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-10 heterocycloalkyl, C 6-10 aryl, C 6-10 arylalkyl, C 3-10 heteroaryl, C3-10 heteroarylalkyl, halo, oxo, -OH, -O-(C 1-4 alkyl), -O-(C 1-4 haloalkyl), -SH, -S- (C 1-4 alkyl), -S-(C 1-4 haloalkyl), -S(O) 2 -(C 1-4 alkyl), -S(O) 2 -(C 1-4 haloalkyl), -S(O) 2 NR a R a , - NR a R a , -NO 2 -CN, -C(O)NR a R a , and–NR a C(O) 2 NR a R
  • each R a is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.
  • m is 0, 1, 2, 3, 4, or 5.
  • the pharmaceutically acceptable salt is an alkaline metal salt or an ammonium salt.
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one compound having the structure of the Formula I, including pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, carriers, diluents, or combination thereof.
  • inventions disclosed herein include a method of ameliorating or treating a mammal having a disease disease or disorder comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • the mammal is a human.
  • Additional medicaments selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti- inflammatory agent, or an anti-allergic agent.
  • FIGURE 1 shows the effect of drug-induced transient mitochondria-SOX induction in MDA-MB-231 cells.
  • FIGURE 2A shows the effect of Compound 1 on downregulation of pSTAT3 Y705 in MCF-7 tumor cells.
  • FIGURE 2B shows the effect of Compound 1 on downregulation of pSTAT3 Y705 in BT-474 tumor cells.
  • FIGURE 2C shows the effect of Compound 1 on downregulation of pSTAT3 Y705 in SK-BR03 tumor cells.
  • FIGURE 3 shows the effect of Compound 1 on the inhibition of pSTAT1 Y701 in HeLa cells.
  • FIGURE 4A shows the effect of Compound 1 in CT26 athymic nude Balb/c (immune deficient) mice.
  • FIGURE 4B shows the effect of anti-PD-1 monoclonal antibody and anti- CTLA-4 monoclonal antibody in CT26 athymic nude Balb/c (immune deficient) mice.
  • FIGURE 4C shows the effect of the combination of Compound 1 and either anti-PD-1 monoclonal antibody or anti-CTLA-4 monoclonal antibody in CT26 athymic nude Balb/c (immune deficient) mice.
  • FIGURE 5 shows the effect of Compound 1 on tumor growth inhibition in CT26 Balb/c (immune competent) mice.
  • FIGURE 6 shows the effect of the combination of Compound 1 and either anti-PD-1 monoclonal antibody or anti-CTLA-4 monoclonal antibody on tumor growth inhibition in CT26 Balb/c (immune competent) mice.
  • nifuroxazide analogs are provided that act as an anti-proliferative agent.
  • Various embodiments of these compounds include compounds having the structure of Formula I as described above or pharmaceutically acceptable salts thereof.
  • prodrugs, metabolites, stereoisomers, hydrates, solvates, polymorphs, and pharmaceutically acceptable salts of the compounds disclosed herein are provided.
  • prodrug refers to an agent that is converted into the parent drug in vivo.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • An example, without limitation, of a prodrug would be a compound which is administered as an ester (the“prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • a prodrug derivative Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is hereby incorporated herein by reference in its entirety.
  • pro-drug ester refers to derivatives of the compounds disclosed herein formed by the addition of any of several ester-forming groups that are hydrolyzed under physiological conditions.
  • pro-drug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art, including a (5-R-2-oxo-1,3-dioxolen-4-yl)methyl group.
  • Other examples of pro-drug ester groups can be found in, for example, T. Higuchi and V. Stella, in "Pro-drugs as Novel Delivery Systems", Vol.14, A.C.S.
  • Metabolites of the compounds disclosed herein include active species that are produced upon introduction of the compounds into the biological milieu.
  • the compounds disclosed herein may exist as a racemate or as enantiomers. It should be noted that all such isomers and mixtures thereof are included in the scope of the present disclosure.
  • some of the crystalline forms for the compounds disclosed herein may exist as polymorphs. Such polymorphs are included in one embodiment of the present disclosure.
  • some of the compounds of the present disclosure may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are included in one embodiment of the present disclosure.
  • the term“pharmaceutically acceptable salt,” as used herein, refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the salt is an acid addition salt of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid and the like.
  • compositions can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid.
  • organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid.
  • Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine, lysine, and the like.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohe
  • the compounds disclosed herein can be used alone, in combination with other compounds disclosed herein, or in combination with one or more other agents active in the therapeutic areas described herein.
  • halogen atom means any one of the radio- stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.
  • esters refers to a chemical moiety with formula -(R)n-COOR’, where R and R’ are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.
  • amide refers to a chemical moiety with formula -(R)n-C(O)NHR’ or -(R)n-NHC(O)R’, where R and R’ are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.
  • An amide may be an amino acid or a peptide molecule attached to a molecule of the present disclosure, thereby forming a prodrug.
  • Any amine, hydroxyl, or carboxyl side chain on the compounds disclosed herein can be esterified or amidified.
  • the procedures and specific groups to be used to achieve this end are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety.
  • aromatic refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl groups (e.g., pyridine).
  • carbocyclic aryl e.g., phenyl
  • heterocyclic aryl groups e.g., pyridine
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
  • carbocyclic refers to a compound which contains one or more covalently closed ring structures, and that the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from heterocyclic rings in which the ring backbone contains at least one atom which is different from carbon.
  • heteroheteroaromatic refers to an aromatic group which contains at least one heterocyclic ring.
  • alkyl refers to a straight or branched hydrocarbon chain fully saturated (no double or triple bonds) hydrocarbon group.
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as“1 to 20” refers to each integer in the given range; e.g.,“1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term“alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 5 carbon atoms.
  • the alkyl group of the compounds may be designated as“C 1 -C 4 alkyl” or similar designations.
  • “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent group(s) is(are) one or more group(s) individually and independently selected from alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
  • An alkenyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.
  • the alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term“alkenyl” where no numerical range is designated.
  • the alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms.
  • the alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms.
  • the alkenyl group of the compounds may be designated as“C2-4 alkenyl” or similar designations.
  • “C2-4 alkenyl” indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl- ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl, buta-1,2,-dienyl, and buta-1,2-dien-4-yl.
  • Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
  • An alkynyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.
  • the alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term“alkynyl” where no numerical range is designated.
  • the alkynyl group may also be a medium size alkynyl having 2 to 9 carbon atoms.
  • the alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms.
  • the alkynyl group of the compounds may be designated as“C2-4 alkynyl” or similar designations.
  • “C2-4 alkynyl” indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn- 4-yl, and 2-butynyl.
  • Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.
  • heteroalkyl refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone.
  • the heteroalkyl group may have 1 to 20 carbon atoms although the present definition also covers the occurrence of the term“heteroalkyl” where no numerical range is designated.
  • the heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms.
  • the heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms.
  • the heteroalkyl group of the compounds may be designated as“C 1-4 heteroalkyl” or similar designations.
  • the heteroalkyl group may contain one or more heteroatoms.
  • “C 1-4 heteroalkyl” indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.
  • aryl refers to a carbocyclic (all carbon) ring or two or more fused rings (rings that share two adjacent carbon atoms) that have a fully delocalized pi- electron system.
  • aryl groups include, but are not limited to, benzene, naphthalene and azulene.
  • An aryl group may be substituted or unsubstituted.
  • substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C- carboxy, O-carboxy, isocyan
  • substituents on an aryl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.
  • heteroaryl refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system), one or two or more fused rings that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
  • heteroaryl rings include, but are not limited to, furan, thiophene, phthalazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine.
  • a heteroaryl group may be substituted or unsubstituted.
  • substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C- carboxy, O-carboxy, isocyan
  • substituents on a heteroayl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.
  • an“aralkyl” or“arylalkyl” refers to an aryl group connected, as a substituent, via an alkylene group.
  • the alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl, and naphtylalkyl.
  • the alkylene group is a lower alkylene group.
  • a“heteroaralkyl” or“heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group.
  • the alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2- thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl, and their substituted as well as benzo-fused analogs.
  • the alkylene group is a lower alkylene group.
  • a“alkylene” refers to a branched, or straight chain fully saturated di-radical chemical group containing only carbon and hydrogenthat is attached to the rest of the molecule via two points of attachment (i.e., an alkanediyl).
  • the alkylene group may have 1 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkylene where no numerical range is designated.
  • the alkylene group may also be a medium size alkylene having 1 to 9 carbon atoms.
  • the alkylene group could also be a lower alkylene having 1 to 4 carbon atoms.
  • the alkylene group may be designated as“C 1-4 alkylene” or similar designations.
  • “C 1-4 alkylene” indicates that there are one to four carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethan-1,1-diyl, propylene, propan-1,1-diyl, propan-2,2-diyl, 1-methyl-ethylene, butylene, butan-1,1-diyl, butan-2,2-diyl, 2-methyl- propan-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, 1,2- dimethyl-ethylene, and 1-ethyl-ethylene.
  • alkenylene refers to a straight or branched chain di- radical chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond that is attached to the rest of the molecule via two points of attachment.
  • the alkenylene group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkenylene where no numerical range is designated.
  • the alkenylene group may also be a medium size alkenylene having 2 to 9 carbon atoms.
  • the alkenylene group could also be a lower alkenylene having 2 to 4 carbon atoms.
  • the alkenylene group may be designated as“C2-4 alkenylene” or similar designations.
  • “C 2-4 alkenylene” indicates that there are two to four carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selected from the group consisting of ethenylene, ethen-1,1-diyl, propenylene, propen-1,1-diyl, prop-2-en-1,1-diyl, 1-methyl- ethenylene, but-1-enylene, but-2-enylene, but-1,3-dienylene, buten-1,1-diyl, but-1,3-dien-1,1- diyl, but-2-en-1,1-diyl, but-3-en-1,1-diyl, 1-methyl-prop-2-en-1,1-diyl, 2-methyl-prop-2-en- 1,1-diyl, 1-ethyl-ethenylene, 1,2-dimethyl-ethenylene, 1-methyl-propenylene, 2-methyl-
  • arylalkylidene refers to an alkylidene group in which either R’ and R’’ is an aryl group. An alkylidene group may be substituted or unsubstituted.
  • alkoxy refers to the formula–OR wherein R is an alkyl is defined as above, e.g. methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n- butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amoxy, tert-amoxy and the like.
  • An alkoxy may be substituted or unsubstituted.
  • alkylthio refers to the formula–SR wherein R is an alkyl is defined as above, e.g. methylmercapto, ethylmercapto, n-propylmercapto, 1- methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec- butylmercapto, tert-butylmercapto, and the like.
  • An alkylthio may be substituted or unsubstituted.
  • aryloxy and arylthio refers to RO- and RS-, respectively, in which R is an aryl, such as but not limited to phenyl. Both an aryloxyl and arylthio may be substituted or unsubstituted.
  • R is hydrogen, C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.
  • cycloalkyl refers to a completely saturated (no double bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. Cycloalkyl groups may range from C 3 to C 10 , in other embodiments it may range from C 3 to C6. A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the substituent(s) may be an alkyl or selected from those indicated above with regard to substitution of an alkyl group unless otherwise indicated.
  • substituents on a cycloalkyl group may form an aromatic ring fused to the cycloalkyl group, including an aryl and a heteroaryl.
  • cycloalkenyl refers to a cycloalkyl group that contains one or more double bonds in the ring although, if there is more than one, they cannot form a fully delocalized pi-electron system in the ring (otherwise the group would be“aryl,” as defined herein).
  • the rings When composed of two or more rings, the rings may be connetected together in a fused, bridged or spiro-connected fashion.
  • a cycloalkenyl group may be unsubstituted or substituted.
  • the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group substitution unless otherwise indicated.
  • substituents on a cycloalkenyl group may form an aromatic ring fused to the cycloalkenyl group, including an aryl and a heteroaryl.
  • cycloalkynyl refers to a cycloalkyl group that contains one or more triple bonds in the ring. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion.
  • a cycloalkynyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group substitution unless otherwise indicated. When substituted, substituents on a cycloalkynyl group may form an aromatic ring fused to the cycloalkynyl group, including an aryl and a heteroaryl.
  • heteroalicyclic or“heteroalicyclyl” refers to a stable 3- to 18 membered ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • The“heteroalicyclic” or “heteroalicyclyl” may be monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be joined together in a fused, bridged or spiro-connected fashion; and the nitrogen, carbon and sulfur atoms in the“heteroalicyclic” or“heteroalicyclyl” may be optionally oxidized; the nitrogen may be optionally quaternized; and the rings may also contain one or more double bonds provided that they do not form a fully delocalized pi-electron system throughout all the rings. Heteroalicyclyl groups may be unsubstituted or substituted.
  • the substituent(s) may be one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyan
  • heteroalicyclic or“heteroalicyclyl” include but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, morpholinyl, oxiranyl, piperidinyl N-Oxide, piperidinyl, piperazinyl, pyrrolidinyl, 4-piperidonyl, pyrazolidinyl, 2-oxopyrrolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone.
  • substituents on a heteroalicyclyl group may form an aromatic ring fused to the heteroalicyclyl group, including an aryl and a heteroaryl.
  • (cycloalkenyl)alkyl refers to a cycloalkenyl group connected, as a substituent, via an alkylene group.
  • the alkylene and cycloalkenyl of a (cycloalkenyl)alkyl may be substituted or unsubstituted.
  • the alkylene group is a lower alkylene group.
  • the alkylene and cycloalkynyl of a (cycloalkynyl)alkyl may be substituted or unsubstituted.
  • the alkylene group is a lower alkylene group.
  • R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein.
  • An O-carboxy may be substituted or unsubstituted.
  • a C-carboxy may be substituted or unsubstituted.
  • trihalomethanesulfonyl refers to an“X 3 CSO 2 -“ group wherein X is a halogen.
  • the term“isocyanato” refers to a“-NCO” group.
  • R can be the same as defined with respect to O-carboxy.
  • a sulfinyl may be substituted or unsubstituted.
  • sulfonyl refers to an“SO 2 R” group in which R can be the same as defined with respect to O-carboxy.
  • R can be the same as defined with respect to O-carboxy.
  • a sulfonyl may be substituted or unsubstituted.
  • the term“S-sulfonamido” refers to a“-SO2NRARB” group in which R A and R B can be the same as defined with respect to O-carboxy. An S-sulfonamido may be substituted or unsubstituted.
  • the term“N-sulfonamido” refers to a“RSO 2 N(R A )-” group in which R and RA can be the same as defined with respect to O-carboxy. A sulfonyl may be substituted or unsubstituted.
  • trihalomethanesulfonamido refers to an “X3CSO2N(R)-“ group with X as halogen and R can be the same as defined with respect to O-carboxy.
  • a trihalomethanesulfonamido may be substituted or unsubstituted.
  • An O-carbamyl may be substituted or unsubstituted.
  • An N-carbamyl may be substituted or unsubstituted.
  • An O-thiocarbamyl may be substituted or unsubstituted.
  • An N-thiocarbamyl may be substituted or unsubstituted.
  • a C-amido may be substituted or unsubstituted.
  • An N-amido may be substituted or unsubstituted.
  • the term“amino” refers to a“-NRARB” group in which RA and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • the term“aminoalkyl” refers to an amino group connected via an alkylene group.
  • lower aminoalkyl refers to an amino group connected via a lower alkylene group.
  • a lower aminoalkyl may be substituted or unsubstituted.
  • lower alkoxyalkyl refers to an alkoxy group connected via a lower alkylene group.
  • a lower alkoxyalkyl may be substituted or unsubstituted.
  • R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein.
  • An O- carbamyl can be substituted or unsubstituted.
  • R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein.
  • An N- carbamyl can be substituted or unsubstituted.
  • R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein.
  • An O- thiocarbamyl can be substituted or unsubstituted.
  • R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein.
  • An N-thiocarbamyl can be substituted or unsubstituted.
  • the term“perhaloalkyl” refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.
  • the term“halogen” or“halo,” refer to any one of the radio- stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.
  • carbocyclyl refers to a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone.
  • carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion.
  • Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic.
  • carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls.
  • the carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term“carbocyclyl” where no numerical range is designated.
  • the carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms.
  • the carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms.
  • the carbocyclyl group may be designated as“C 3-6 carbocyclyl” or similar designations.
  • carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.
  • (cycloalkyl)alkyl refers to a cycloalkyl group connected, as a substituent, via an alkylene group.
  • the alkylene and cycloalkyl of a (cycloalkyl)alkyl may be substituted or unsubstituted.
  • Examples include but are not limited cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like.
  • the alkylene group is a lower alkylene group.
  • cycloalkyl refers to a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • cycloalkenyl means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic.
  • An example is cyclohexenyl.
  • heterocyclyl refers to three-, four-, five-, six-, seven-, and eight- or more membered rings wherein carbon atoms together with from 1 to 3 heteroatoms constitute said ring.
  • a heterocyclyl can optionally contain one or more unsaturated bonds situated in such a way, however, that an aromatic pi-electron system does not arise.
  • the heteroatoms are independently selected from oxygen, sulfur, and nitrogen.
  • heterocyclyl can further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, and the like.
  • heterocyclyl refers to a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system.
  • the heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term“heterocyclyl” where no numerical range is designated.
  • the heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members.
  • the heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members.
  • the heterocyclyl group may be designated as“3-6 membered heterocyclyl” or similar designations.
  • the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S.
  • heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4- dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro
  • heterocyclylalkyl refers to a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.
  • the terms“purified,”“substantially purified,” and“isolated” as used herein, refer to compounds disclosed herein being free of other, dissimilar compounds with which the compounds of the disclosure are normally associated in their natural state, so that the compounds of the disclosure comprise at least 0.5%, 1%, 5%, 10%, or 20%, and most preferably at least 50% or 75% of the mass, by weight, of a given sample.
  • a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group.
  • substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 7 carbocyclyl (optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy), C 3 - C 7 -carbocyclyl-C 1 -C 6 -alkyl (optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alk
  • substituted group(s) is (are) substituted with one or more substituent(s) individually and independently selected from C1-C4 alkyl, amino, hydroxy, and halogen.
  • radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical. For example, a substituent identified as alkyl that requires two points of attachment includes di-radicals such as–CH2–,–CH2CH2–,–CH2CH(CH3)CH2–, and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as“alkylene” or“alkenylene.”
  • substituent is a group that may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl
  • the term“agent” or“test agent,” as used herein includes any substance, molecule, element, compound, entity, or a combination thereof. It includes, but is not limited to, e.g., protein, polypeptide, peptide or mimetic, small organic molecule, polysaccharide, polynucleotide, and the like. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances. Unless otherwise specified, the terms“agent”,“substance”, and“compound” are used interchangeably herein.
  • analog is used herein to refer to a molecule that structurally resembles a reference molecule but which has been modified in a targeted and controlled manner, by replacing a specific substituent of the reference molecule with an alternate substituent. Compared to the reference molecule, an analog would be expected, by one skilled in the art, to exhibit the same, similar, or improved utility. Synthesis and screening of analogs, to identify variants of known compounds having improved characteristics (such as higher binding affinity for a target molecule) is an approach that is well known in pharmaceutical chemistry.
  • mammal is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rats and mice but also includes many other species.
  • microbial infection refers to the invasion of the host organism, whether the organism is a vertebrate, invertebrate, fish, plant, bird, or mammal, by pathogenic microbes. This includes the excessive growth of microbes that are normally present in or on the body of a mammal or other organism. More generally, a microbial infection can be any situation in which the presence of a microbial population(s) is damaging to a host mammal.
  • a mammal is“suffering” from a microbial infection when excessive numbers of a microbial population are present in or on a mammal’s body, or when the effects of the presence of a microbial population(s) is damaging the cells or other tissue of a mammal.
  • this description applies to a bacterial infection.
  • the compounds of preferred embodiments are also useful in treating microbial growth or contamination of cell cultures or other media, or inanimate surfaces or objects, and nothing herein should limit the preferred embodiments only to treatment of higher organisms, except when explicitly so specified in the claims.
  • pharmaceutically acceptable carrier or“pharmaceutically acceptable excipient,” as used herein, includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
  • various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.
  • subject refers to a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
  • a non-human mammal e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
  • the term“effective amount” or a“therapeutically effective amount” as used herein, refers to an amount of a therapeutic agent that is effective to relieve, to some extent, or to reduce the likelihood of onset of, one or more of the symptoms of a disease or condition, and includes curing a disease or condition.“Curing” means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).
  • the term“treat,”“treatment,” or“treating,” as used herein, refers to administering a pharmaceutical composition for prophylactic and/or therapeutic purposes.
  • the term“prophylactic treatment” refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition.
  • therapeutic treatment refers to administering treatment to a
  • Some embodiments of the present application generally relate to a compound of Formula I or a pharmaceutically acceptable salt thereof: [0133] wherein: represents a single bond or a double bond; R 1 is selected from the group consisting of unsubstituted C6-10 aryl; substituted C6-10 aryl; unsubstituted five- to ten-membered heteroaryl having 1-4 atoms selected from the group consisting of O, N, and S; and substituted five- to ten-membered heteroaryl having 1-4 atoms selected from the group consisting of O, N, and S; wherein a moiety indicated as substituted is substituted with one or more Q, wherein Q is selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-10 heterocycloalkyl, C 6-10 aryl, C 6-10 arylalkyl, C 3-10 heteroaryl, C3-10 heteroarylalkyl, hal
  • R A when R A is–NO2, R 1 is not unsubstituted phenyl.
  • the compound of Formula (I) is not
  • the thiazolidinedione moiety can be replaced with a heterocyclic moiety. In some embodiments, the thiazolidinedione moiety can be replaced with five-membered heterocyclic moiety. For example, the thiazolidinedione moiety can be
  • the nitrofuran moiety i.e. , wherein one
  • R A , R B , and R C is–NO 2
  • R C is a nitrothiophenyl moiety
  • R A , R B , and R C is–NO 2 ).
  • R A can be–NO2.
  • R B can be –NO2.
  • R C can be–NO2.
  • R 1 can be unsubstituted C 6-10 aryl or substituted C 6- 10 aryl.
  • suitable C6-10 aryl groups include, but are not limited to, phenyl and naphthyl.
  • R 1 can be unsubstituted five- to ten-membered heteroaryl having 1-4 atoms selected from the group consisting of O, N, and S or substituted five- to ten-membered heteroaryl having 1-4 atoms selected from the group consisting of O, N, and S.
  • Examples of five- to ten-membered heteroaryl having 1-4 atoms selected from the group consisting of O, N, and S include, but are not limited to, furanyl, thiophenyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, quinolinyl, indazolyl, benzothiazolyl, benzimidazolyl, and quinazolinyl.
  • the moieties indicated as substituted can be substituted with one or more Q. In some embodiments, the moieties indicated as substituted can be substituted with one, two, three, four, or five Q.
  • Q can be C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-10 heterocycloalkyl, C 6-10 aryl, C 6-10 arylalkyl, C 3-10 heteroaryl, C3-10 heteroarylalkyl, halo, oxo, -OH, -O-(C 1-4 alkyl), -O-(C 1-4 haloalkyl), -SH, -S-(C 1-4 alkyl), -S-(C 1-4 haloalkyl), -S(O)2-(C 1-4 alkyl), -S(O)2-(C 1-4 haloalkyl), -S(O)2NR a R a ,
  • R a can be independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.
  • R 1 can be phenyl and Q can be C 1-4 alkyl.
  • R 1 can be phenyl and Q can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.
  • R 1 can be phenyl and Q can be C 1-4 haloalkyl.
  • R 1 can be phenyl and Q can be–CF 3 , -CF 2 H, -CFH 2 , -C 2 F 5 , -C 2 F 4 H, -C 2 F 3 H 2 , -C 2 F 2 H 3 , -C 2 FH 4 , or–CH(CF 3 ) 2 .
  • R 1 can be phenyl and Q can be -OH.
  • R 1 can be phenyl and Q can be -O-(C 1-4 alkyl).
  • R 1 can be phenyl and Q can be–O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-sec-butyl, -O- isobutyl, or -O-tert-butyl.
  • R 1 can be phenyl and Q can be C 1-4 haloalkyl.
  • R 1 can be phenyl and Q can be–O-CF 3 ,–O- CF2H,–O-CFH2,–O-C2F5,–O-C2F4H,–O-C2F3H2,–O-C2F2H3,–O-C2FH4, or–O-CH(CF3)2.
  • R 1 can be phenyl and Q can be C3-6 cycloalkyl. In some embodiments, R 1 can be phenyl and Q can be C3-10 heterocycloalkyl. In some embodiments, R 1 can be phenyl and Q can be C 6-10 aryl. In some embodiments, R 1 can be phenyl and Q can be C6-10 arylalkyl. In some embodiments, R 1 can be phenyl and Q can be C 3-10 heteroaryl. In some embodiments, R 1 can be phenyl and Q can be C 3-10 heteroarylalkyl. In some embodiments, R 1 can be phenyl and Q can be halo.
  • R 1 can be phenyl and Q can be -SH. In some embodiments, R 1 can be phenyl and Q can be -S-(C1- 4 alkyl). In some embodiments, R 1 can be phenyl and Q can be -S-(C 1-4 haloalkyl). In some embodiments, R 1 can be phenyl and Q can be -S(O)2-(C 1-4 alkyl). In some embodiments, R 1 can be phenyl and Q can be -S(O)2-(C 1-4 haloalkyl).
  • R 1 can be phenyl and Q can be -S(O) 2 NR a R a , -NR a R a , -C(O)NR a R a , or–NR a C(O)R a , wherein each R a can be independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.
  • R 1 can be pyridinyl and Q can be C 1-4 alkyl.
  • R 1 can be pyridinyl and Q can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.
  • R 1 can be pyridinyl and Q can be C 1-4 haloalkyl.
  • R 1 can be pyridinyl and Q can be –CF3, -CF2H, -CFH2, -C2F5, -C2F4H, -C2F3H2, -C2F2H3, -C2FH4, or –CH(CF 3 ) 2 .
  • R 1 can be pyridinyl and Q can be -OH.
  • R 1 can be pyridinyl and Q can be -O-(C 1-4 alkyl).
  • R 1 can be pyridinyl and Q can be–O-methyl, -O-ethyl, -O-n-propyl, -O- isopropyl, -O-n-butyl, -O-sec-butyl, -O-isobutyl, or -O-tert-butyl.
  • R 1 can be pyridinyl and Q can be C 1-4 haloalkyl.
  • R 1 can be pyridinyl and Q can be–O-CF3,–O-CF2H,–O-CFH2,–O-C2F5,–O-C2F4H,–O-C2F3H2, –O-C 2 F 2 H 3 ,–O-C 2 FH 4 , or–O-CH(CF 3 ) 2 .
  • R 1 can be pyridinyl and Q can be C3-6 cycloalkyl. In some embodiments, R 1 can be pyridinyl and Q can be C3-10 heterocycloalkyl. In some embodiments, R 1 can be pyridinyl and Q can be C 6-10 aryl. In some embodiments, R 1 can be pyridinyl and Q can be C6-10 arylalkyl. In some embodiments, R 1 can be pyridinyl and Q can be C3-10 heteroaryl. In some embodiments, R 1 can be pyridinyl and Q can be C3-10 heteroarylalkyl.
  • R 1 can be pyridinyl and Q can be halo. .In some embodiments, R 1 can be pyridinyl and Q can be -SH. In some embodiments, R 1 can be pyridinyl and Q can be -S-(C 1-4 alkyl). In some embodiments, R 1 can be pyridinyl and Q can be -S-(C 1-4 haloalkyl). In some embodiments, R 1 can be pyridinyl and Q can be -S(O) 2 -(C 1-4 alkyl). In some embodiments, R 1 can be pyridinyl and Q can be -S(O)2-(C 1-4 haloalkyl).
  • R 1 can be pyridinyl and Q can be -S(O)2NR a R a , -NR a R a , -C(O)NR a R a , or–NR a C(O)R a , wherein each R a can be independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.
  • the compound of Formula I can be a compound of
  • n can be 1, 2, or 3.
  • the compound of Formula I can be a compound of
  • Formula Ib having the structure including pharmaceutically acceptable salts thereof.
  • m can be 0, 1, 2, 3, 4, or 5.
  • the compound of Formula I can be a compound selected from the group consisting of:
  • the pharmaceutically acceptable salt can be an alkaline metal salt. In some embodiments, the pharmaceutically acceptable salt can be an alkali metal salt. In some embodiments, the pharmaceutically acceptable salt can be an alkali earth metal salt. In some embodiments, the pharmaceutically acceptable salt can be an ammonium salt.
  • the compounds disclosed herein may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., and will be obvious to those skilled in the art.
  • it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and Greene & Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are both hereby incorporated herein by reference in their entirety.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • Synthetic chemistry transformations useful in synthesizing applicable compounds are known in the art and include e.g. those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, which are both hereby incorporated herein by reference in their entirety.
  • the processes for the preparation of the compounds disclosed herein give rise to mixtures of stereoisomers
  • such isomers may be separated by conventional techniques such as preparative chiral chromatography.
  • the compounds may be prepared in racemic form or individual enantiomers may be prepared by stereoselective synthesis or by resolution.
  • the compounds may be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved using a chiral auxiliary by formation of diastereomeric derivatives such as esters, amides or ketals followed by chromatographic separation and removal of the chiral auxiliary.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a physiologically acceptable surface active agents, carriers, diluents, excipients, smoothing agents, suspension agents, film forming substances, and coating assistants, or a combination thereof; and a compound disclosed herein.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference in its entirety.
  • Preservatives, stabilizers, dyes, sweeteners, fragrances, flavoring agents, and the like may be provided in the pharmaceutical composition.
  • sodium benzoate, ascorbic acid and esters of p- hydroxybenzoic acid may be added as preservatives.
  • antioxidants and suspending agents may be used.
  • alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surface active agents; sucrose, glucose, lactose, starch, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium methasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium acid carbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose, and the like may be used as excipients; magnesium stearate, talc, hardened oil and the like may be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, soya may be used as suspension agents or lubricants; cellulose acetate phthalate as a derivative of a carbohydrate such as cellulose or sugar, or methylacetate-me
  • composition refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration.
  • Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • carrier refers to a chemical compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • carrier facilitates the uptake of many organic compounds into the cells or tissues of an organism.
  • diot refers to chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art.
  • buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.
  • physiologically acceptable refers to a carrier or diluent that does not abrogate the biological activity and properties of the compound.
  • an“excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
  • A“diluent” is a type of excipient.
  • compositions comprising the compound, alone or in a mixture with other compounds of the genus or sub- genus, or with alternative compounds described herein, or with one or more alternative pharmaceutically active compounds, and one or more pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • the pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.
  • compositions disclosed herein may be manufactured in any manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.
  • compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s).
  • suitable carriers or excipient(s) include, for example, lactitol
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
  • the compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • compositions of the present disclosure may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.
  • Pharmaceutical compositions for use in accordance with the present disclosure thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington’s Pharmaceutical Sciences, above.
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like.
  • the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like.
  • Physiologically compatible buffers include, but are not limited to, Hanks’s solution, Ringer’s solution, or physiological saline buffer. If desired, absorption enhancing preparations (for example, liposomes), may be utilized.
  • penetrants appropriate to the barrier to be permeated may be used in the formulation.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water- soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or other organic oils such as soybean, grapefruit or almond oils, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the disclosure to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross- linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present disclosure are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
  • compositions well known in the pharmaceutical art for uses that include intraocular, intranasal, and intraauricular delivery. Suitable penetrants for these uses are generally known in the art.
  • Pharmaceutical compositions for intraocular delivery include aqueous ophthalmic solutions of the active compounds in water-soluble form, such as eyedrops, or in gellan gum (Shedden et al., Clin.
  • compositions for intranasal delivery may also include drops and sprays often prepared to simulate in many respects nasal secretions to ensure maintenance of normal ciliary action.
  • suitable formulations are most often and preferably isotonic, slightly buffered to maintain a pH of 5.5 to 6.5, and most often and preferably include antimicrobial preservatives and appropriate drug stabilizers.
  • Pharmaceutical formulations for intraauricular delivery include suspensions and ointments for topical application in the ear. Common solvents for such aural formulations include glycerin and water.
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a suitable pharmaceutical carrier may be a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • a common cosolvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • VPD co-solvent system is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • co- solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of POLYSORBATE 80TM; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • Agents intended to be administered intracellularly may be administered using techniques well known to those of ordinary skill in the art.
  • such agents may be encapsulated into liposomes. All molecules present in an aqueous solution at the time of liposome formation are incorporated into the aqueous interior.
  • the liposomal contents are both protected from the external micro-environment and, because liposomes fuse with cell membranes, are efficiently delivered into the cell cytoplasm.
  • the liposome may be coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the desired organ.
  • small hydrophobic organic molecules may be directly administered intracellularly.
  • compositions may be incorporated into the pharmaceutical compositions.
  • pharmaceutical compositions may be combined with other compositions that contain other therapeutic or diagnostic agents.
  • Parenteral Pharmaceutical Composition
  • a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous, or the like)
  • 0.1 mg to 100 mg of a water-soluble salt/soluble material itself/solubilized complex of a compound of a preferred embodiment is dissolved in sterile water and then mixed with 10 ⁇ of 0.9% sterile saline.
  • the mixture is incorporated into a dosage unit form suitable for administration by injection.
  • a pharmaceutical composition for oral delivery 0.1 mg to 100 mg of a compound of a preferred embodiment is mixed with 750 mg of starch.
  • the mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, or 0.1 mg to 100 mg of compound is granulated with binder solution such as starch solution along with suitable diluents such as microcrystalline cellulose or like, disintegrants such as croscaramellose sodium, dry the resultant mixture and add lubricant and compress into tablet which is suitable for oral administration.
  • a pharmaceutical composition for buccal delivery such as a hard lozenge
  • 0.1 mg to 100 mg of a compound of a preferred embodiment is mixed with 420 mg of powdered sugar/mannitol/xylitol or such sugars that provide negative heat of solution to the system, 1.6 mL of light corn syrup, 2.4 mL distilled water, and 0.42 mL mint extract or other flavorants.
  • the mixture is blended and poured into a mold to form a lozenge suitable for buccal administration.
  • a fast-disintegrating sublingual tablet is prepared by mixing 48.5% by weight of a compound of a preferred embodiment, 20% by weight of microcrystalline cellulose (KG-802), 24.5% by weight of either mannitol or modified dextrose or combination that help dissolve the compressed tablet faster in the mouth, 5% by weight of low-substituted hydroxypropyl cellulose (50 ⁇ m), and 2% by weight of magnesium stearate. Tablets are prepared by direct compression (AAPS PharmSciTech. 2006; 7(2):E41). The total weight of the compressed tablets is maintained at 150 mg.
  • the formulation is prepared by mixing the amount of the compound of a preferred embodiment with the total quantity of microcrystalline cellulose (MCC) and mannitol/modified dextrose or combination, and two- thirds of the quantity of low-substituted hydroxypropyl cellulose (L-HPC) by using a three dimensional manual mixer (Inversina, Bioengineering AG, Switzerland) for 4.5 minutes. All of the magnesium stearate (MS) and the remaining one-third of the quantity of L-HPC are added 30 seconds before the end of mixing.
  • MCC microcrystalline cellulose
  • L-HPC low-substituted hydroxypropyl cellulose
  • a pharmaceutical composition for inhalation delivery 0.1 mg to 100 mg of a compound of a preferred embodiment is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.
  • an inhalation delivery unit such as a nebulizer
  • a compound of a preferred embodiment (0.1 mg to 100 mg) is suspended in sterile water (100 mL); Span 85 (1 g) is added followed by addition of dextrose (5.5 g) and ascorbic acid (10 mg). Benzalkonium chloride (3 mL of a 1:750 aqueous solution) is added and the pH is adjusted to 7 with phosphate buffer. The suspension is packaged in sterile nebulizers.
  • a pharmaceutical composition for transdermal delivery 0.1 mg to 100 mg of a compound of a preferred embodiment is embedded in, or deposited on, a patch with a single adhesive face. The resulting patch is then attached to the skin via the adhesive face for transdermal administration.
  • a pharmaceutical topical gel composition 0.1 mg to 100 mg of a compound of a preferred embodiment is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.
  • a pharmaceutical ophthalmic solution composition 0.1 mg to 100 mg of a compound of a preferred embodiment is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.
  • Nasal Spray Solution 0.1 mg to 100 mg of a compound of a preferred embodiment is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter.
  • the resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.
  • a pharmaceutical nasal spray solution 0.1 mg to 100 mg of a compound of a preferred embodiment is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 ⁇ l of spray for each application.
  • a 0.05M phosphate buffer solution pH 4.4
  • Some embodiments disclosed herein relate to a method of treating and/or ameliorating IL-6 that can include administering to a subject suffering from immunosuppression an effective amount of one or more compounds described herein (such as a compound of Formula I, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula I, or a pharmaceutically acceptable salt thereof).
  • inventions disclosed herein relate to a method of treating and/or ameliorating immunosuppression that can include administering to a subject identified as suffering from immunosuppression an effective amount of one or more compounds described herein (such as a compound of Formula I, or a pharmaceutically acceptable salt thereof), or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition that includes a compound described herein such as a compound of Formula I, or a pharmaceutically acceptable salt thereof).
  • compounds described herein such as a compound of Formula I, or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes a compound described herein such as a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • Some embodiments described herein relate to using one or more compounds described herein (such as a compound of Formula I, or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for ameliorating and/or treating autoimmune diseases that can include administering to a subject an effective amount of one or more compounds described herein (such as a compound of Formula I, or a pharmaceutically acceptable salt thereof)). Still other embodiments described herein relate to one or more compounds described herein (such as a compound of Formula I, or a pharmaceutically acceptable salt thereof)) that can be used for ameliorating and/or treating autoimmune diseases by administering to a subject an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
  • Some embodiments disclosed herein relate to methods of ameliorating and/or treating cancer that can include contacting a cancerous cell an effective amount of one or more compounds described herein (such as a compound of Formula I, or a pharmaceutically acceptable salt thereof)), or a pharmaceutical composition that includes one or more compounds described herein (such as a compound of Formula I, or a pharmaceutically acceptable salt thereof)).
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof can act as an IL-6 antagonist, and thus, inhibit an anti-IL-6 receptor antibody.
  • the compounds or pharmaceutical compositions may be administered to the patient by any suitable means.
  • methods of administration include, among others, (a) administration though oral pathways, which administration includes administration in capsule, tablet, granule, spray, syrup, or other such forms; (b) administration through non-oral pathways such as rectal, vaginal, intraurethral, intraocular, intranasal, or intraauricular, which administration includes administration as an aqueous suspension, an oily preparation or the like or as a drip, spray, suppository, salve, ointment or the like; (c) administration via injection, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, intraorbitally, intracapsularly, intraspinally, intrasternally, or the like, including infusion pump delivery; (d) administration locally such as by injection directly in the renal or cardiac area, e.g., by depot implantation; as well as (e) administration topically; as deemed appropriate by those of skill in the art
  • compositions suitable for administration include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose.
  • the therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed.
  • the determination of effective dosage levels can be accomplished by one skilled in the art using routine pharmacological methods. Typically, human clinical applications of products are commenced at lower dosage levels, with dosage level being increased until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to establish useful doses and routes of administration of the compositions identified by the present methods using established pharmacological methods.
  • dosages may range broadly, depending upon the desired effects and the therapeutic indication. Typically, dosages may be between about 10 microgram/kg and 100 mg/kg body weight, preferably between about 100 microgram/kg and 10 mg/kg body weight. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art.
  • compositions of the present disclosure can be chosen by the individual physician in view of the patient’s condition. (See e.g., Fingl et al. 1975, in“The Pharmacological Basis of Therapeutics”, which is hereby incorporated herein by reference in its entirety, with particular reference to Ch. 1, p. 1).
  • dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient’s body weight.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient.
  • human dosages for compounds have been established for at least some condition, the present disclosure will use those same dosages, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage.
  • a suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
  • the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
  • the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 2000 mg of each active ingredient, preferably between 1 mg and 500 mg, e.g.5 to 200 mg.
  • an intravenous, subcutaneous, or intramuscular dose of each active ingredient of between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg is used.
  • dosages may be calculated as the free base.
  • the composition is administered 1 to 4 times per day.
  • compositions of the disclosure may be administered by continuous intravenous infusion, preferably at a dose of each active ingredient up to 1000 mg per day.
  • each active ingredient up to 1000 mg per day.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • the amount of composition administered may be dependent on the subject being treated, on the subject’s weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods.
  • the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity of particular compounds in an animal model such as mice, rats, rabbits, or monkeys, may be determined using known methods.
  • the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • Such notice for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising a compound of the disclosure formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • a daily dose may be from about 0.25 mg/kg to about 120 mg/kg or more of body weight, from about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight, or from about 1.5 mg/kg to about 10 mg/kg of body weight.
  • the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day.
  • the amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
  • Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.
  • compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereoisomers, tautomers, polymorphs, and solvates thereof), or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • compositions containing a pharmaceutically-acceptable carrier include compositions containing a pharmaceutically-acceptable carrier.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.
  • substances which can serve as pharmaceutically- acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyr
  • a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.
  • compositions described herein are preferably provided in unit dosage form.
  • a "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice.
  • the preparation of a single or unit dosage form does not imply that the dosage form is administered once per day or once per course of therapy.
  • Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded.
  • the skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.
  • compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration.
  • routes for administration for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration.
  • oral and nasal compositions comprise compositions that are administered by inhalation, and made using available methodologies.
  • a variety of pharmaceutically-acceptable carriers well-known in the art may be used.
  • Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances.
  • Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow- inducing agents, and melting agents.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
  • the pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for peroral administration is well-known in the art.
  • Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc.
  • Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture.
  • Coloring agents such as the FD&C dyes, can be added for appearance.
  • Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.
  • Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.
  • Peroral compositions also include liquid solutions, emulsions, suspensions, and the like.
  • the pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate;
  • typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
  • Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
  • compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action.
  • dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
  • compositions described herein may optionally include other drug actives.
  • compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms.
  • Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • a liquid composition which is formulated for topical ophthalmic use, is formulated such that it can be administered topically to the eye.
  • the comfort should be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort.
  • the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use.
  • an ophthalmically acceptable liquid should either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
  • solutions or medicaments are often prepared using a physiological saline solution as a major vehicle.
  • Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system.
  • the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate.
  • a useful surfactant is, for example, Tween 80.
  • various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
  • Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
  • buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
  • an ophthalmically acceptable antioxidant includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • excipient components which may be included in the ophthalmic preparations, are chelating agents.
  • a useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
  • Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.
  • the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution.
  • a pharmaceutically acceptable diluent such as a saline or dextrose solution.
  • Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid.
  • the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7.
  • Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA.
  • excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety.
  • Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.
  • compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
  • a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
  • the compositions are provided in solution ready to administer parenterally.
  • the compositions are provided in a solution that is further diluted prior to administration.
  • the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.
  • the second therapeutic agent is anti-inflammatory agent. In some embodiments, the second therapeutic agent is a non-steroidal anti- inflammatory agent. In some embodiments, the second therapeutic agent is anti-cancer agent. [0233] In some embodiments, the second therapeutic agent is selected from aspirin; diflunisal; salsalate; acetaminophen; ibuprofen; dexibuprofen; naproxen; fenoprofen; ketoprofen; dexketoprofen; flurbiprofen; oxaprozin; loxoprofen; indomethacin; tolmetin; sulindac; etodolac; ketorolac; diclofenac; aceclofenac; nabumetone; enolic acid; piroxicam; meloxicam; tenoxicam; droxicam; lornoxicam; isoxicam; mefenamic acid; meclofenamic
  • the second therapeutic agent is selected from mechlorethamine; cyclophosphamide; melphalan; chlorambucil; ifosfamide; busulfan; N- nitroso-N-methylurea (MNU); carmustine (BCNU); lomustine (CCNU); semustine (MeCCNU); fotemustine; streptozotocin; dacarbazine; mitozolomide; temozolomide; thiotepa; mytomycin; diaziquone (AZQ); cisplatin; carboplatin; and oxaliplatin.
  • MNU N- nitroso-N-methylurea
  • BCNU carmustine
  • CCNU lomustine
  • Semustine MeCCNU
  • fotemustine streptozotocin
  • dacarbazine mitozolomide
  • temozolomide temozolomide
  • thiotepa mytomycin
  • the second therapeutic agent is selected from vincristine; vinblastine; vinorelbine; vindesine; vinflunine; paclitaxel; docetaxel; etoposide; teniposide; tofacitinib; ixabepilone; irinotecan; topotecan; camptothecin; doxorubicin; mitoxantrone; and teniposide.
  • the second therapeutic agent is selected from actinomycin; bleomycin; plicamycin; mitomycin; daunorubicin; epirubicin; idarubicin; pirarubicin; aclarubicin; mitoxantrone; cyclophosphamide; methotrexate; 5-fluorouracil; prednisolone; folinic acid; methotrexate; melphalan; capecitabine; mechlorethamine; uramustine; melphalan; chlorambucil; ifosfamide; bendamustine; 6-mercaptopurine; and procarbazine.
  • the second therapeutic agent is selected from cladribine; pemetrexed; fludarabine; gemcitabine; hydroxyurea; nelarabine; cladribine; clofarabine; ytarabine; decitabine; cytarabine; cytarabine liposomal; pralatrexate; floxuridine; fludarabine; colchicine; thioguanine; cabazitaxel; larotaxel; ortataxel; tesetaxel; aminopterin; pemetrexed; pralatrexate; raltitrexed; pemetrexed; carmofur; and floxuridine.
  • the second therapeutic agent is selected from azacitidine; decitabine; hydroxycarbamide; topotecan; irinotecan; belotecan; teniposide; aclarubicin; epirubicin; idarubicin; amrubicin; pirarubicin; valrubicin; zorubicin; mitoxantrone; pixantrone; mechlorethamine; chlorambucil; prednimustine; uramustine; estramustine; carmustine; lomustine; fotemustine; nimustine; ranimustine; carboquone; thioTEPA; triaziquone; and triethylenemelamine.
  • the second therapeutic agent is selected from nedaplatin; satraplatin; procarbazine; dacarbazine; temozolomide; altretamine; mitobronitol; pipobroman; actinomycin; bleomycin; plicamycin; aminolevulinic acid; methyl aminolevulinate; efaproxiral; talaporfin; temoporfin; verteporfin; alvocidib; seliciclib; palbociclib; bortezomib; carfilzomib; anagrelide; masoprocol; olaparib; belinostat; panobinostat; romidepsin; vorinosta; idelalisib; atrasentan; bexarotene; testolactone; amsacrine; trabectedin; alitretinoin; tretinoin; demecol
  • the second therapeutic agent is selected from azathioprine; Mycophenolic acid; leflunomide; teriflunomide; tacrolimus; cyclosporin; pimecrolimus; abetimus; gusperimus; lenalidomide; pomalidomide; thalidomide; anakinra; sirolimus; everolimus; ridaforolimus; temsirolimus; umirolimus; zotarolimus; eculizumab; adalimumab; afelimomab; certolizumab pegol; golimumab; infliximab; nerelimomab; mepolizumab; omalizumab; faralimomab; elsilimomab; lebrikizumab; ustekinumab; etanercept; otelixizumab; teplizumab; visili
  • the second therapeutic agent is selected from pascolizumab; gomiliximab; lumiliximab; teneliximab; toralizumab; aselizumab; galiximab; gavilimomab; ruplizumab; belimumab; blisibimod; ipilimumab; tremelimumab; bertilimumab; lerdelimumab; metelimumab; natalizumab; tocilizumab; odulimomab; basiliximab; daclizumab; inolimomab; zolimoma; atorolimumab; cedelizumab; fontolizumab; maslimomab; morolimumab; pexelizumab; reslizumab; rovelizumab; siplizumab; talizumab; tel
  • BSA bovine serum albumin
  • Na 2 SO 4 sodium sulfate
  • NaHCO3 sodium bicarbonate
  • PHOSPHORYLATED-STAT3 PHARMACODYNAMIC ASSAY
  • IL-6 interleukin-6
  • IL6R receptor
  • IL6ST co-receptor
  • STAT3 Signal Transducer and Activator of Transcription-3
  • JNK Janus Activiated Kinase
  • Disruption of IL-6 signaling lead to reductions in nuclear pSTAT3, and pharmacologic reductions in nuclear pSTAT3 levels, in tumor cells or immune cells, represent a pharmacodynamic (PD) biomarker associated with desired drug activity.
  • PD pharmacodynamic
  • the pSTAT3 Pharmacodynamic Assay was performed using an ImageXpress Micro Confocal High-Content Imaging System in a 96-well format (CostarTM 96-Well Black Clear-Bottom Plates - Tissue culture treated; Cat # 07-200-588). Adjustable 1 mL, 5 mL, 10 mL, 25 mL pipettes were used for reagent preparation and Pipetmen (Precision) 50 ⁇ L and 20-200 ⁇ L or equivalent with sterile tips (e.g., Eppendorf) were used to dispense media for the assay. Cells were counted using a TC10 cell counter or hemocytometer.
  • Tumor cells were counted using a hemocyometer or cell counter and plated at 8,000 cells/well in complete medium (RPMI-1640 (ThermoFisher #11835030; pH 6.8); 10% FBS (HyClone # SH30910.03); 100U/mL Pen/Strep (ThermoFisher #15140122) in a 96-well plate. Caution was taken to avoid plating in the outer wells to prevent any cell stress or dehydration. After 48 h in culture (based on cell health and number), the culture medium was removed and RPMI-1640 (ThermoFisher #11835030; pH 6.8) without phenol red to wash the cells. The cells were diluted in RPMI-1640 without phenol red and incubated at 37 oC for 1 hour and 50 ng/mL recombinant interleukin-6 (IL-6) for 0.5 hours.
  • IL-6 interleukin-6
  • the medium was removed and replaced with 100 ⁇ L/well of a 7.4% formaldehyde fixative solution and incubated at room temperature for 10 minutes.
  • the fixative formaldehyde solution was removed and the cells were washed twice with PBS followed by permeabilization using 100% ice-cold methanol (100 ⁇ L/well) at 4 oC for 30 min.
  • the permeablized cells were washed twice with PBS and blocked with 5% BSA, 0.1% Tween-20/PBS (100 ⁇ L/well) for 30 min at room temperature. After blocking, the cells were washed twice with 0.1% Tween-20/PBS.
  • the primary antibody was diluted at 1:100 v/v in 1% BSA, 0.1% Tween-20/PBS and incubated over wells (50 ⁇ L/well) overnight at 4 oC.
  • the primary antibody was washed off and the cells were washed twice with 0.1% Tween-20/PBS (100 ⁇ L/well).
  • the secondary antibody at 1:500 (v/v) in PBS/0/.1% Tween-20) and incubate at room temperature for 1 hour.
  • the cells were then washed twice with 100 ⁇ L/well 0.1% Tween-20/PBS.
  • 100 ⁇ L of 4',6- diamidino-2-phenylindole (DAPI; Sigma Cat # D8417, diluted at 1:1000 v/v) was added to the wells and incubated for 10 minutes.
  • DAPI was washed off twice using 100 ⁇ L PBS and the plates using the High Content Imager. The results are presented in Table 2 below. TABLE 2: pSTAT3 results
  • BME should be thawed at 4 o C overnight, but it can be thawed more quickly by placing it on ice for approximately three to four hours.
  • Verify cells have detached from surface by observation using an inverted phase contrast microscope.
  • Drugs should be diluted into Matrix Media Plus, supplemented with hormone cocktail consisting of E2 (50 pg/mL final in well), DHT (250 pg/mL final in well), and progesterone (1 ng/mL final in well). Add L-glutamine to 2 mM final concentration.
  • Working stock of drug dilution should be at 3x the desired final concentration. [0286] All required volumes should be calculated based on adding 50 ⁇ L/well, giving a final volume of 150 ⁇ L/well post application, with enough overage to accommodate 5% for pipetting error.
  • First wash is quick, on and off with 100 ⁇ l of PBS
  • Second wash is longer, 5-10 minutes RT in dark with 200 ⁇ l PBS
  • Drugs should be diluted into phenol red free RPMI-1640 supplemented as above.
  • Working stock of drug dilution should be at 3x the desired final concentration.
  • Second wash is longer, 5-10 minutes RT in dark with 200 ⁇ l PBS
  • mice bearing the MDA- MB-231 tumor line were orally (p.o) dosed at 1, 3, 10, 30, and 100 mg/kg of (Z)-3-(4- hydroxyphenyl)-5-((5-nitrofuran-2-yl)methylene)thiazolidine-2,4-dione (1) once daily (Q.D.) over ten days.
  • Administration of compound 1 showed efficacy in inhibiting the growth of large tumors (approximately 500 mm 3 starting size).
  • Doses of 3, 10, 30, and 100 mg/kg of compound 1 exhibited tumor growth inhibition (TGI).
  • the 3 mg/kg dose exhibited greater than 40% tumor growth inhibition relative to control, while the 100 mg/kg dose exhibited greater than 60% tumor growth inhibition relative to control.
  • the maximum tolerated dose was not reached at the highest administered dose of 100 mg/kg p.o. Q.D. for 10 days.
  • mice bearing the MDA-MB-231 tumor line were orally (p.o) dosed at 0, 3, 10, 30, 100, and 300 mg/kg of (Z)-3-(4-hydroxyphenyl)-5-((5- nitrofuran-2-yl)methylene)thiazolidine-2,4-dione (1) once daily (Q.D.) over ten days.
  • Administration of compound 1 showed efficacy in inhibiting the growth of standard size tumors (approximately 123 mm 3 starting size).
  • Doses of 3, 10, 30, 100, and 300 mg/kg of compound 1 exhibited tumor growth inhibition (TGI). The maximum tolerated dose was not reached at the highest administered dose of 300 mg/kg p.o. Q.D. for 20 days.
  • TGI tumor growth inhibition
  • HCS High Content System
  • MitoSOX was purchased from ThermoFisher Scientific (Catalog No. M36008) and was resuspended directly prior to use in DMSO, as per manufacturer’s instructions.
  • Day 0 Plating of Cells [0399] Cells should be in exponential growth phase in standard 2D culture. Using standard cell culture technique, cells are trypsinized, pelleted, resuspended in cell culture media and counted as per SOP-11-022. Cells were plated in a Perkin Elmer Cell Carrier Ultra plate and allowed to expand in culture for 48 hours. Day 2: Experiment: sequential kinetic high content imaging
  • NUCLEAR STAT1 Y701 IN HeLa CELLS FOLLOWING IFN-GAMMA EXPOSURE Cells were counted using TC10 Automated cell counter (Bio-Rad) and plate at 7,000 cells/well in complete medium in a 96-well plate (avoid plating in the outer wells to prevent any cell stress or dehydration). After 48 hours in culture (based on cell health and number), the culture medium was removed and 100 ⁇ l RPMI1640 without phenol red was added to wash the cells briefly. Dilute drugs (50 ⁇ l/well) in RPMI1640 without phenol red and incubated at 37 oC for 30 min.
  • KINASE ACTIVITY The KiNativ TM Kinome Screen screened kinase inhibition following exposure of a 1 ⁇ M of either Compound 1, Nifuroxazide, and Ruxolitinib.
  • Compound 1 displayed no kinase activity at doses of 0.1 ⁇ M, 1.0 ⁇ M, and 10 ⁇ M.
  • Table 6 shows inhibition data for the top 20 kinases as ranked by ruxolitinib. Unlike ruxolitinib, Compound 1 and Nifuroxazide are not kinase inhibitors. TABLE 6: Kinase Activity

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Abstract

L'invention concerne des analogues de nifuroxazide et leurs sels et dérivés pharmaceutiquement acceptables. L'invention concerne également des procédés et des utilisations qui comprennent l'administration d'une quantité efficace des analogues de nifuroxazide, ou de leurs sels ou dérivés pharmaceutiquement acceptables. Les composés présentent une activité anti-proliférative et sont utiles pour le traitement de toute une gamme de troubles, tels que des maladies auto-immunes, le cancer et des maladies infectieuses.
PCT/US2018/066921 2017-12-22 2018-12-20 Analogues de nifuroxazide et leurs utilisations thérapeutiques WO2019126568A1 (fr)

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CN113024530A (zh) * 2021-03-15 2021-06-25 合肥工业大学 一种靛红-1,2,4-噁二唑类化合物及其制备方法和用途
CN113336729A (zh) * 2021-05-31 2021-09-03 四川大学华西医院 硝呋齐特类衍生物及其制备方法和用途

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US20060276520A1 (en) * 2002-11-13 2006-12-07 Rigel Pharmaceuticals, Inc. Rhodanine derivatives and pharmaceutical compositions containing them
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US20130096125A1 (en) * 2010-06-18 2013-04-18 Avixgen Inc. Novel rhodanine derivatives, method for preparing same, and pahrmaceutical composition for the prevention or treatment of aids containing the rhodanine derivatives as active ingredients
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US20130090339A1 (en) * 2010-06-17 2013-04-11 The Uab Research Foundation Compounds useful as antiviral agents, compositions, and methods of use
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CN113024530A (zh) * 2021-03-15 2021-06-25 合肥工业大学 一种靛红-1,2,4-噁二唑类化合物及其制备方法和用途
CN113024530B (zh) * 2021-03-15 2023-07-18 合肥工业大学 一种靛红-1,2,4-噁二唑类化合物及其制备方法和用途
CN113336729A (zh) * 2021-05-31 2021-09-03 四川大学华西医院 硝呋齐特类衍生物及其制备方法和用途
CN113336729B (zh) * 2021-05-31 2022-05-27 四川大学华西医院 硝呋齐特类衍生物及其制备方法和用途

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