Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D277/62—Benzothiazoles
  • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
  • C07D277/82—Nitrogen atoms
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  • 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
  • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
• • 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
• • 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
  • C07D417/12—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 chain containing hetero atoms as chain links
• • 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
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  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

• each of substituents R 5000A andR 5000B is independently selected from the group consisting of -Ci-Ce alkyl; and -Ci-Ce alkyl substituted with one or more groups selected from -Ci-Ce alkoxy, and -O(CH 2 ) 2 OCH3; alternatively R 5000A and R 5000B together with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl;
• Z 1000 is selected from the group consisting of H, -CH 2 OCH3, -CH 2 OCH 2 CH3, -CH 2 O(CH 2 ) 2 OH, -CH 2 O(CH 2 ) 2 OCH 3 , -CH 2 O(CH 2 ) 2 N(CH 3 ) 2 , -CH 2 O(CH 2 ) 2 NHSO 2 CH 3 , -(CH2)O(CH 2 ) 2 NR 2000A R 2000B , -(CH 2 ) S R 3000 , -CI FOCI F Ar 1 , OCH3 CH 2 NHC(O)CH 2 CH 3 , -CH 2 NHC(O)CH 2 OCH 3 , -CH 2 NHSO 2 CH 3 , -(CH 2 )t’NR 7000A R 7000B , and -(CH 2 ) t R 8000 ;
• R 3000 is a 5 to 6-membered heterocyclic ring
• Ar 1 is a 5 to 6-membered aryl or heteroaryl group optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl, halo, hydroxyl and alkoxy;
• each of R 7000A and R 7000B is independently selected from Ci-Ce alkyl; alternatively, R7OOOA an j R 7000B t O g e th er with the nitrogen to which they are attached, form a 4 to 8- membered heterocyclyl optionally substituted with one or more substituents independently selected from Ci-Ce alkyl;
• R 5000A and R 5000B are not both Ci-Ce alkyl; and when Z 1000 is H; R 1000a is not Ci- C 6 alkyl, -C 3 -C 6 cycloalkyl, CH 3 or CH 2 CH 3; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
• each of R 5A andR 5B is independently selected from the group consisting of -Ci-Ce alkyl; and -Ci-Ce alkyl substituted with one or more groups selected from -Ci-Ce alkoxy, and -O(CH 2 ) 2 OCH 3 ; alternatively R 5A and R 5B together with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino, carboxyamido, -SO 2 CH 3 , -CF 3 , Ci-Ce alkyl, halo, and acyl;
• R 6 is selected from the group consisting of a 5 to 6-membered heterocyclyl, pyridinyl and thiazolyl; m’ is an integer selected the group consisting of 1, 2 and 3; m is an integer selected the group consisting of 0, 1, 2 and 3;
• R lc is selected from the group consisting of chloro, fluoro, iodo, and bromo; each of R 4b and R 4d is independently selected from the group consisting of Y and Z, provided that when R 4b is Y, R 4d is Z and when R 4b is Z, R 4d is Y;
• Y is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF 3 , -CHF 2 , fluoro(Ci-C6)alkyl, halo(Ci-C6)alkyl, -OCF 3 , -SO 2 (Ci-C6)alkyl, cyano, and -CO 2 (Ci-C 6 )alkyl;
• R B is a conventional mitochondrial uncoupler prior to being covalently linked to R A ; provided the mitochondrial membrane-retaining uncoupler compound is not
• Oligo is oligomycin 2.5 pM; AA isantimycin A 2 pM; Rot isrotenone 2 pM.
• Figure 4B shows mitochondrial membrane potential (MMP) determined by fluorescence microscopy using two different dyes, tetramethylrhodamine ethyl ester (TMRE) staining and DilCl(5) staining, respectively, in the presence of FCCP at the indicated concentrations. The fluorescent intensity is indicative of MMP.
• FCCP has a ratio of CIO%TMRE / Cmin-OCR less than 3, where CIO%TMRE is the concentration leading to 10% MMP retention (or 90% MMP loss, measured by TMRE staining) and Cmin-ocR is the minimal concentration leading to OCR increase.
• SUBSTITUTE SHEET (RULE 26 ) represents Compound 25 at 9.0 pM, and the circle represents Compound 25 atl2.0 pM.
• Oligo isoligomycin 2.5 pM; AA is antimycin A 2 pM; Rot isrotenone 2 pM.
• Figure 5B shows mitochondrial membrane potential (MMP) determined by fluorescence microscopy using two different dyes, tetramethylrhodamine ethyl ester (TMRE) staining and DilCl(5) staining, respectively, in the presence of Compound 25(#25) at the indicated concentrations. The fluorescent intensity is indicative of MMP.
• Compound 25 represents the MMP -retaining uncouplers that do not cause observable MMP reduction while uncoupling mitochondria (with a ratio of CIO%TMRE I Cmin-ocR greater than 25).
• Figure 6 shows the effect of Compound 64 (#64), on oxygen consumption rate (Figure 6A) and mitochondrial membrane potential (Figure 6B).
• Compound 64 increases OCR without drastically dissipating mitochondrial membrane potential.
• Figure 6A shows cellular oxygen consumption rates determined by Seahorse OCR assay using C2C12 cells at the indicated concentrations.
• the diamond in Figure 6A represents vehicle treatment control, the square represents Compound 64 (#64) at 0.3 pM, the triangle represents Compound 64 at 1.0 pM, the X represents Compound 64 at 2.0 pM, the * represents Compound 64 at 3.0 pM, and the circle represents Compound 64 at 4.0 pM.
• Oligo is oligomycin 2.5 pM; AA is antimycin A 2 pM; Rot is rotenone 2 pM.
• Figure 6B shows mitochondrial membrane potential (MMP) determined by fluorescence microscopy using two different dyes, tetramethylrhodamine ethyl ester (TMRE) staining and DilCl(5) staining, respectively, in the presence of Compound 64 (Comp #64) at the indicated concentrations. The fluorescent intensity is indicative of MMP.
• Compound 64 represents the MMP-retaining uncouplers that do not drastically reduce MMP while uncoupling mitochondria (with a ratio of CIO%TMRE / Cmin-ocR between 10 and 25).
• Figure 7 shows a schematic illustration of the mechanism of action of a conventional mitochondrial uncoupler ( Figure 7A) and a proposed mechanism of action of an MMP-retaining uncoupler (Figure 7B), as well as diagrams and an example of how to convert a conventional uncoupler to an MMP-retaining uncoupler ( Figure 7C-E).
• Figure 7A and Figure 7B show mitochondrial electron transport chain complexes I, II, III, IV, ATP synthase, as well as uncouplers (UH or U").
• Conventional uncouplers allow proton translocation across the mitochondrial inner membrane, causing loss of MMP (Figure 7A).
• SUBSTITUTE SHEET ( RULE 26 ) conventional uncoupler ( Figure 7C), for example, by adding a tertiary amine- (or secondary amine-) containing side chain to obtain an MMP -retaining uncoupler (Figure 7D), where N is nitrogen; and X and Y are optimally substituted side chains.
• Figure 7E shows an example of an MMP -retaining uncoupler, showing a conventional uncoupling component in the frame.
• Compounds 64 and 25 were prepared to a fine suspension in 0.5% CMC-Na / 1% Tween80 water solution. The tests were performed under fed condition, by oral gavage of 100-400 pL compound suspension according to the body weight to desired dosages (mg/kg). The mice were supplied with drinking water all through the testing time. Mouse behaviors were monitored every 15-30 minutes and LD50 were determined. MED was determined in diabetic and steatosis mouse models (Table 9).
• Figures 9 shows the safety profile of Compound 64 (#64) compared to DNP.
• Figure 9A shows the NOAEL(no-observable-adverse-effect-level)/MED of DNP. https://www.atsdr.cdc.gov/ToxProfiles/tp64.pdf; (US EP A, 2, 4-dinitrophenol. https://www.epa.gov/sites/default/files/2016-09/documents/2-4-dinitrophenol.pdf; and US CDC).
• Figure 9B shows the MED, intermediate NOAEL and NOAEL/MED of Compound 64 calculated by oral dosage.
• Figure 9C shows the MED, intermediate NOAEL and NOAEL/MED of Compound 64 over DNP calculated by Cmax (maximal blood concentration).
• Figure 9D shows the MED, intermediate NOAEL and NOAEL/MED of Compound 64 calculated byAUC (Area Under Curve).
• the Figures demonstrate that the MMP-retaining uncoupler, Compound 64 exhibits drastically improved short-term safety profiles over the conventional uncoupler DNP.
• Figure 10 show the safety profile of Compound 25 (#25)
• Figure 10A shows the MED, intermediate NOAEL and NOAEL/MED of Compound 25 calculated by oral dosage.
• Figure 10B shows the MED, intermediate NOAEL and NOAEL/MED of Compound 25 over DNP calculated by Cmax (maximal blood concentration).
• Figure 10C shows the MED, intermediate NOAEL and NOAEL/MED of Compound 25 calculated byAUC (Area Under Curve).
• the Figures demonstrate that the MMP -retaining uncoupler, Compound 25 exhibits drastically improved short-term safety profiles over the conventional uncoupler DNP.
• Figure 14 shows the effects of Compound 25 on blood triglyceride (Figure 14A), total cholesterol (Figure 14B), and nori-HDI. cholesterol levels (Figure 14C) in high-fat diet induced diabetic/hepatic steatosis mice.
• Figure 18 shows the efficacy of Compound 25 in reducing liver fibrosis determined by histology and molecular analysis.
• Figure 18A is microscope images of liver sections of CCL treated mice, subjected to H & E staining (top left panel); CCI4 plus Compound 25 (7.5 mg/kg/day) treated mice subjected to H & E staining (bottom left panel); CCL treated mice, subjected to Picrosirius Red staining(staining fibrotic collagen, top right panel) and CCL plus Compound 25 (7.5 mg/kg/day) treated mice subjected to Picrosirius Red staining (staining fibrotic collagen, bottom left panel.
• Figure 19 is an immunoblotting analysis that shows the inhibitory effect of Compound 6464 on TGF-0 activation in T-cells.
• Figure 19A is an immunoblotting analysis of Human Jurkat cells treated with either vehicle alone (first lanes), TGF-0 alone (second lanes), TGF-0 plus Compound 64 at 0.5, 1.0 or 2.0 pM of compound (third through 5th lanes), as indicated, for 6 hours.
• Figure 19B is an immunoblotting analysis of mouse primary T-cells (B) were treated with either vehicle alone (first lanes), TGF-0 alone (second lanes), or TGF-0 plus varying concentrations of Compound 64 atl.O or 2.0 pM of compound (third and fourth lanes), as indicated, for 6 hours. Immunoblotting analyses were performed with antibodies against p-Smad2/3 (phosphorylated Smad2/3), Smad2/3, or GAPDH, as indicated.
• Figure 20 shows Compound 64 is efficacious in combinatory therapy with PD-1 antibody in treating metastatic cancer in mice.
• Figure 20A is the experimental design (see Example B 12). Briefly, C57/B16 mice intrahepatically transplanted with MC38 cancer cells (day 0) were subject to various treatments starting on day 7: aPD-1 or isotype, mice were either treated with PD-1 antibody or its isotype antibody (control) by intraperitoneal (IP) injection on indicated days (PD-1 antibody has a half-life of over 1 week in mice); #64 or vehicle, mice were either treated with Compound #64 or vehicle by daily gavage.
• Figure 20B is a table depicting outcomes of the experiments described in Figure 20A and Example B12.
• aPD-1 +#64 represents mice treated with PD-1 antibody (IP) and #64 (daily gavage); aPD-1 represents mice treated with PD-1 antibody (IP) and vehicle (gavage); control, represents mice treated with isotype antibody (IP) and vehicle (gavage); n is number of mice in each group. Tumor-positive is the number of tumor- bearing mice in each group; tumor- free is thenumber of tumor-free mice in each group; tumor-free % is thepercentage of tumor- free animals in each group. Fisher Exact 2x2 test is theP value comparing each experimental group to control group using statistical analysis with Fisher Exact 2x2 test. P ⁇ 0.05 is indicative of a statistically significant difference.
• Figure 21 shows antiviral activity (EC50), cytotoxicity (TC50), and specificity index (SI) of Compounds 64, 25 and 57 against enveloped viruses.
• EC50 isthe compound concentration that reduces virus- induced cytopathic effects (CPE) by 50%.
• TC50 isthe compound concentration that leads to 50% of cell viability of uninfected cells; SI is the ratio between TC50 and EC50.
• the experiments were performed as follows. The host cells, either Vero 760 or MRC-5, as indicated, were seeded in 96-well flat-bottom tissue culture plates and allowed to adhere overnight.
• the cells were either infected with virus (either SARS-CoV-2 or alpha coronavirus 229E) or uninfected, and diluted test compounds were added to each well. Following incubation at 37°C, 5% CO2 for three days or six days, cell viability was determined. Percent of CPE reduction of the virus-infected wells and the percent of cell viability of uninfected drug control wells, were measured to calculate and determine the EC50 and TC50 values. SI, was calculated accordingly.
• virus either SARS-CoV-2 or alpha coronavirus 229E
• mitochondria are the ultimate site where lipid or glucose metabolites are consumed (oxidized); (2) mitochondria are critical in regulating the abundance of metabolic intermediates that become building blocks of biosynthesis essential for cell growth and proliferation of cancer cells, as well as for viral envelop production and assembly; (3) mitochondria are the major production site of ROS in neurons and many other cells ( Figure 1).
• Mitochondrial uncoupling is a unique way to modulate mitochondrial activity and functions.
• mitochondrial uncoupling is a process by which the activity of mitochondrial electron transport chain is de-coupled from ATP synthesis.
• mitochondrial uncoupling is caused by the action of mitochondrial uncouplers that carry protons across the mitochondrial inner membrane into the mitochondrial matrix, independent of the ATP synthase (Terada, H. (1990) Environmental Health Perspectives 87, 213-218).
• the technical definition of mitochondrial uncouplers is an increase of oxygen consumption rate (OCR) by cells in the presence of an ATP synthase inhibitor such as oligomycin.
• OCR oxygen consumption rate
• Metabolic diseases are a family of diseases characterized by symptoms of abnormal glucose and/or lipid metabolism, such as obesity, type 2 diabetes, alcoholic fatty liver disease, non-alcoholic fatty liver diseases, nonalcoholic steatohepatitis. These diseases are associated with age-, environmental-, or genetic- related decrease in mitochondrial functions such as reduced oxidative capacity. Importantly, these diseases also share a common causal factor, namely abnormal accumulation of intracellular lipid in cells of various tissues as well as insulin resistance in most cases. For example, obesity is characterized by excessive fat accumulation in cells of adipose tissue. Metabolic syndrome is characterized with insulin resistance in peripheral tissues, usually caused by ectopic fat accumulation in cells of liver, muscle, or adipose tissue. Type 2
• Mitochondrial uncoupling reduces energy efficiency thereby undermining the energy requirement of cancer cells.
• mitochondrial uncoupling promotes the complete mitochondrial oxidation of glucose and lipid, thereby diminishing the production of metabolic intermediates essential for biosynthesis of macromolecules required for cell proliferation.
• mitochondrial uncoupling could lead to AMPK activation, a known event for inhibiting cell growth.
• prior documents showed that mitochondrial uncouplers exhibit anti-cancer activities (U. S. Patent 10,227,315). Targeting cancer cells through mitochondrial uncoupling would deprive energy as well as biosynthetic metabolic intermediates that are absolutely essential for cancer cell growth and proliferation, which is proven to be an effective anti-cancer strategy (Alasadi, A. et al., (2016) Cell Death Dis., 9(2), 215)
• Autoimmune diseases are conditions where the body’s immune system attacks their own healthy organs.
• the common autoimmune diseases include celiac disease, diabetes mellitus type 1, Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.
• the body’s own self-attaching immune cells need amplification (proliferation) which requires metabolic changes similar to the Warburg effect observed in cancer cells to provide sufficient building blocks for biosynthesis (Ganeshan, K., et al. (2014) Annual Review of Immunology, 32, 609-634). Therefore, mitochondrial uncoupling would potentially inhibit the activation and amplification of self-attacking immune cells.
• Neurodegenerative diseases are a large group of disabling disorders of the nervous system such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease, characterized by the relative selective death of neuronal subtypes.
• Parkinson's disease Huntington's disease
• amyotrophic lateral sclerosis amyotrophic lateral sclerosis
• Alzheimer's disease characterized by the relative selective death of neuronal subtypes.
• mitochondrial ROS production As one of the most important one (Elfawy, H. A., and Das, B. (2019) Life Sci., 218, 165-184.)
• Mitochondrial uncouplers increase mitochondrial electron transport chain flux and decrease the electron stall in the complexes of the electron transport chain, thus they could effectively reduce mitochondrial ROS. Therefore, mitochondrial uncoupling is
• Mitochondria are ancient bacteria that formed a symbiotic relationship with host cells. Bacterial plasma membrane contains electron transport chain and ATP synthase that are similar to those of mitochondria, therefore compounds that impact mitochondrial uncoupling could be useful inhibitors of bacterial growth and effective as antibiotics (US Patent 10,227,315).
• Benzamide mitochondrial uncouplers have been developed (International Patent Publication Number WO 2012/068274, International Patent Publication Number WO 2016/081599, U. S. Patent 10,227,315, and Tao et al., 2014) for potential therapeutic applications.
• One main limitation of the prior benzamide compounds are poor pharmacokinetic properties and low systemic exposure.
• studies in animal models required the compound to be mixed with food, and high doses of the compounds were required to achieve efficacy (e.g. 1500 ppm niclosamide ethanolamine (NEN) in diet, equivalent to 150 mg/kg/day (Tao, et al.
• MMP-retaining compounds exhibit drastically improved safety profiles compared to the bench mark conventional mitochondrial uncoupler, DNP. These compounds exhibit a wider therapeutic index when used for treating metabolic diseases.
• 6-membered heterocyclyl is selected from the group consisting piperidinyl optionally substituted with one or Ci-Ce alkyl substituents, and morpholinyl optionally substituted with one or Ci-Ce alkyl substituents.
• R la of Formula I, or of Formula la or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -(CH2) m R 6 ; wherein R 6 is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, thiazolyl and piperidinyl and m is as previously described. In some embodiments m is 0. In some embodiments m is 1. In some embodiments -(CH2) m R 6 is selected from the group
• R la of Formula I, or of Formula la or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from the group consisting of -CH 3 , -CH2CH3, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH 2 O(CH 2 )2OH, -CH 2 O(CH 2 )2OCH 3 , CH 2 )NH(CH 2 ) 2 OCH3, -CH 2 NHC(O)CH 3 , -(CH 2 )2NHCO 2 CH3,
• R la of Formula I, or of Formula la or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from the group consisting of -CH3, -CH2CH3 and -CH2NR 5A R 5B wherein R 5A and R 5B are as previously described in any embodiment described herein.
• each of R 5A and R 5B is independently selected from Ci-Ce alkyl substituted with one or more methoxy; alternatively, R 5A and R 5B together with the nitrogen to which they are attached, form a 6-membered heterocyclyl optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl.
• R lc of Formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is chloro.
• Some embodiments describe a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4b is Y and R 4d is Z.
• Y of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -CF 3 .
• Z of Formula I, or R 4d of Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -(CH2)O(CH2)2NR 2A R 2B wherein R 2A and R 2B are as previously described herein.
• R 2A and R 2B together with the nitrogen to which they are attached form a 6-membered heterocyclyl optionally substituted with a methyl group.
• R 2A and R 2B together with the nitrogen to which they are attached form a heterocyclyl selected from piperazinyl or a 4- methyl piperazinyl.
• Z of Formula I, or R 4d of Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -(CH2) n R 3 , wherein R 3 is as previously described herein.
• R 3 is a 5-membered heterocyclic ring.
• R 3 is selected from the group consisting of tetrahydrofuranyl, and phenoxy.
• R 3 is tetrahydrofuranyl.
• R 3 is selected from the group consisting of and phenoxy.
• n is 0.
• n is 1.
• -(CH2)nR 3 is selected from the group consisting
• Z of Formula I, or R 4d of Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -CH 2 OCH 2 Ar, wherein Ar is as previously described herein.
• Ar is a 5 to 6-membered aryl or heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro, chloro, hydroxy, and methoxy.
• Ar is selected from the group consisting of thiazolyl, phenyl, and phenyl substituted with one or more groups independently selected from methyl, fluoro, chloro, hydroxy, and methoxy.
• Ar is selected from the group consisting of, phenyl,
• Z of Formula I, or R 4d of Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from the group consisting of -CH 2 OH, -CH2OCH2CH3, -CH2OCH3, -CH 2 O(CH 2 )2OH, -CH 2 O(CH 2 )2OCH3, CH 2 O(CH2)2NHCH3,-CH 2 O(CH2)2N(CH3)2, -CH 2 O(CH 2 )2NHSO2CH3, -(CH 2 )O(CH 2 )2 NR 2A R 2B , -(CH2) n R 3 , -CH 2 OCH 2 Ar and OCH3; wherein R 2A R 2B , R 3 , n and Ar are as described in any embodiment herein.
• Z of Formula I, or R 4d of Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from the group consisting of -CH2OCH2CH -CH 2 O(CH 2 )2N(CH3)2, -CH 2 -CFLOCJTAr and OCH3; wherein R 2A R 2B , R 3 , n and Ar are as described in any embodiment herein.
• Z of Formula I, or R 4d of Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from the group consisting of -CH2OCH2CH3, -CH2OCH3, -CH 2 O(CH2)2OH, -CH 2 O(CH2) 2 OCH3, -CH 2 O(CH 2 ) 2 N(CH3)2, -CH 2 O(CH 2 )2NHSO2CH3, -(CH 2 )O(CH 2 ) 2 NR 2A R 2B , -(CH 2 ) n R 3 , -CFLOCJTAr and OCH3; wherein R 2A and R 2B together with the nitrogen to which they are attached, form a heterocyclyl selected from the group consisting of piperazinyl and 4-methyl piperazinyl; R 3 is tetrahydrofuranyl; and Ar is a 5 to 6-membered aryl or heteroaryl group
• SUBSTITUTE SHEET ( RULE 26 ) optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro, chloro, hydroxy, and methoxy.
• Z of Formula I, or R 4d of Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from the group consisting of -CH 2 OH,-CH 2 OCH 2 CH 3 , -CH 2 OCH 3 , -CH 2 O(CH 2 )2OH, -CH 2 O(CH 2 )2OCH 3 ,
• Z of Formula I, or R 4d of Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group
• Z of Formula I or R 4d of Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from the group consisting of -CH 2 OH, -CH 2 OCH 2 CH 3 , -CH 2 OCH 3 , -CH 2 O(CH 2 ) 2 OH, -CH 2 O(CH 2 ) 2 OCH 3 ,
• the compound is or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
• the present disclosure describes a compound of
• SUBSTITUTE SHEET ( RULE 26 ) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
• R 50A and R 50B are independently selected from the group consisting of -Ci-Ce alkyl; and -Ci-Ce alkyl substituted with one or more groups selected from -Ci-Ce alkoxy, and -O(CH 2 ) 2 OCH 3 , with the proviso that R 50A and R 50B are not both Ci-Ce alkyl; alternatively R 50A and R 50B together with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino , carboxyamido, -SO 2 CH 3 , -CF 3 , Ci-Ce alkyl
• R 10a of Formula II, or of Formula Ila or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from the group consisting of -CH2NR 50A R 50B ; wherein R 50A and R 50B together with the nitrogen to which they are attached, form a 4-7 membered heterocyclyl selected from the group consisting of azetindinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl, and dioxothiomorphylinyl; wherein the 4-7 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, methoxy, -NHC(0)CH3, -C(0)NH2, -SO2CH3, -CF3, methyl, fluoro, and acetyl.
• SUBSTITUTE SHEET ( RULE 26 ) substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl;
• R 60 is selected from the group consisting of tetrahydrofuranyl, thiazolyl, and pyridinyl o is 0;
• R 10c is selected from the group consisting of chloro, fluoro, iodo.
• R 40d is H and R 40b is selected from the group consisting of fluoro, -CF3, -CHF2, and -OCF3;
• R 10c is selected from the group consisting of chloro, fluoro, iodo.
• R 10c is selected from the group consisting of chloro, fluoro, iodo.
• R 40d is H and R 40b is selected from the group consisting of fluoro, -CF3, -CHF2, and -OCF3.
• R 10a is selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH 2 O(CH 2 )2OH, - CH 2 O(CH 2 ) 2 OCH3,
• R 10c is chloro
• R 40d is H and R 40b is -CF 3 .
• R 10a is selected from the group consisting of -OCH 3 , -CH 2 OCH 3 , -CH 2 OCH 2 OCH 3 ,
• Some embodiments describe a compound of Formula Ila or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
• SUBSTITUTE SHEET (RULE 26) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
• R 100a of Formula III, or of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from the group consisting of -CH2NR 500A R 500B ; wherein R 500A and R 500B together with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, -acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl.
• the 4-8-membered heterocyclyl is selected from the group consisting of azetindinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl, dioxothiomorphylinyl, and azabicyclo[3.2.1]octanyl; wherein the heterocyclyl is optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, -acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl.
• the 4-8-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, methoxy, -NHC(O)CH3, -C(O)NH 2 , -SO2CH3, -CF3, methyl, fluoro, and acetyl. In some embodiments the 4-8-membered heterocyclyl is optionally substituted with one or more methyl substituents.
• the 4 to 8-membered heterocyclyl is selected from the group consisting of azetindinyl; pyrrolidinyl; pyrrolidinyl substituted with one or more substituents selected from the group consisting of cyano, hydroxyl, methoxy, -NHC(O)CH3, - C(O)NH2, -SO2CH3, -CF3 and methyl; piperidinyl; piperidinyl substituted with one or more substituents selected from the group consisting of -CF3, and fluoro; piperazinyl substituted with one or more substituents selected from the group consisting of oxo, methyl, and acetyl; morpholinyl; morpholinyl substituted with one or more methyl groups; dioxothiomorphylinyl, and azabicyclo[3.2.1]octanyl.
• R 100a of Formula III, or of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from the group consisting of -CH2NR 500A R 500B ; wherein R 500A and R 500B together with the nitrogen to which they are attached, form a 6-membered heterocyclyl optionally substituted with one or more
• SUBSTITUTE SHEET ( RULE 26 ) substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy,
• 6-membered heterocyclyl is selected from the group consisting piperazinyl optionally substituted with one or Ci-Ce alkyl substituents, and morpholinyl optionally substituted with one or Ci-Ce alkyl substituents.
• R 100a of Formula III, or of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from the group consisting of -CH 2 NR 500A R 500B ; wherein -CH2NR 500A R 500B is selected from the group embodiments -CH2NR 500A R 500B is selected from the group consisting of
• R 100a of Formula III, or of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -(CH 2 ) P R 600 ; wherein R 600 is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, piperidinyl,
• SUBSTITUTE SHEET ( RULE 26 ) thiazolyl and piperidinyl and m is as previously described.
• p is 0.
• p is 1.
• -(CH 2 ) P R 600 is selected from the group
• R 100a of Formula III, or of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from the group consisting of -CH 3 , -OCH 3 , -CH 2 OCH 3 , -CH 2 OCH 2 OCH 3 , -CH 2 O(CH 2 )2OH, -
• R 100a of Formula III, or of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from the group consisting of -CH 3 , and -CH2NR 500A R 500B wherein R 500A and R 500B are as previously described in any embodiment described herein.
• each of R 500A and R5°° B J S i n d e p encien tiy selected from Ci-Ce alkyl substituted with one or more methoxy; alternatively, R 500A and R 500B together with the nitrogen to which they are attached, form a 6- membered heterocyclyl optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl.
• R 100a of Formula III, or of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group
• R 100c of Formula III, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is chloro.
• Some embodiments describe a compound of Formula III, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 400b is Y 1 and R 400d is Z 1 .
• Y'of Formula III or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is -CF 3 .
• SUBSTITUTE SHEET ( RULE 26 ) embodiments R 7A and R 7B together with the nitrogen to which they are attached, form a heterocyclyl selected from the group consisting of, 4-methylpiperazinyl, and morpholinyl; and R 8 is 4-methylpiperidinyl.
• R 100a is selected from the group consisting of -CH3, -(CH2)N(CH2CH2OCH3)2,
• R1°°C j s c hl oro - each of R 400b and R 400d is independently selected from the group consisting of Y 1 and Z 1 , provided that when R 400b is Y 1 , R 400d is Z 1 and when R 400b is Z 1 , R 400d is Y 1 ; Y 1 is CF3; and Z 1 is selected from the group consisting of -CH2NHC(O)CH2OCH3, -
• R 100a is selected from the group consisting of -CH3, -(CH2)N(CH2CH2OCH3)2,
• SUBSTITUTE SHEET (RULE 26) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
• SUBSTITUTE SHEET (RULE 26) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
• SUBSTITUTE SHEET (RULE 26 ) followed by liberation of the optically active bases from these salts.
• An alternative process for separation of optical isomers includes the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
• Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate.
• the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain the enantiomerically pure compound.
• the optically active compounds of the invention can likewise be obtained by utilizing optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
• compositions according to embodiments described herein may be in the form of pharmaceutically acceptable salts.
• a pharmaceutically acceptable salt of the compounds described herein includes acid addition salts and base addition salts.
• Pharmaceutically-acceptable salt embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases The nature of the salt is not critical, provided that it is pharmaceutically-acceptable.
• Suitable pharmaceutically-acceptable acid addition salts of the compounds described herein may be prepared from an inorganic acid or an organic acid. Examples of such inorganic acids include, without limitation, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
• the salt is a hydrochloride salt.
• Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include, without limitation, formic, acetic, propionic, succinic, glycolic, gluconic, maleic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, P-hydroxybutyric, malonic, galactic, and galacturonic acid.
• Salts derived from inorganic bases include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
• Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di (substituted alkenyl) amines, tri (substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cyclo alkyl) amines, substituted cycl
• SUBSTITUTE SHEET (RULE 26 ) trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalky
• amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.
• suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri (iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
• carboxylic acid derivatives would be useful in the preparation of pharmaceutically acceptable salts, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and the like.
• Acceptable salts may be obtained using standard procedures well known in the art, for example by treating a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
• a sufficiently basic compound such as an amine
• a suitable acid affording a physiologically acceptable anion.
• Alkali metal for example, sodium, potassium or lithium
• alkaline earth metal for example calcium
• prodrug forms Any compound that will be converted in vivo to provide the bioactive agent is a prodrug within the scope and spirit of the invention.
• Various forms of prodrugs are well known in the art (see, for example, Medicinal Chemistry: Principles and Practice, F.D. King, ed., The Royal Society of Chemistry, Cambridge, UK, 1994; Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, B. Testa, J. M. Mayer, VCHA and Wiley-VCH, Zurich, Switzerland, 2003; The Practice of Medicinal Chemistry, C. G. Wermuth, 2 nd ed., Academic Press, San Diego, CA, 1999).
• Some prodrugs of the present invention include a compound according to any embodiment described herein in which the 2-
• SUBSTITUTE SHEET ( RULE 26 ) hydroxy of the benzamide is converted to a group such as, but not limited to,
• a prodrug of a compound according to any embodiment described herein may take the form of a carbamate.
• the 2-hydroxy group of a benzamide according to any embodiment described may converted to a carbamate group, -OC(O)NR 9 R 10 at the same position.
• R 9 and R 10 is independently selected from the group consisting of hydrogen, and optionally substituted Ci-Ce-alkyl; alternatively R 9 and R 10 taken together with the nitrogen to which they are attached form an optionally substituted Cs- -heterocyclyl.
• the invention also embraces isolated compounds.
• An isolated compound refers to a compound which represents at least 10%, preferably at least 20%, more preferably at least 50% and most preferably at least 80% of the compound present in the mixture.
• one or more hydrogen atoms is replaced by a deuterium. It is well established that deuteration of physiologically active compounds offer the advantage of retaining the pharmacological profile of their hydrogen counterparts while positively impacting their metabolic outcome. Selective replacement of one or more hydrogen with deuterium, in a compound of the present invention, could improve the safety, tolerability and efficacy of the compound when compared to its all hydrogen counterpart.
• Some embodiments describe a pharmaceutical composition
• a pharmaceutical composition comprising: a compound according to an embodiment described herein, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof; and a pharmaceutically acceptable carrier or diluent.
• Compounds, or pharmaceutically acceptable salts thereof can be formulated for oral, intravenous, intramuscular, subcutaneous or parenteral administration for the therapeutic or prophylactic treatment of diseases, disorders or infections described herein.
• SUBSTITUTE SHEET ( RULE 26 )
• compounds of this invention can be mixed with conventional pharmaceutical carriers and excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, wafers and the like.
• the pharmaceutical compositions comprising a compound of this invention will contain from about 0.1 to about 99% by weight of the active compound, and more generally from about 10 to about 30%.
• compositions of the invention are prepared in accordance with standard procedures and are administered at dosages that are selected to reduce, prevent or eliminate the infection (See, e. g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. and Goodman and Gilman's. The Pharmaceutical Basis of Therapeutics, Pergamon Press, New York, N.Y., the contents of which are incorporated herein by reference, for a general description of the methods for administering various agents for human therapy).
• the pharmaceutical compositions of the invention can be delivered using controlled (e.g., capsules) or sustained release delivery systems (e.g., bioerodable matrices).
• the pharmaceutically acceptable pharmaceutical compositions of the present invention comprise one or more compounds of the invention in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants and/or excipients, collectively referred to herein as “carrier” materials, and if desired other active ingredients.
• the pharmaceutical compositions may contain common carriers and excipients, such as com starch or gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid.
• the pharmaceutical compositions may contain croscarmellose sodium, microcrystalline cellulose, com starch, sodium starch glycolate and alginic acid.
• Tablet binders that can be included are acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose.
• Lubricants that can be used include magnesium stearate or other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica.
• Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring or the like can also be used. It may also be desirable to add a coloring agent to make the dosage form more aesthetic in appearance or to help identify the product.
• the pharmaceutical compositions are in the form of, for example, a tablet, capsule, suspension or liquid.
• the pharmaceutical composition is preferably made in the form of a dosage unit containing a therapeutically effective amount of the active ingredient. Examples of such dosage units are tablets and capsules.
• the tablets and capsules which can contain, in addition to the active ingredient, conventional carriers such as binding agents, for example, acacia gum, gelatin, polyvinylpyrrolidone, sorbitol, or tragacanth; fillers, for example, calcium phosphate, glycine, lactose, maize-starch, sorbitol, or sucrose; lubricants, for example, magnesium stearate, polyethylene glycol, silica, or talc, disintegrants, for example, potato starch, flavoring or coloring agents, or acceptable wetting agents.
• binding agents for example, acacia gum, gelatin, polyvinylpyrrolidone, sorbitol, or tragacanth
• fillers for example, calcium phosphate, glycine, lactose, maize-starch, sorbitol, or sucrose
• lubricants for example, magnesium stearate, polyethylene glycol, silica, or talc, disintegrants,
• Oral liquid preparations generally are in the form of aqueous or oily solutions, suspensions, emulsions, syrups or elixirs may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous agents, preservatives, coloring agents and flavoring agents.
• additives for liquid preparations include acacia, almond oil, ethyl alcohol, fractionated coconut oil, gelatin, glucose syrup, glycerin, hydrogenated edible fats, lecithin, methyl cellulose, methyl or propyl parahydroxybenzoate, propylene glycol, sorbitol, or sorbic acid.
• IV intravenous
• a compound according to the invention can be dissolved or suspended in any of the commonly used intravenous fluids and administered by infusion.
• Intravenous fluids include, without limitation, physiological saline or Ringer's solution.
• Intravenous administration may be accomplished by using, without limitation, syringe, minipump or intravenous line.
• Formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions or suspensions can be prepared from sterile powders or granules having one or more of the carriers mentioned for use in the formulations for oral administration.
• the compounds can be dissolved in polyethylene glycol, propylene glycol, ethanol, com oil, benzyl alcohol, sodium chloride, and/or various buffers.
• the compounds of the present invention can be presented in liquid or semi-liquid form formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints or powders.
• Compound 17 of the present invention unexpectedly has drastically decreased metabolic stability (from 2,132 minutes to 145 minutes, Example B7), and concomitant decreased oral half-life (from 66.9 hrs to 8.6 hrs, Example B8).
• the structural modification does not decrease the mitochondrial uncoupling activity thus are expected to have better toxicology properties when used to treat chronic conditions or disorders, which require prolonged use .
• the mitochondrial uncouplers described herein represent a fundamentally different category of mitochondrial uncouplers which effectively induce mitochondrial uncoupling (increase mitochondrial oxygen consumption in the presence of oligomycin) without significantly decreasing mitochondrial membrane potential over a wide concentration range ( Figures 5 and 6, Example B2).
• Figure 5 shows that Compound 25 does not appear to reduce MMP over a wide concentration range where OCR increases and reaches maximal levels.
• the ratio of CIO%TMRE / Cmin-ocR for Compound 25 is over 25.
• Figure 6 shows that Compound 64 effectively induces mitochondrial uncoupling without significantly decreasing MMP over a wide concentration range.
• the ratio of CIO%TMRE / Cmin-ocR for Compound 64 is between 10 to 25.
• TMRE tetramethylrhodamine ethyl ester
• Results are categorized into three groups, the Compound 25-like compounds are denoted as MMP -Retaining Uncoupling Compounds (CIO%TMRE / Cmin-OCR>25); The Compound 64-like compounds are denoted as MMP -Retaining Uncoupling Compounds (Cio%TMRE / Cmin-ocR between 10 to 25), and Conventional Uncouplers (CIO%TMRE / Cmin-ocR less or equal to 3). The results are summarized in Table 6.
• CW%TMRE is the concentration leading to 10% MMP retention (or 90% MMP loss, measured by TMRE staining) and C m in-ocR is the minimal concentration leading to OCR increase
• a MMP- retaining uncoupler molecule consists of two functional parts (Figure 7C).
• the first part functions as a conventional uncoupler, which transports proton from the mitochondrial intermembrane space to the mitochondrial matrix ( Figure 7B).
• the second part is a positively charged functional group that is poorly impermeable to the mitochondrial inner membrane.
• This feature allows an asymmetrical distribution and orientation of the compounds across mitochondrial inner membrane, with higher concentration of the charged molecules in the intramembrane space than in the mitochondrial matrix, as well as with the positively charged moiety primarily distributed at the outer surface of the membrane (facing the intermembrane space, Figure 7B).
• mitochondrial uncoupling occurs and consequently reduction of proton gradient across the membrane
• the loss of membrane potential due to proton gradient reduction is compensated by the asymmetrical positive charge distribution across the membrane provided by MMP-retaining uncouplers.
• the overall mitochondrial membrane potential is minimally impacted over a wide concentration range of the uncouplers.
• FIG. 9-10 show that the ratio ofNOAELs (no-observable-adverse-effect-level) over MED of Compounds 64 is over 40 (between 40-57 using different parameters), NOAEL/MED ratio of Compound 25 is over 19, while NOAEL/MED ratio of DNP is reportedly less than 3.
• Some embodiments describe a method of preparing a mitochondrial membrane-retaining mitochondrial uncoupler comprising
• the moiety capable of becoming positively charge in a cellular environment is a secondary or tertiary amine moiety.
• Some embodiments describe a method of preparing a mitochondrial membrane-retaining mitochondrial uncoupler comprising
• the secondary or tertiary amino moiety or R A is selected from the group consisting of -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, - previously described in any embodiment described herein.
• a method of treating a mitochondria-related condition or diorder, in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition according to embodiments described herein.
• the mitochondria-related condition or disorder is a metabolic disease.
• the metabolic disease is selected from the group consisting of type 2 diabetes, a disease characterized by insulin resistance or hyperglycemia; obesity or obesity related complications, and a disease characterized by abnormal lipid accumulation.
• a metabolic disease or disorder described in any embodiment herein is a complication caused by type 2 diabetes, selected from the group consisting of diabetes-induced cardiovascular diseases, neurodegenerative disorders, atherosclerosis, hypertension, coronary heart diseases, nephropathy, retinopathy, neuropathy, and diabetic heart failure.
• the metabolic disease or disorder is obesity or obesity related complications.
• a metabolic disease or disorder described in any embodiment herein is non-alcoholic fatty liver disease (NAFLD), comprising at least one prognosis stage of this disease selected from the group consisting of hepatic steatosis, nonalcoholic steatohepatitis (NASH), cirrhosis, and NAFLD induced hepatocellular carcinoma (HCC).
• the metabolic disease or disorder is alcoholic fatty liver disease, or a complication caused by alcoholic fatty liver diseases.
• the complication of alcoholic fatty liver disease comprises alcoholic hepatitis, cirrhosis, or a combination thereof.
• the metabolic disease or disorder is dyslipidemia, or a complication caused by dyslipidemia.
• the cancer is a primary cancer selected from the group consisting of hepatocellular carcinoma, colorectal carcinoma, pancreatic cancer, breast cancer, prostate cancer, leukemia, lymphoma, melanoma, ovarian cancer, and lung cancer.
• the cancer is a metastatic cancer originated from a primary tumor of other tissue types.
• the metastatic sites are selected from the group consisting of liver, lung and the intraperitoneal cavity.
• the compound of embodiments described herein is administered in combination with a second agent indicated for the above-mentioned disorders or diseases, either concomitant with, prior to, or after the administration of the second agent.
• the second agent is an anti-diabetic agent selected from the group consisting of metformin, insulin, insulin analogs, sulfonylureas, biguanides, meglitinides, thiazolidinediones, alpha glucosidase inhibitors, GLP-1 agonists, SGLT2 inhibitors and DPP-
• the second agent is an anti-obesity agent. In some embodiments, the second agent is an anti -nonalcoholic fatty liver disease agent. In some embodiments, the second agent is anti-alcoholic fatty liver disease agent. In some embodiments, the second agent is an anti-dyslipidemia agent.
• a compound of embodiments described herein is administered in combination with a second anti- non-alcoholic fatty liver disease agent. In some embodiments, a compound of the invention is administered in combination with a second anti- alcoholic fatty liver disease agent. In some embodiments, a compound of the invention is administered in combination with a second anti- dyslipidemia agent.
• the compound may be administered in combination with a second anti-cancer agent or anti-cancer regimen.
• the second anti-cancer agent s an immunoncological agent.
• the immunocological agent is selected from the group consisting of an antibody against PD-1/PD-L1, an antibody against other immune check point proteins, CAR-T cells, and other therapeutic immune cells.
• the compound may be administered prior to, concomitantly with, or subsequently to administration of the second anti-metabolic disease or anti-cancer agent.
• the subject is a mammalian animal. In some embodiments, the subject is a human. In some embodiments, the compound described herein is used as a veterinarian drug to treat diabetes or a diabetes-associated disease, and the subject is a mammalian animal.
• Some embodiments are directed to a method for long-term disease management of a metabolic disease or disorder comprising administering to a subject in need of such long-term management an effective amount of a compound or a pharmaceutical composition described herein.
• a method for long-term disease management of a metabolic disease or disorder, or for long-term disease management of cancer comprises administering to a subject in need of such long-term management an effective amount of a compound or a pharmaceutical composition according to any of the embodiments described herein.
• the metabolic disease or disorder is obesity, obesity -related complications, type 2 diabetes, or type 2 diabetes related complications.
• the cancer is any primary tumor or metastatic tumor.
• SUBSTITUTE SHEET ( RULE 26 ) accumulation in tissue is a symptom, or related disorders or complications, including, but not limited to, hepatic steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, or NAFLD induced hepatocellular carcinoma (HCC).
• the compound of embodiments herein may be used to manufacture a medicament for the treatment of cancer, a disease where cell proliferation (hyperplasia) is a symptom, or cancer or hyperplasia related complications.
• Some embodiments herein are directed to a method of treating or preventing a metabolic disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.
• diseases or disorders may be caused by dietary, environmental, medical and/or genetic factors.
• the methods described herein may also be used for prevention of the above-mentioned metabolic diseases for a subject with risk factors including, but not limited to, dietary, environmental, medical, and genetic predispositions.
• some embodiments provide a method for long-term chronic disease management and longevity management by reducing insulin resistance or reducing glucose levels in the blood.
• the metabolic disease or disorder is type 2 diabetes, or related diseases leading to insulin resistance or hyperglycemia. In some embodiments, the metabolic disease or disorder is obesity or one or more obesity related complications.
• the metabolic disease or disorder is non-alcoholic fatty liver disease, (NAFLD), including nonalcoholic steatohepatitis (NASH) and cirrhosis, or alcoholic fatty liver disease (AFLD).
• NAFLD non-alcoholic fatty liver disease
• AFLD alcoholic fatty liver disease
• the metabolic disease or disorder is non-alcoholic fatty liver disease, including nonalcoholic steatohepatitis (NASH) and cirrhosis, or alcoholic fatty liver disease (AFLD).
• NASH nonalcoholic steatohepatitis
• AFLD alcoholic fatty liver disease
• SUBSTITUTE SHEET (RULE 26 ) is hepatic steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, or NAFLD induced hepatocellular carcinoma (HCC).
• NASH non-alcoholic steatohepatitis
• HCC NAFLD induced hepatocellular carcinoma
• the cancer may be primary cancer or metastatic cancer.
• the cancer is primary cancer including but not limited to hepatocellular carcinoma, colorectal carcinoma, pancreatic cancer, breast cancer, prostate cancer, leukemia, lymphoma, melanoma, ovarian cancer, lung cancer.
• the cancer is metastatic liver cancer originated from the primary tumor of other tissue types.
• the cancer is metastatic lung cancer originated from the primary tumor of other tissue types.
• the cancer is metastatic cancer to other sites including intraperitoneal cavity.
• Some embodiments are directed to a method of treating or preventing autoimmune diseases in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.
• the autoimmune disease is celiac disease, diabetes mellitus type 1, Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.
• Some embodiments are directed to a method of treating or preventing a dermatological disorder in a subject in need thereof, comprising administering to the subject a
• the dermatological disorder is eczema, dyshidrotic eczema, seborrheic eczema psoriasis, rosacea, dermatitis and atopic dermatitis.
• Some embodiments are directed to a method of treating or preventing an infectious disease of non-viral parasites in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.
• the infectious disease is a viral infections.
• the viral infection is an envelope viral infection.
• the viral infection is selected from the group consisting of SARS- CoV-2 , a corana virus infection and an Ebola viral infection.
• the disease to be treated may be a heart disorder comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.
• the heart disorder may be hypertension or cardiovascular disease.
• the disease to be treated may be a central nervous system (CNS) disease.
• the CNS disease may be stroke, Alzheimer’s, Parkinson’s, Huntington’s, or ALS (amyotropic lateral sclerosis).
• the disease to be treated may be a disorder associated with increased ROS (reactive oxygen species) production comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.
• Increased ROS has been associated with aging, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS (amyotropic lateral sclerosis), mitochondrial diseases, and various cancers.
• the compounds and pharmaceutical compositions described herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), by inhalation spray, ophthalmic, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
• the compounds and pharmaceutical compositions described herein may also be formulated as a controlled-release formulation.
• compositions comprising an active ingredient and a dermatologically acceptable base and/or an ophthalmically
• SUBSTITUTE SHEET ( RULE 26 ) acceptable base.
• Such pharmaceutical compositions can be formulated, e.g., as solutions, suspensions, spray, lotions, gels, pastes, medicated sticks, balms, shampoos, soap bars, liquid soaps, creams or ointments.
• the pharmaceutical composition is the form of an ointment that can be applied in or around the eye of a mammal, including a human.
• a dermatologically and/or ophthalmically acceptable base includes a pharmaceutically acceptable ointment base.
• suitable ointment bases include, but are not limited to oleaginous ointment bases such as petrolatum (e.g., liquid petrolatum or white petrolatum), plastibase, hard paraffin, white soft paraffin, yellow soft paraffin, liquid paraffin, emulsifying wax, microcrystalline wax, white bees wax, yellow bees wax, carnauba wax, wool wax (wool fat), mineral oil, olive oil, purified lanolin, anhydrous lanolin, and water soluble ointment bases such as polyethylene glycol (e.g., polyethylene glycol 400 or polyethylene glycol 3350), propylene glycol, polyoxyethylene, polyoxypropylene, or any combinations thereof.
• polyethylene glycol e.g., polyethylene glycol 400 or polyethylene glycol 3350
• propylene glycol polyoxyethylene, polyoxypropylene, or any combinations thereof
• a dermatologically and/or ophthalmically acceptable base includes one or more polymers as suspending agents.
• Useful polymers include, but are not limited to, water-soluble polymers such as cellulosic polymers, e g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl- containing polymers.
• a dermatologically and/or ophthalmically acceptable base includes one or more viscosity enhancing agents.
• suitable viscosity enhancing agents include, but are not limited to, methyl cellulose, xanthan gum, gum tragacanth, carboxymethyl cellulose, silica, silicone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate stearate, hydroxypropylmethyl cellulose phthalate, carbomer, polyvinyl alcohol, alginates, acacia, chitosans, acacia, com starch, gelatin, or combinations thereof.
• a dermatologically and/or ophthalmically acceptable base includes one or more dermatologically and/or ophthalmically acceptable pH adjusting agents or buffering agents, including, but not limited to, acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium, lactate and tris-
• acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids
• bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium, lactate and tris-
• SUBSTITUTE SHEET ( RULE 26 ) hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in a dermatologically and/or ophthalmically acceptable range.
• a dermatologically and/or ophthalmically acceptable base includes one or more dermatologically and/or ophthalmically acceptable salts in an amount required to bring osmolality of the composition into a dermatologically and/or ophthalmically acceptable range.
• Such salts include, but are not limited to, those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; specific salts include, e.g., sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.
• a dermatologically and/or ophthalmically acceptable base includes one or more dermatologically and/or ophthalmically acceptable preservatives to inhibit microbial activity.
• Suitable preservatives include, but are not limited to, mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.
• a dermatologically and/or ophthalmically acceptable base includes one or more dermatologically and/or ophthalmically acceptable surfactants to enhance physical stability, or for other purposes.
• Suitable nonionic surfactants include isohexadecane, cyclomethicone, copolymers of ethylene glycol and propylene glycol, polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.
• a dermatologically and/or ophthalmically acceptable base includes one or more dermatologically and/or ophthalmically acceptable penetration enhancers to enhance physical stability, or for other purposes.
• Penetration enhancers are substances which enhance passage of topically-applied compounds into the stratum, comeum of the skin and therefrom into the epidermis and dermis.
• SUBSTITUTE SHEET (RULE 26 ) polysorbates, fatty acids (e g., oleic), bile salts, N-methylpyrrolidone, polyglycosylated glycerides, l-dodecylazacycloheptan-2-one (Azone®), Cyclopentadecalactone (CPE-215®), Alkyl -2-(N,N-disubstituted amino)-alkanoate ester (NexAct®), 2-(n-nonyl)- 1,3 -di oxolane (DEP A®), and penetration enhancers shown for example in U.S. Pat. Nos.
• a dermatologically and/or ophthalmically acceptable base includes one or more dermatologically and/or ophthalmically acceptable permability enhancers to enhance physical stability, or for other purposes.
• a variety of classes of compounds may serve as suitable permeability enhancers according to the invention.
• a first category includes fatty acids and salts and esters thereof, including mono-, di-, and triglycerides. Medium chain length fatty acids, especially C8 and CIO acids, and their salts and esters are particularly useful.
• Suitable specific examples include sodium caprylate, sodium caprate, CAPMUL® glycerides (available from Abitec of Columbus, Ohio), LABRASOL® glycerides (PEG-8 caprylic/capric glycerides, available from Gattefosse SAS of Saint Priest, Cedex, France), GELUCIRE® 44/14 (PEG-32 glyceryl laurate EP, available from Gattefosse), other glycerides & fatty acid esters, CREMOPHOR® (BASF, Ludwigshafen, Germany), D-a-tocopheryl polyethylene glycol 1000 succinate, vegetable oils, polyoxylglycerides, and medium chain mono- and diacylglycerides.
• GATTEFOSSE compositions 61 A through 61H which are proprietary to Gattefosse SAS, but generally are composed of mixtures containing one or more of medium chain mono-, di-, or triglycerides, polysorbate derivatives, polyoxyl castor oil derivatives, polyethylene glycol derivatives including polyethylene glycol glycerides, polyoxyl ethers, vegetable oils, glycerin, and similar GRAS (generally regarded as safe) lipidic components in varying amounts.
• CAPRYOLTM 90 CAPRYOLTM PGMC
• LAUROGLYCOLTM 90 GELUCIRE® 44/14
• Plurol Oleique CC497 LABRASOL®
• LABRAFIL® M1944CS apricot kernel oil PEG-6 esters
• Transcutol HP Peceol
• Maisine 35-1 all of which are available from Gattefosse SAS.
• a second category of enhancers includes surfactants having a steroidal structure, such as bile acid salts.
• suitable compounds include sodium cholate, sodium deoxycholate, glycocholate, glycoursodeoxycholate, taurocholate, taurodeoxycholate, and steroid detergents/bile salts.
• Other surfactants may also be suitable permeability enhancers, including cationic, anionic, and nonionic surfactants.
• Examples include polysorbate 80, hexadecyldimethylbenzylammonium chloride, N-hexadecylpyridinium bromide, dodecyltrimethylammonium bromide, hexadecyltrimethylammonium bromide, tetradecyl-P-D-maltoside, octylglucoside, glycyrrhetinic acid, 3-(N,N- dimethylpalmitylammonio)propane-sulfonate, and sodium lauryl sulfate.
• Cyclodextrins may also be used as suitable enhancers. Examples include P-cyclodextrin, hydroxypropyl-P-cyclodextrin, y-cyclodextrin, and hydroxypropyl-y- cyclodextrin.
• the permeability enhancer and the polar agent may be mixed in any proportion so long as there is provided a therapeutically effective amount of the polar agent and a permeability-enhancing amount of the enhancer compound. Enhancement in dermal bioavailability of topically administered polar agents can depend on the nature and
• SUBSTITUTE SHEET ( RULE 26 ) concentration of the enhancer compound with which the agent is formulated. It is thus contemplated that the required therapeutic amount may be contained in a single dosage form or divided between one or more dosages intended for application at the same time or in sequence.
• the permeability enhancers act relatively independently of the concentration of polar agent. Differing permeability enhancers can reach either optimal or maximum enhancement over a wide concentration range depending on their particular inherent enhancement potential. Often, enhancers have a non-linear dose response relationship between concentration of enhancer present and amount of increased polar agent absorption.
• the amount of enhancer to be utilized in an oral dosage form with a polar agent is initially based upon the enhancement properties observed in Caco-2 cell assays at varying fixed enhancer concentrations. Based upon those results, an effective in vivo amount of enhancer compound for a human formulation can be estimated, demonstrated and optimized without undue experimentation using methods well known to those skilled in the formulation art, to achieve a desired pharmacokinetic in vivo profile.
• the amount of enhancer may be at least about 0.1 wt % of the combined weight of enhancer and polar agent, more preferably at least about 50 wt %, and more preferably at least 70 wt % of the combined weight of enhancer and polar agent.
• the amount is preferably at most 95 wt %, more preferably at most 80 wt %, and more preferably at most 75 wt % of the combined weight of the enhancer and polar agent.
• a typical dosage form may contain a wide range of concentrations of enhancer compounds depending on the compound itself and its efficacy in enhancing the permeability of polar agents following oral administration. Concentrations as low as 0.001% by weight up to 20% have been demonstrated to be effective in enhancement of the permeability of polar agents.
• a dermatologically and/or ophthalmically acceptable base includes one or more antioxidants to enhance chemical stability where required.
• Suitable antioxidants include, by way of example only, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite, and tocopherol.
• antioxidants enhance chemical stability where required.
• any other surfactant, moisturizer, gelling agent, preservative, colorant or pigment, antioxidant, radical scavenger, emulsifier, humectant, pH modifier, chelating agent, or other dermatologically acceptable excipient commonly known to those of ordinary skill in the art as useful in topical compositions is contemplated as useful in the compositions described herein.
• any non-toxic, inert, and effective topical carrier may be used to formulate the compositions described herein.
• Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Office of Management, http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm, the contents of which are hereby incorporated by reference in their entirety.
• useful pharmaceutically acceptable excipients, carriers and diluents include distilled water, physiological saline, Ringer's solution, dextrose solution, Hank's solution, and DMSO, which are among those preferred for use herein.
• composition may be used immediately or stored for later use in any type of container known to one of skill in the art such as, for example, pouch, jar, bottle, tube, ampule and pre-filled syringe. Finally, the composition may be sterilized by any method known to one of skill in the art such as, for example, y radiation.
• compositions described herein may be administered at prophylactically effective dosage levels to prevent the above-recited conditions and disorders, as well as to prevent other conditions and disorders characterized by insulin resistance or hyperglycemia.
• compositions and compounds of embodiments herein can be administered in a wide range of dosage-forms including, for example, solid dosage
• Solid dosage forms may include powders, tablets, pills, capsules, suppositories, or dispersible granules.
• a solid carrier can be one or more substances that function as a diluting agent, flavor additive, solvent, lubricant, suspension agent, binder, preservative, tablet-disintegrating substance or encapsulating material.
• the carrier may be a finely pulverized solid including lactose, hydroxypropylmethylcellulose and PVP, mixed with an appropriate amount of the active ingredient.
• Appropriate carriers for powder and tablet forms include for example magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, stiffeners, gelatins, tragacanth, methylcellulose, and sodium carboxymethylcellulose.
• Liquid dosage forms include for example solutions, suspensions, and emulsions. Also included are pharmaceutical compositions in solid form that are meant to be converted to liquid form shortly prior to consumption. These forms may include, in addition to the active ingredients, artificial colors, flavors, stabilizers, buffers, natural or artificial sweeteners, dispersing agents, thickeners, dissolving agents and the like.
• Solutions or mixtures may be administered directly to the nasal cavity using conventional means, such as drops or sprays.
• the pharmaceutical composition may be produced in individual or multi-dose forms. Multi-dose forms would include a dropper, pipette or atomizer that delivers a predetermined volume of the pharmaceutical composition.
• the pharmaceutical compositions and compounds of embodiments herein may be provided in individual dosage units that contain a suitable amount of the active ingredient.
• the individual doses may be provided in a package, or as a kit that includes a measuring device, e.g., a device for measuring oral or injectable dosages (i.e., a measuring cup, needle, or syringe).
• the kit can also include, other materials such buffers, diluents, filters, and package inserts with instructions for use.
• a label may be present on the on the kit to indicate that the pharmaceutical composition is used for a specific therapy, and may also indicate directions for use.
• the pharmaceutical compositions of the present invention may further comprise one or more additional active agents.
• any of the active agents may be administered in the form of the compound per se, and/or in the form of a salt, polymorph, ester, amide, prodrug, derivative, or the like, provided the salt, polymorph, ester, amide, prodrug or derivative is suitable pharmacologically.
• salts, esters, amides, prodrugs and other derivatives of the active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms
• the active agent may be incorporated into the present pharmaceutical compositions either as the racemate or in enantiomerically enriched form.
• the dosage of the active compound(s) being administered will depend on the condition being treated, the particular compound, and other clinical factors such as age, sex, weight, and health of the subject being treated, the route of administration of the compound(s), and the type of pharmaceutical composition being administered (tablet, gel cap, capsule, solution, suspension, inhaler, aerosol, elixir, lozenge, injection, patch, ointment, cream, etc.) It is to be understood that the present disclosure has application for both human and animal use. The amount of the compound, or an active salt or derivative thereof, required for use in treatment will be ultimately at the discretion of the attendant physician or clinician.
• the compounds of the invention are useful for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.
• the dosage of the compound as an active ingredient in the pharmaceutical compositions of this invention may be varied so that a suitable dosage form is obtained.
• the active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
• the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment.
• the dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize. Generally, dosage levels of between 0.001 to 100 mg/kg.
• the therapeutically effective amount will generally be about 0.5 mg to 10g per patient per day which may be administered in single or multiple doses. In some embodiments the therapeutically effective amount is between a lower limit of 0.5 mg, 10 mg, 1 mg, 500.0 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg, 5000 mg, 5500 mg, 6000 mg, 6500 mg, 7000 mg, 7500 mg, 8000 mg, 8500 mg, 9000 mg, 9500 mg, and 10000 mg; and an upper limit of 10000 mg, 9500 mg, 9000 mg, 8500 mg, 8000 mg, 7500 mg, 7000 mg, 6500 mg, 6000 mg, 5500 mg, 5000 mg, 4500 mg, 4000 mg, 3500 mg, 3000 mg, 2500 mg, 2000 mg, 1500 mg, 1000 mg, 500.0 mg, 100 mg, 10 mg and 0.5 mg. In some embodiments, the therapeutically
• SUBSTITUTE SHEET ( RULE 26 ) per patient per day; in some embodiments about 0.5 mg to 1000 mg per patient per day; and in yet some other embodiments about 5 mg to 50 mg per patient per day.
• Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient.
• the pharmaceutical composition may be provided in a solid dosage formulation comprising for example about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 500 mg or 1000 mg of active ingredient.
• acylamino denotes a nitrogen radical adjacent to an acyl group.
• alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
• C1-C17- alkyl or “C1.17 alkyl” (or alkylene)
• Ci-Ce alkyl or "Ci-6 alkyl” denotes alkyl having 1 to 6 carbon atoms.
• alkenyl is intended to include hydrocarbon chains of either straight or branched configuration having the specified number of carbon atoms and one or more, preferably one to three, carbon-carbon double bonds that may occur in any stable point along the chain.
• C2-C6 alkenyl or “C2-6 alkenyl” (or alkenylene)
• C2-17 alkenyl is intended to include C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cn, C12, C13, C14, C15, Ci6, and C17 alkenyl groups.
• alkoxy refers to an -O-alkyl group.
• Ci-Ce alkoxy or “Ci-6 alkoxy” (or alkyloxy)
• alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy.
• aryl may be unsubstituted or substituted with 1 to 5 groups selected from -OH, -OCH3, -CI, -F, -Br, -I, -CN, -NO2, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -CF 3 , -OCF3, -C(O)CH 3 , - SCH3, -S(O)CH 3 , -S(O) 2 CH3, -CH 3 , -CH2CH3, -CO2H, and -CO2CH3.
• benzyl refers to a methyl group on which one of the hydrogen atoms is replaced by a phenyl group, wherein said phenyl group may optionally be substituted by one to five, preferably one to three, substituents independently selected from methyl, trifluoromethyl (-CF3), hydroxyl (-OH), methoxy (-OCH3), halogen, cyano (-CN), nitro (-NO2), -CO2Me, -CO2Et, and -CO2H.
• a "compound,” as used herein, refers to any type of substance or agent that is commonly considered a drug, or a candidate for use as a drug, as well as combinations and mixtures of the above.
• the term “compound” is intended to encompass not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, polymorphs, esters, amides, prodrugs, adducts, conjugates, active metabolites, and the like, where such modifications to the molecular entity are appropriate.
• a “conventional mitochondrial uncoupler” as used herein describes a mitochondrial uncoupler that has properties that increase OCR and decreased MMP, and the concentrations for increasing OCR and dissipating MMP correlate.
• a "derivative" of a compound refers to a chemical compound that may be produced from another compound of similar structure in one or more steps. Non-limiting examples include replacement of H by an alkyl, acyl, or amino group.
• an "effective amount” or “therapeutically effective amount” means an amount sufficient to produce a selected effect, such as alleviating symptoms of a disease or disorder.
• an effective amount of a combination of compounds refers collectively to the combination as a whole, although the actual amounts of each compound may vary.
• the term "more effective” means that the selected effect is alleviated to a greater extent by one treatment relative to the second treatment to which it is being compared.
• halo refers to fluoro, chloro, bromo, and iodo.
• Haloalkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluorom ethyl, and tri chloromethyl.
• heteroaryl is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons that include at least one heteroatom ring member, such as sulfur, oxygen, or nitrogen.
• Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl,
• SUBSTITUTE SHEET ( RULE 26 ) imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane.
• heteroaryl groups may be unsubstituted or substituted with 1 to 5 groups selected from -OH, -OCH 3 , -CI, -F, -Br, -I, -CN, -NO 2 , -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -CF 3 , -OCF 3 , - C(O)CH 3 , -SCH 3 , -S(O)CH 3 , -S(O) 2 CH 3 , -CH 3 , -CH 2 CH 3 , -CO 2 H, and -CO 2 CH 3
• the nitrogen atom is substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined).
• the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N— >0 and S(O) P , wherein p is 0, 1 or 2).
• heterocyclyl is defined as a saturated or partially unsaturated ring containing one to four hetero atoms or hetero groups selected from O, N, NH, -N(R Z )-, -S(O)- or -S(O) 2 - , wherein R z is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, optionally substituted heterocyclyl, in a single or fused heterocyclic ring system having from three to twelve ring members.
• a heterocyclyl is a ring system having three to seven ring members
• a heterocyclyl group include, without limitation, azetindinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl, dioxothiomorphylinyl, tetrahydrofuranyl and azabicyclo[3.2.1]octanyl.
• heteroaryl groups may be unsubstituted or substituted with at least one groups selected from oxo, cyano, hydroxyl, alkoxy, -acylamino , carboxyamido, -SO 2 CH 3 , -CF 3 , Ci-Ce alkyl, halo, and acyl.
• infectious disease referes to a bacterial infection, or viral infection. Infectious diseases do not include infections caused by parasitic organism.
• the viral infection is an envelope virus. Examples of envelope viruses include SARS-CoV-2 , corana viruses and Ebola viruses.
• mitochondrial malfunction is defined as pathologic conditions caused by mitochondrial malfunction as reviewed and summarized in: A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine, Annu Rev Genet. 2005; 39: 359, The rise of mitochondria in medicine, Mitochondrion 2016, 30:105-16, and Is Mitochondrial Dysfunction a Common Root of Noncommuni cable Chronic Diseases? Endocrine Reviews 2020,41(491-517), all of which are incorporated herein by reference. These conditions include, but are not limited to: genetic mitochondrial diseases, various types of cancer, autisim, neurodegenerative diseases, neuromuscular diseases, immunological diseases, metabolic diseases, aging, and aging- related noncommuni cable chronic diseases.
• mitochondrial uncoupling also referred to as “uncoupling” refers to the process whereby protons enter the mitochondrial matrix via a pathway independent of ATP synthase and thereby uncouple nutrient oxidation from ATP production.
• This process can be pharmacologically induced by small molecule mitochondrial protonophores, which directly shuttle protons across the mitochondrial inner membrane into the matrix.
• the primary pathway for energy production in aerobic cells involves the oxidation of nutrients (including fats, carbohydrates, and amino acids) in mitochondria, which promotes the efflux of protons out of the mitochondrial matrix. This process creates a pH and electrochemical gradient across the mitochondrial inner membrane.
• Protons normally re-enter the mitochondrial matrix via ATP synthase, which results in ATP production. Protons can also re-enter the mitochondrial matrix via pathways independent of ATP synthase, which 'uncouples' nutrient oxidation and proton efflux from ATP production.
• opthalmically acceptable is employed herein to refer to those compounds, materials, pharmaceutical compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the eyes of human beings and animals without excessive toxicity, irritation, allergic response, and/or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• SUBSTITUTE SHEET (RULE 26 ) acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
• acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane
• the term "pharmaceutically acceptable carrier” includes any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions such as an oil/water or water/oil emulsion, and various types of wetting agents.
• the term also encompasses any of the agents approved by a regulatory agency of the US Federal government or listed in the US Pharmacopeia for use in animals, including humans.
• a "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, or may demonstrate increased palatability, or be easier to formulate.
• treating refers to administration of a compound or agent to a subject who has a disorder or is at risk of developing the disorder with the purpose to cure, alleviate, relieve, remedy, delay the onset of, prevent, or ameliorate the disorder, the symptom of the disorder, the disease state secondary to the disorder, or the predisposition toward the disorder.
• Example 2 0.33 mmol, Example 2 was dissolved in DCM (3.0 mL), followed by the addition of catalytic amount of DMF (10 pL) and oxalyl chloride (34 pL, 0.39 mmol) respectively. The reaction was allowed to stir at rt for 30 minutes, concentrated in vacuo, and the 5-chloro-2- methoxy-3-((2-methoxyethoxy)methyl)benzoyl chloride residue was re-dissolved in THF (3.0 mL).

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