US 20150265555A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0265555 A1 BARON et al. (43) Pub. Date: Sep. 24, 2015
(54) CHEMOSENSORY RECEPTOR Publication Classification LGAND-BASED THERAPES (51) Int. Cl. (71) Applicant: Elcelyx Therapeutics, Inc., San Diego, A613 L/55 (2006.01) CA (US) A6II 45/06 (2006.01) (52) U.S. Cl. (72) Inventors: Alain D. BARON, San Diego, CA (US); CPC ...... A61K 31/155 (2013.01); A61K 45/06 Nigel R.A. BEELEY, Solana Beach, CA (2013.01) (US); Mark S. FINEMAN, San Diego, CA (US) (57) ABSTRACT (21) Appl. No.: 14/733,750 Provided herein are methods for treating conditions associ 1-1. ated with a chemosensory receptor, including diabetes, obe (22) Filed: Jun. 8, 2015 sity, and other metabolic diseases, disorders or conditions by Related U.S. Application Dat administrating a composition comprising a chemosensory e pplication Uata receptor ligand, Such as a bitter receptor ligand. Also provided (63) Continuation of application No. 13/978,514, filed on herein are chemosensory receptor ligand compositions, Sep. 18, 2013, now Pat. No. 9,050,292, filed as appli- including bitter receptor ligand compositions, and methods cation No. PCT/US2012/020548 on Jan. 6, 2012. for the preparation thereof for use in the methods of the (60) Provisional application No. 61/430.914, filed on Jan. present invention. Also provided herein are compositions 7, 2011. comprising metformin and salts thereof and methods of use. Patent Application Publication Sep. 24, 2015 Sheet 1 of 2 US 2015/0265555 A1
FIG. 1
Base-coffected a PYY tota Baselite-corrected ea Pi active
-o- Contro: a. -- Bitter S 6 s 3. 4 2 2 d, O -2 -3 3. 6 a -3 3. s 2 50 Ere (min) Tire mir)
AUC 27% Difference AUC 89% Difference p=0.14 p=0.07 Patent Application Publication Sep. 24, 2015 Sheet 2 of 2 US 2015/0265555 A1
FIG 2
Baseline-corrected L-cell Output index 2OOO
1 5 O O
s
& US 2015/0265555 A1 Sep. 24, 2015
CHEMOSENSORY RECEPTOR (MeridiaR), taken off the market in Europe and the USA, LGAND-BASED THERAPES decreases appetite by inhibiting deactivation of the neu rotransmitters norepinephrine, serotonin, and dopamine CROSS-REFERENCE Undesirable side-effects, including effects on blood pressure, have been reported with these drugs. (See, e.g., “Prescription 0001. This application is a continuation of U.S. patent Medications for the Treatment of Obesity.” NIH Publication application Ser. No. 13/978,514, filed Sep. 18, 2013, which is No. 07-4191, December 2007). Surgical treatments, includ a National Phase Entry of PCT Application No. PCT/ ing gastric bypass Surgery and gastric banding, are available, US2012/020548, filed Jan. 6, 2012, which claims the benefit but only in extreme cases. These procedures can be danger of U.S. Provisional Application No. 61/430.914, filed Jan. 7, ous, and furthermore may not be appropriate options for 2011, each of which is incorporated herein by reference. patients with more modest weight loss goals. BACKGROUND OF THE INVENTION Enteroendocrine Cells and Chemosensory Receptor Ligands 0002. Despite the longstanding, massive, effort to develop 0006 Certain intestinal cells, L cells, have been reported effective treatments for diabetes, metabolic syndrome, obe to produce GLP-1 in response to glucose, fat and amino acid sity, overweight and related metabolic conditions, the number stimulation. These and other such “enteroendocrine cells' of people worldwide who suffer from them is rapidly grow also reportedly produce other hormones involved in pro ing. These conditions result in numerous medical complica cesses relating to glucose and fuel metabolism, including tions, a lowered quality of life, shortened lifespan, lost work oxyntomodulin, reported to ameliorate glucose intolerance productivity, a strain on medical systems, and a burden on and suppress appetite, PYY (peptide YY), also observed to medical insurance providers that translates into increased Suppress appetite, CCK (cholecystokinin), which reportedly costs for all. Additionally, maintenance of health, including stimulates the digestion of fat and protein and also reduces healthy body weight and healthy blood glucose levels is desir food intake, GLP-2, which reportedly induces gut cell prolif able. eration, and GIP (gastric inhibitory polypeptide, also called 0003 Type II diabetes treatments in use or development glucose-dependent insulinotropic peptide), an incretin are designed to lower blood glucose levels. They include secreted from the intestinal K cells that has been observed to mimetics of GLP-1 (glucagon-like peptide-1), a hormone that augment glucose-dependent insulin secretion. (See, e.g., plays a key role in regulating insulin, glucose and hunger. Jang, et al., 2007, “Gut-expressed gustducin and taste recep Examples of mimetics are the GLP-1 receptor agonist, tors regulate secretion of glucagon-like peptide-1. PNAS Exenatide (Byetta R) and the GLP-1 analog Liraglutide. 104(38): 15069-74 and Parlevliet, et al., 2007, "Oxyntomodu Other drugs inhibit DPP-IV, an enzyme that rapidly degrades lin ameliorates glucose intolerance in mice fed a high-fat endogenous GLP-1. Exenatide is a GLP-1 receptor agonist diet.” Am J Physiol Endocrinol Metab 294(1):E142-7). Gua that is degraded more slowly by DPP-IV. Liraglutide, a nylin and uroguanylinare peptides of 15- and 16-amino acids GLP-1 analog, is attached to a fatty acid molecule that binds in length, respectively, that are reportedly secreted by intes to albumin and slows the rate of GLP-1 release and its deg tinal epithelial cells as prohormones and require enzymatic radation. (See, e.g., Nicolucci, et al., 2008, “Incretin-based conversion into active hormones. Recently, it has been therapies: a new potential treatment approach to overcome reported that uroguanylin may have a satiety-inducing func clinical inertia in type 2 diabetes.” Acta Biomedica 79(3): tion. (See Seeley & Tschop, 2011, “Uroguanylin: how the gut 184-91 and U.S. Pat. No. 5,424,286 “Exendin-3 and exen got another satiety hormone. J Clin Invest 121 (9):3384 din-4 polypeptides, and pharmaceutical compositions com 3386; Valentino et al., 2011, “A Uroguanylin-GUCY2C prising same.) Endocrine Axis Regulates Feeding in Mice. J Clin Invest 0004 Metformin is an antihyperglycemic agent which doe:10.1172/JCI57925.) improves glucose tolerance in patients with type II diabetes 0007. It has also been reported that there are taste receptor by lowering both basal and post-prandial plasma glucose. Its like elements present on the L-cells and K-cells in the intes pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin tine (Hofer, et al., 1996, “Taste receptor-like cells in the ratgut decreases hepatic glucose production, decreases intestinal identified by expression of alpha-gustducin’ Proc Natl Acad absorption of glucose, and improves insulin sensitivity by Sci USA 93:6631-6634). For example, the sweet taste recep increasing peripheral glucose uptake and utilization. How tors are heterodimers of the T1R2 and T1R3 GPCRs and have ever, metformin is reported to be substantially excreted by the been proposed to be identical to those sweet taste receptors kidney, and the risk of metformin accumulation and lactic found on taste buds. The umami receptors are reported to be acidosis increases with the degree of impairment of renal T1R1 and T1R3 heterodimers (Xu, et al., 2004, “Different function. For example, in patients with known or Suspected functional roles of T1R subunits in the heteromeric taste impaired renal function Such as those with advanced age, receptors.” Proc Natl AcadSci USA 101: 14258-14263 and metforminadministration requires close dose monitoring and titration to prevent lactic acidosis, a potentially fatal meta Sternini, et al., 2008, “Enteroendocrine cells: a site of taste bolic complication. Patients with concomitant cardiovascular in gastrointestinal chemosensing. Curr Opin Endocrinol or liver disease, sepsis, and hypoxia have also increased the Diabetes Obes 15: 73-78). Stimulation of taste or taste-like risk of lactic acidosis. Thus, metformin remains an unavail receptors by luminal nutrients has reportedly resulted in api able and/or risky treatment for certain patient groups due to its cal secretion of L-cell products such as GLP-1, PYY. oxyn side effects. tomodulin and glycentin, and K-cell products Such as GIP. 0005. Until very recently, obesity treatments include two and into the portal vein (Jang, et al., 2007, PNAS 104(38): FDA-approved drugs. Orlistat (Xenical(R) reduces intestinal 15069-74). In a glucose-dependent manner, GLP-1 and GIP fat absorption by inhibiting pancreatic lipase. Sibutramine reportedly increase insulin release from beta cells (an effect US 2015/0265555 A1 Sep. 24, 2015
known as the incretin effect). In addition, GLP-1 reportedly drome), delayed gastric emptying, dyslipidemia, post-pran inhibits glucagon release and gastric emptying. GLP-1, oxyn dial dyslipidemia, hyperlipidemia, hypertriglyceridemia, tomodulin and PYY 3-36 are considered to be satiety signals post hypertriglyceridemia, insulin resistance, bone loss dis (Strader, et al., 2005, "Gastrointestinal hormones and food orders, osteopenia, osteoporosis, muscle wasting disease, intake. Gastroenterology 128: 175-191). Receptors for fatty muscle degenerative disorders, polycystic ovary syndrome acids (e.g., GPR40 and/or GPR120) (Hirasawa, et al., 2005, (PCOS), non-alcoholic fatty liver disease (NAFL), non-alco Free fatty acids regulate gut incretin glucagon-like peptide-1 holic steatohepatitis (NASH), immune disorders of the gut secretion through GPR120, NatMed 11:90-94) and bile acids (e.g., celiac disease), bowel irregularity, irritable bowel syn (e.g., Gpbar1/M-Bar/TGRS) (Maruyama, et al., 2006. “Tar drome (IBS), inflammatory bowel disease (IBD), including, geted disruption of G protein-coupled bile acid receptor 1 e.g., ulcerative colitis, Crohn's disease, short bowel syn (Gpbar1/M-Bar) in mice.” J Endocrinol 191: 197-205 and drome and peripheral neuropathy (e.g., diabetic neuropathy). Kawamata, et al., 2003, “A G protein-coupled receptor 0009. In certain embodiments, the methods comprise responsive to bile acids.” J Biol Chem 278: 9435-9440) are modulation of hormone concentrations in a subject having a also reported to be present in enteroendocrine cell lines. disease or disorder associated with a chemosensory receptor There are also a large number of over 50 T2Rs along with a in which the disease or disorder is sadness, stress, grief, large number of haplotypes which have been proposed to anxiety, anxiety disorder (e.g., generalized anxiety disorder, comprise bitter receptors. The putative sour and salty recep obsessive-compulsive disorder, panic disorder, post-trau tors, which may include ion channels, have not been com matic stress disorder or Social anxiety disorder or a mood pletely characterized in humans. See, e.g., Chandrashekar et disorder (e.g., depression, bipolar disorder, dysthymic disor der and cyclothymic disorder). In certain embodiments, the al., 2010. “The cells and peripheral representation of sodium methods comprise methods of inducing feelings of happi taste in mice.” Nature 464(7286): 297-301. Although it has ness, well-being or contentment in Subjects by administering been proposed that ablation of certain taste cells resulted in a composition comprising a chemosensory receptor modula loss of behavior response to only sour stimuli, no specific tor that modulates the concentrations of one or more hor taste behavior tests were performed. Thus, the status of iden mones in a subject. tification of a Sour receptor is unclear. See, e.g., Shin et al., 0010 Additionally, the compositions and methods of the “Ghrelin is produced in taste cells and ghrelin receptor null embodiment herein may be used for the dietary management mice show reduced taste responsivity to salty (NaCl) and sour of the conditions associated with a chemosensory receptor (citric acid) taste, 2010, PLoSONE 5(9): e12729. GP120, a listed above. For example, disorders such as frailty, anorexia, GPCR corresponding to a fatty acid receptor, has also been cachexia, loss of lean body mass, food associated or food identified in the taste buds of mice and, furthermore, ()3 fatty induced nausea and Vomiting, food allergies, food associated acids have been shown to mediate anti-inflammatory effects aversive reactions may be treated with chemosensory recep and reverse insulin resistance in obese mice via their actions tor antagonists. on GP120 present in macrophages. See, e.g., Oh et al., 0011. The compositions described herein can be adapted “GPR120 Is an Omega-3 Fatty Acid Receptor Mediating for release to the upper or small intestine, to the lower or large Potent Anti-inflammatory and Insulin-Sensitizing Effects.” intestine, or both. For certain indications, the compositions 2010, Cell 142(5): 687-698; Satiel, “Fishing Out a Sensor for described herein can be adapted for release in the stomach. Anti-inflammatory Oils,’ 2010, Cell 142(5): 672-674; also Administration of the compositions into the intestine is via see Matsumura et al., “Colocalization of GPR120 with phos any known method including oral. pholipase Cbeta2 and alpha-gustducin in the taste bud cells in 0012. In one aspect, the compositions described herein mice. 2009, Neurosci Lett 450: 186-190. comprise a bitter receptor ligand selected from absinthine, artemorine, amorogentine, arglabine, azathioprine, azepi SUMMARY OF THE INVENTION none, benzoin, brucine, camphor, cascarillin, chlorhexidine, N,N'-diethylthiourea, herbolide A, isohumulone, noscapine, 0008 Provided herein are compositions having at least papaverine, parthenolide, picrotoxinin, arborescine, or (-)-C.- one bitter receptor ligand and methods of treatment using the thujone, including but not limited to suitable derivatives, wherein the composition is adapted to release a therapeuti compositions. Conditions, disorders or diseases to be treated cally effective amount of the ligand to one or more regions of with the compositions provided herein disorders or condi the intestine of a subject. The structural formulae of these tions associated with chemosensory receptors. In certain compounds are shown below, embodiments, the methods comprise modulating hormone concentrations in a subject having a disorder or condition associated with a chemosensory receptor selected from meta bolic syndrome, diabetes type I, diabetes type II, obesity, binge eating, undesired food cravings, food addiction, a desire to reduce food intake or to lose weight or maintain weight loss, desire to maintain healthy weight, desire to main tain normal blood glucose metabolism, anorexia, pre-diabe tes, glucose intolerance, gestational diabetes mellitus (GDM), impaired fasting glycemia, (IFG), post-prandial hyperglycemia, accelerated gastric emptying (dumping Syn US 2015/0265555 A1 Sep. 24, 2015
-continued -continued
US 2015/0265555 A1 Sep. 24, 2015
-continued 0021 In some embodiments, for a compound of Formula I. 0022 Y is selected from: N NO 0023 O. , S: , NH , and N—(C-C) straight chain or branched chain alkyl, O , S: , NH , N-(C-C) CC O cycloalkyl and O—, S - NH-, N-(C-C) alkylcy / S H O OH. cloalkyl, and 0024 R is selected from: N1S-N 0.025 O-alkyl selected from O—(C-C) straight chain or branched chain alkyl, 0026 O-cycloalkyl selected from O (C-C) O) cycloalkyl, 0027 O-alkylcycloalkyl selected from O (C-C) 0013. In another aspect, the compositions described alkylcycloalkyl, herein comprise a bitter receptor ligand selected from com pounds structurally related to absinthine, arglabine, 0028 O-acyl selected from O-ester and O-thioester, arborescine, artemorine, noscapine, or parthenolide having 0029) C-C straight chain or branched chain alkyl, C-Co straight chain or branched chain alkyl hetero the structural Formula I, Substituted with oxygen, C-Co straight chain or branched chain alkyl hetero substituted with silicon, C-Co straight chain or branched chain alkyl hetero (I) Substituted with Sulphur, C-Co straight chain or branched chain alkyl substituted with OH, C-Co straight chain or branched chain alkyl substituted with O-alkyl, C-C straight chain or branched chain alkyl substituted with SH, C-C straight chain or branched chain alkyl Substituted with S-alkyl, C-Co straight chain or branched chain alkyl substituted with NH, C-Co straight chain or branched chain alkyl Substituted wherein with NH-alkyl, 0014) X is O or S: 0030 C-C straight chain or branched chain alkenyl, 0015 Y is selected from: C-Co straight chain or branched chain alkenyl hetero O-, S-, NH-, and N-alkyl; Substituted with oxygen, C-C straight chain or 0016 branched chain alkenyl hetero substituted with silicon, 0017 R and R are joined together to form: C-Co straight chain or branched chain alkenyl hetero 0018 a substituted or unsubstituted cycloalkyl ring, a Substituted with Sulphur, C-Co straight chain or substituted or unsubstituted heterocycloalkyl ring where branched chain alkenyl substituted with OH, C-Co the heterocycle contains one or more hetero atoms straight chain or branched chain alkenyl substituted with selected from O, S, and N, a substituted or unsubstituted O-alkyl, C-Co straight chain or branched chain alkenyl alicyclic system, a Substituted or unsubstituted aryl ring, substituted with SH, C-C straight chain or branched or a substituted or unsubstituted heteroaryl ring where chain alkenyl Substituted with S-alkyl, C-Co straight the heterocycle contains one or more hetero atoms chain or branched chain alkenyl substituted with NH, selected from O, S, and N; and C-Co straight chain or branched chain alkenyl Substi 0019 R is selected from: tuted with NH-alkyl, 0020 H, OH, O-alkyl, O-cycloalkyl, O-alkylcy 0031 C-C straight chain or branched chain alkynyl, cloalkyl, O-acyl, C-Co straight chain or branched C-Co straight chain or branched chain alkynyl hetero chain alkyl, C-Co straight chain or branched chain Substituted with oxygen, C-Co straight chain or alkenyl, C-Co straight chain or branched chain alky branched chain alkynyl hetero substituted with silicon, nyl, C-C, cycloalkyl, C-C heterocycloalkyl, where C-Co straight chain or branched chain alkynyl hetero the heterocycle contains one or two hetero atoms Substituted with Sulphur, C-C straight chain or selected from O, S, and N, C-C alkylcycloalkyl, branched chain alkynyl substituted with OH, C-Co C-C alkylheterocycloalkyl, where the heterocycle straight chain or branched chain alkynyl substituted with contains one or two hetero atoms selected from O, S, and O-alkyl, C-Co straight chain or branched chain alkynyl N and in the case of the presence of NH in the hetero substituted with SH, C-C straight chain or branched cyclic ring, the nitrogenatom is in the form of an amide, chain alkynyl Substituted with S-alkyl, C-Co straight carbamate or urea, Substituted or unsubstituted aryl, Sub chain or branched chain alkynyl substituted with NH, stituted or unsubstituted alkylaryl, substituted or unsub C-Co straight chain or branched chain alkynyl substi stituted heteroaryland substituted or unsubstituted alkyl tuted with NH-alkyl, heteroaryl; 0.032 substituted or unsubstituted aryl selected from wherein the bond adjacent to R is a single or a double bond; phenyl, Substituted phenyl, naphthyl, Substituted naph and thyl, wherein the composition is adapted to release a therapeuti 0033 substituted or unsubstituted alkylaryl selected cally effective amount of the ligand to one or more regions of from alkylphenyl, alkylsubstituted phenyl, alkylnaph the intestine of a subject. thyl, alkylsubstituted naphthyl, US 2015/0265555 A1 Sep. 24, 2015
0034 substituted or unsubstituted heteroaryl selected -continued from substituted or unsubstituted pyridyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrrolyl, substi tuted or unsubstituted oxazolyl, substituted or unsubsti tuted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted diazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, and 0035 substituted or unsubstituted alkyl heteroaryl selected from substituted or unsubstituted alkylpyridyl, substituted or unsubstituted alkyl furanyl, substituted or unsubstituted alkylthiophenyl, substituted or unsubsti tuted alkyl pyrrolyl, substituted or unsubstituted alkyl oxazolyl, substituted or unsubstituted alkyl isoxazolyl, substituted or unsubstituted alkyl diazolyl, substituted or unsubstituted alkyl pyrazolyl, and substituted or unsubstituted alkyl triazolyl. 0036. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from andrographolide, antazoline, amorogentine, artemorine, ber berine chloride, brucine, camphor, and cascarillin, including but not limited to suitable derivatives wherein the composi tion is adapted to release atherapeutically effective amount of the ligand to one or more regions of the intestine of a Subject. The structural formulae of these compounds are shown below,
HO O
OH
OH
OH
0037. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from a com pound of structural Formula II, US 2015/0265555 A1 Sep. 24, 2015
0050 or R and R, join together to form a substituted or
(II) unsubstituted heteroaryl or a heterocycloalkyl system; 0051 A is selected from: 0.052 O-alkyl, O-cycloalkyl, O-alkylcycloalkyl, O-acyl, C-C straight chain or branched chain alkynyl, C-Cs cycloalkyl, C-C, heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N. Ca-Co alkylcycloalkyl, C-C alkyl heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N and in the case of the presence of NH in the heterocyclic ring, the wherein nitrogen atom is in the form of an amide, carbamate or 0038 X is O or S; urea, substituted or unsubstituted aryl, substituted or 0039 Y is selected from: unsubstituted alkylaryl, substituted or unsubstituted het 0040 O-, S-, NH-, and N-alkyl: eroaryland substituted or unsubstituted alkylheteroaryl; 0041 Z is CRRs in each instance wherein the bond adja 0053 m is an integer from 0 to 4; and cent to (Z), is a single or a double bond; 0054 n is an integer from 1 to 5; and 0042 R is selected from: 0043 H, OH, O-alkyl, O-cycloalkyl, O-alkylcy wherein the composition is adapted to release a therapeuti cloalkyl, O-acyl, C-Co straight chain or branched cally effective amount of the ligand to one or more regions of chain alkyl, C-Co straight chain or branched chain the intestine of a subject. alkenyl, C-C, cycloalkyl, C-C heterocycloalkyl, 0055. In some embodiments, for a compound of Formula where the heterocycle contains one or two hetero atoms II, selected from O, S, and N, C-C alkylcycloalkyl, 0056 Y is selected from: C-C alkylheterocycloalkyl, where the heterocycle 0057 O S NH , and N—(C-C) straight chain contains one or two hetero atoms selected from O, S, and or branched chain alkyl, O—, S NH N—(C-C) N and in the case of the presence of NH in the hetero cycloalkyl and O—, S-, NH-, N-(C-C) alkylcy cyclic ring, the nitrogenatom is in the form of an amide, cloalkyl, and carbamate or urea; 0058 R is selected from: 0044) R is selected from: 0059) O-alkyl selected from O (C-C) straight chain 0045 C-C straight chain or branched chain alkyl, or branched chain alkyl, C-Co straight chain or branched chain alkenyl, C-Co 0060 O-cycloalkyl selected from O (C-C) straight chain or branched chain alkynyl, C-Cs cycloalkyl, cycloalkyl, an alicyclic system, C to C, heterocy 0061 O-alkylcycloalkyl selected from O (C-C) cloalkyl, where the heterocycle contains one or two het alkylcycloalkyl, ero atoms selected from O, S, and N. Ca-Co alkylcy 0062 O-acyl selected from O-ester and O-thioester, cloalkyl, C-C alkylheterocycloalkyl, where the 0.063 C-C straight chain or branched chain alkyl, heterocycle contains one or two hetero atoms selected C-Co straight chain or branched chain alkyl hetero from O, S, and N and in the case of the presence of NH Substituted with oxygen, C-Co straight chain or in the heterocyclic ring, the nitrogenatom is in the form branched chain alkyl hetero substituted with silicon, of an amide, carbamate or urea, Substituted or unsubsti C-Co straight chain or branched chain alkyl hetero tuted aryl, substituted or unsubstituted alkylaryl, substi Substituted with Sulphur, C-Co straight chain or tuted or unsubstituted heteroaryl and substituted or branched chain alkyl substituted with OH, C-Co unsubstituted alkyl heteroaryl; straight chain or branched chain alkyl substituted with 0046 R is in each instance independently selected from: O-alkyl, C-Co straight chain or branched chain alkyl 0047 Halogen, NO, CN, OR, NRR, COOR, substituted with SH, C-C straight chain or branched CONRR, NRCORs, NRCONRR, NRSOA, chain alkyl Substituted with S-alkyl, C-Co straight COR SONRR, OOCR, CRROH, ROH and A: chain or branched chain alkyl substituted with NH, 0048. R. R. R. and R, are each independently selected C-Co straight chain or branched chain alkyl Substituted from: with NH-alkyl, 0049 H.C.-Co straight chain or branched chain alkyl, 0064 C-C straight chain or branched chain alkenyl, C-Co straight chain or branched chain alkenyl, C-Co C-Co straight chain or branched chain alkenyl hetero straight chain or branched chain alkynyl, C-Cs Substituted with oxygen, C-C straight chain or cycloalkyl, an alicyclic system, C to C, heterocy branched chain alkenyl hetero substituted with silicon, cloalkyl, where the heterocycle contains one or two het C-Co straight chain or branched chain alkenyl hetero ero atoms selected from O, S, and N. Ca-Co alkylcy Substituted with Sulphur, C-Co straight chain or cloalkyl, C-C alkylheterocycloalkyl, where the branched chain alkenyl substituted with OH, C-Co heterocycle contains one or two hetero atoms selected straight chain or branched chain alkenyl substituted with from O, S, and N and in the case of the presence of NH O-alkyl, C-Co straight chain or branched chain alkenyl in the heterocyclic ring, the nitrogenatom is in the form substituted with SH, C-C straight chain or branched of an amide, carbamate or urea, Substituted or unsubsti chain alkenyl Substituted with S-alkyl, C-Co straight tuted aryl, substituted or unsubstituted alkylaryl, substi chain or branched chain alkenyl substituted with NH, tuted or unsubstituted heteroaryl and substituted or C-Co straight chain or branched chain alkenyl Substi unsubstituted alkyl heteroaryl; tuted with NH-alkyl: US 2015/0265555 A1 Sep. 24, 2015
0065 R is selected from: substituted or unsubstituted alkyl diazolyl, substituted 0066 C-C straight chain or branched chain alkyl, or unsubstituted alkyl pyrazolyl, and substituted or C-Co straight chain or branched chain alkyl hetero unsubstituted alkyl triazolyl: Substituted with oxygen, C-C straight chain or 0073. R. R. R. and R, are each independently selected branched chain alkyl hetero substituted with silicon, from: C-Co straight chain or branched chain alkyl hetero 0.074 C-C straight chain or branched chain alkyl, C-Co straight chain or branched chain alkyl hetero Substituted with Sulphur, C-Co straight chain or Substituted with oxygen, C-Co straight chain or branched chain alkyl substituted with OH, C-Co branched chain alkyl hetero substituted with silicon, straight chain or branched chain alkyl substituted with C-Co straight chain or branched chain alkyl hetero O-alkyl, C-Co straight chain or branched chain alkyl Substituted with Sulphur, C-Co straight chain or substituted with SH, C-C straight chain or branched branched chain alkyl substituted with OH, C-Co chain alkyl Substituted with S-alkyl, C-Co straight straight chain or branched chain alkyl substituted with chain or branched chain alkyl substituted with NH, O-alkyl, C-C straight chain or branched chain alkyl C-Co straight chain or branched chain alkyl Substituted substituted with SH, C-C straight chain or branched with NH-alkyl, chain alkyl Substituted with S-alkyl, C-Co straight 0067 C-C straight chain or branched chain alkenyl, chain or branched chain alkyl substituted with NH, C-Co straight chain or branched chain alkenyl hetero C-Co straight chain or branched chain alkyl Substituted Substituted with oxygen, C-Co straight chain or with NH-alkyl, branched chain alkenyl hetero substituted with silicon, 0075 C-C straight chain or branched chain alkenyl, C-Co straight chain or branched chain alkenyl hetero C-Co straight chain or branched chain alkenyl hetero Substituted with Sulphur, C-C straight chain or Substituted with oxygen, C-Co straight chain or branched chain alkenyl substituted with OH, C-Co branched chain alkenyl hetero substituted with silicon, straight chain or branched chain alkenyl substituted with C-Co straight chain or branched chain alkenyl hetero O-alkyl, C-Co straight chain or branched chain alkenyl Substituted with Sulphur, C-Co straight chain or substituted with SH, C-C straight chain or branched branched chain alkenyl substituted with OH, C-Co chain alkenyl Substituted with S-alkyl, C-Co straight straight chain or branched chain alkenyl substituted with chain or branched chain alkenyl substituted with NH, O-alkyl, C-C straight chain or branched chain alkenyl C-Co straight chain or branched chain alkenyl substi substituted with SH, C-C straight chain or branched tuted with NH-alkyl, chain alkenyl substituted with S-alkyl, C-Co straight 0068 C-C straight chain or branched chain alkynyl, chain or branched chain alkenyl substituted with NH, C-Co straight chain or branched chain alkynyl hetero C-Co straight chain or branched chain alkenyl Substi Substituted with oxygen, C-Co straight chain or tuted with NH-alkyl, branched chain alkynyl hetero substituted with silicon, 0.076 C-C straight chain or branched chain alkynyl, C-Co straight chain or branched chain alkynyl hetero C-Co straight chain or branched chain alkynyl hetero Substituted with Sulphur, C-C straight chain or Substituted with oxygen, C-Co straight chain or branched chain alkynyl substituted with OH, C-Co branched chain alkynyl hetero substituted with silicon, straight chain or branched chain alkynyl substituted with C-Co straight chain or branched chain alkynyl hetero O-alkyl, C-Co straight chain or branched chain alkynyl Substituted with Sulphur, C-Co straight chain or substituted with SH, C-C straight chain or branched branched chain alkynyl substituted with OH, C-Co chain alkynyl substituted with S-alkyl, C-Co straight straight chain or branched chain alkynyl substituted with chain or branched chain alkynyl substituted with NH, O-alkyl, C-Co straight chain or branched chain alkynyl C-Co straight chain or branched chain alkynyl substi substituted with SH, C-C straight chain or branched tuted with NH-alkyl, chain alkynyl Substituted with S-alkyl, C-Co straight 0069 substituted or unsubstituted aryl selected from chain or branched chain alkynyl substituted with NH, phenyl, Substituted phenyl, naphthyl, Substituted naph C-Co straight chain or branched chain alkynyl Substi thyl, tuted with NH-alkyl, 0070 substituted or unsubstituted alkylaryl selected 0.077 substituted or unsubstituted aryl selected from from alkylphenyl, alkylsubstituted phenyl, alkylnaph phenyl, Substituted phenyl, naphthyl, Substituted naph thyl, alkylsubstituted naphthyl, thyl, 0071 substituted or unsubstituted heteroaryl selected 0078 substituted or unsubstituted alkylaryl selected from substituted or unsubstituted pyridyl, substituted or from alkylphenyl, alkylsubstituted phenyl, alkylnaph unsubstituted furanyl, substituted or unsubstituted thyl, alkylsubstituted naphthyl, thiophenyl, substituted or unsubstituted pyrrolyl, substi 0079 substituted or unsubstituted heteroaryl selected tuted or unsubstituted oxazolyl, substituted or unsubsti from substituted or unsubstituted pyridyl, substituted or tuted isoxazolyl, substituted or unsubstituted thiazolyl, unsubstituted furanyl, substituted or unsubstituted substituted or unsubstituted diazolyl, substituted or thiophenyl, substituted or unsubstituted pyrrolyl, substi unsubstituted pyrazolyl, substituted or unsubstituted tuted or unsubstituted oxazolyl, substituted or unsubsti triazolyl, and tuted isoxazolyl, substituted or unsubstituted thiazolyl, 0072 substituted or unsubstituted alkyl heteroaryl substituted or unsubstituted diazolyl, substituted or selected from substituted or unsubstituted alkylpyridyl, unsubstituted pyrazolyl, substituted or unsubstituted substituted or unsubstituted alkyl furanyl, substituted or triazolyl, and unsubstituted alkylthiophenyl, substituted or unsubsti 0080 substituted or unsubstituted alkyl heteroaryl tuted alkyl pyrrolyl, substituted or unsubstituted alkyl selected from substituted or unsubstituted alkylpyridyl, oxazolyl, substituted or unsubstituted alkyl isoxazolyl, substituted or unsubstituted alkyl furanyl, substituted or US 2015/0265555 A1 Sep. 24, 2015
unsubstituted alkylthiophenyl, substituted or unsubsti tuted alkyl pyrrolyl, substituted or unsubstituted alkyl oxazolyl, substituted or unsubstituted alkyl isoxazolyl, substituted or unsubstituted alkyl diazolyl, substituted or unsubstituted alkyl pyrazolyl, and substituted or unsubstituted alkyl triazolyl; and A is selected from: I0081 O-alkyl selected from O (C-C) straight chain or branched chain alkyl, I0082 O-cycloalkyl selected from O (C-C-7) cycloalkyl, I0083) O-alkylcycloalkyl selected from O (C-C) alkylcycloalkyl, 0084 O-acyl selected from O-ester and O-thioester, I0085 C-C straight chain or branched chain alkynyl, C-Co straight chain or branched chain alkynyl hetero Substituted with oxygen, C-Co straight chain or branched chain alkynyl hetero substituted with silicon, C-Co straight chain or branched chain alkynyl hetero Substituted with Sulphur, C-C straight chain or branched chain alkynyl substituted with OH, C-Co straight chain or branched chain alkynyl substituted with O-alkyl, C-Co straight chain or branched chain alkynyl substituted with SH, C-C straight chain or branched chain alkynyl Substituted with S-alkyl, C-Co straight chain or branched chain alkynyl substituted with NH, C-C straight chain or branched chain alkynyl substi tuted with NH-alkyl, I0086) substituted or unsubstituted aryl selected from phenyl, Substituted phenyl, naphthyl, Substituted naph thyl, I0087 substituted or unsubstituted alkylaryl selected from alkylphenyl, alkylsubstituted phenyl, alkylnaph thyl, alkylsubstituted naphthyl, I0088 substituted or unsubstituted heteroaryl selected from substituted or unsubstituted pyridyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrrolyl, substi tuted or unsubstituted oxazolyl, substituted or unsubsti tuted isoxazolyl, substituted or unsubstituted thiazolyl, 0091. In another aspect, the compositions described substituted or unsubstituted diazolyl, substituted or herein comprise a bitter receptor ligand ligand selected from unsubstituted pyrazolyl, substituted or unsubstituted 1.8-naphthaldehyde acid, 1-naphthoic acid, 1-nitronaphtha triazolyl, and lene, picrotin, picrotoxinin, piperonylic acid, sodium ben I0089 substituted or unsubstituted alkyl heteroaryl Zoate, (-)-C-thujone, parthenolide, herbolide A, herbolide D selected from substituted or unsubstituted alkylpyridyl, acetate, hydroxyl-8C-parthenolide, pseudo-artabsine, includ substituted or unsubstituted alkyl furanyl, substituted or ing but not limited to suitable derivatives, wherein the com unsubstituted alkylthiophenyl, substituted or unsubsti position is adapted to release a therapeutically effective tuted alkyl pyrrolyl, substituted or unsubstituted alkyl amount of the ligand to one or more regions of the intestine of oxazolyl, substituted or unsubstituted alkyl isoxazolyl, a Subject. The structural formulae of these compounds are substituted or unsubstituted alkyl diazolyl, substituted shown below, or unsubstituted alkyl pyrazolyl, and substituted or unsubstituted alkyl triazolyl. 0090. In another aspect, the compositions described herein comprise a bitter receptor ligand selected androgra pholide, antazoline, amorogentine, artemorine, berberine chloride, brucine, camphor, and cascarillin, including but not limited to suitable derivatives, wherein the composition is adapted to release a therapeutically effective amount of the ligand to one or more regions of the intestine of a Subject. The structural formulae of these compounds are shown below, US 2015/0265555 A1 Sep. 24, 2015
-continued (III) YR1. R2 COOH
R3
R4
0093 R is selected from: 0094) H, C-C straight chain or branched chain alkyl, C-C cycloalkyl, Ca-Cs alkylcycloalkyl, and M wherein M is a cation selected from Li', Na', K, NH, Ba, Ca,Mg, and Al"; and I0095 R. R. and R are each independently selected from: (0.096 H, OH, O-alkyl, O-cycloalkyl, O-alkylcy cloalkyl, O-acyl, C-Co straight chain or branched chain alkyl, C-Co straight chain or branched chain alkenyl, C-Co straight chain or branched chain alky nyl, C-C cycloalkyl, C-C heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N, C-C alkylcycloalkyl, C-C alkylheterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N and in the case of the presence of NH in the hetero cyclic ring, the nitrogenatom is in the form of an amide, carbamate or urea, Substituted or unsubstituted aryl, Sub stituted or unsubstituted alkylaryl, substituted or unsub stituted heteroaryland substituted or unsubstituted alkyl heteroaryl; O097 or 0.098 R and R, and/or R and Rjoin together to form: 0099 a substituted or unsubstituted 3-10 membered cyclic ring, a substituted or unsubstituted 5-6 membered aryl ring, a substituted or unsubstituted 3-10 membered heterocyclic ring where the heterocycle contains one or two hetero atoms selected from O, S, and N, a substi
OAc OAc OAc tuted or unsubstituted 5-6 membered heteroaryl ring where the heterocycle contains one or two hetero atoms selected from O, S, and N; and wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of the intestine of a subject. 0100. In some embodiments, for a compound of Formula III, 0101 R. R. and R are each independently selected from: 0102 O-alkyl selected from O—(C-C) straight chain or branched chain alkyl, (0103) O-cycloalkyl selected from O (C-C) cycloalkyl, 01.04] O-alkylcycloalkyl selected from O (C-C) alkylcycloalkyl, 0105 O-acyl selected from O-ester and O-thioester, 01.06 C-C straight chain or branched chain alkyl, C-Co straight chain or branched chain alkyl hetero Substituted with oxygen, C-C straight chain or branched chain alkyl hetero substituted with silicon, 0092. In another aspect, the compositions described C-Co straight chain or branched chain alkyl hetero herein comprise a bitter receptor ligand selected from a com Substituted with Sulphur, C-Co straight chain or pound of structural Formula III, branched chain alkyl substituted with OH, C-Co US 2015/0265555 A1 Sep. 24, 2015 10
straight chain or branched chain alkyl substituted with
O-alkyl, C-Co straight chain or branched chain alkyl (IV) substituted with SH, C-C straight chain or branched chain alkyl substituted with S-alkyl, C-C straight chain or branched chain alkyl substituted with NH, C-Co straight chain or branched chain alkyl substituted with NH-alkyl, I0107 C-Co straight chain or branched chain alkenyl, C-Co straight chain or branched chain alkenyl hetero Substituted with oxygen, C-C straight chain or branched chain alkenyl hetero substituted with silicon, C-Co straight chain or branched chain alkenyl hetero 0114 R is selected from: Substituted with Sulphur, C-Co straight chain or 0115 acyl ester, acylthioester, C-Co straight chain or branched chain alkenyl substituted with OH, C-Co branched chain alkyl, C-Co straight chain or branched straight chain or branched chain alkenyl substituted with chain alkenyl, C-Co straight chain or branched chain O-alkyl, C-Co straight chain or branched chain alkenyl alkynyl, an alicyclic system, C-C, cycloalkyl, C-C, Substituted with SH, C-C straight chain or branched heterocycloalkyl, where the heterocycle contains one or chain alkenyl substituted with S-alkyl, C-Co straight two hetero atoms selected from O, S, and N, C-Co chain or branched chain alkenyl substituted with NH, alkylcycloalkyl, C-C alkylheterocycloalkyl, where the C-Co straight chain or branched chain alkenyl substi heterocycle contains one or two hetero atoms selected tuted with NH-alkyl, from O, S, and N and in the case of the presence of NH 0108 C-Co straight chain or branched chain alkynyl, in the heterocyclic ring, the nitrogen atom is in the form C-Co straight chain or branched chain alkynyl hetero of an amide, carbamate or urea, substituted or unsubsti Substituted with oxygen, C-Co straight chain or tuted aryl, substituted or unsubstituted alkylaryl, substi branched chain alkynyl hetero substituted with silicon, tuted or unsubstituted heteroaryl and substituted or C-Co straight chain or branched chain alkynyl hetero unsubstituted alkyl heteroaryl; and Substituted with Sulphur, C-Co straight chain or wherein the composition is adapted to release a therapeuti branched chain alkynyl substituted with OH, C-C, cally effective amount of the ligand to one or more regions of straight chain or branched chain alkynyl substituted with the intestine of a subject. O-alkyl, C-Co straight chain or branched chain alkynyl I0116. In some embodiments, for a compound of Formula substituted with SH, C-C straight chain or branched IV, chain alkynyl substituted with S-alkyl, C-Co straight 0117 R is selected from: chain or branched chain alkynyl substituted with NH, 0118 C-Co straight chain or branched chain alkyl, C-Co straight chain or branched chain alkynyl substi C-Co straight chain or branched chain alkyl hetero tuted with NH-alkyl, Substituted with oxygen, C-Co straight chain or branched chain alkyl hetero substituted with silicon, 0109 substituted or unsubstituted aryl selected from C-Co straight chain or branched chain alkyl hetero phenyl, substituted phenyl, naphthyl, substituted naph Substituted with Sulphur, C-Co straight chain or thyl, branched chain alkyl substituted with OH, C-C, I0110 substituted or unsubstituted alkylaryl selected straight chain or branched chain alkyl substituted with from alkylphenyl, alkylsubstituted phenyl, alkylnaph O-alkyl, C-Co straight chain or branched chain alkyl thyl, alkylsubstituted naphthyl, substituted with SH, C-C straight chain or branched 10111 substituted or unsubstituted heteroaryl selected chain alkyl substituted with S-alkyl, C-Co straight from substituted or unsubstituted pyridyl, substituted or chain or branched chain alkyl substituted with NH, unsubstituted furanyl, substituted or unsubstituted C-Co straight chain or branched chain alkyl substituted thiophenyl, substituted or unsubstituted pyrrolyl, substi with NH-alkyl, tuted or unsubstituted oxazolyl, substituted or unsubsti 0119) C-Co straight chain or branched chain alkenyl, tuted isoxazolyl, substituted or unsubstituted thiazolyl, C-Co straight chain or branched chain alkenyl hetero Substituted or unsubstituted diazolyl, substituted or Substituted with oxygen, C-Co straight chain or unsubstituted pyrazolyl, substituted or unsubstituted branched chain alkenyl hetero substituted with silicon, triazolyl, and C-Co straight chain or branched chain alkenyl hetero Substituted with Sulphur, C-Co straight chain or I0112 substituted or unsubstituted alkyl heteroaryl branched chain alkenyl substituted with OH, C-C, selected from substituted or unsubstituted alkylpyridyl, straight chain or branched chain alkenyl substituted with substituted or unsubstituted alkylfuranyl, substituted or O-alkyl, C-Co straight chain or branched chain alkenyl unsubstituted alkylthiophenyl, substituted or unsubsti substituted with SH, C-Co straight chain or branched tuted alkyl pyrrolyl, substituted or unsubstituted alkyl chain alkenyl substituted with S-alkyl, C-Co straight oxazolyl, substituted or unsubstituted alkyl isoxazolyl, chain or branched chain alkenyl substituted with NH, substituted or unsubstituted alkyl diazolyl, substituted C-Co straight chain or branched chain alkenyl substi or unsubstituted alkyl pyrazolyl, and substituted or tuted with NH-alkyl, unsubstituted alkyl triazolyl. 0120 C-Co straight chain or branched chain alkynyl, 0113. In another aspect, the compositions described C-Co straight chain or branched chain alkynyl hetero herein comprise a bitter receptor ligand selected from a com Substituted with oxygen, C-Co straight chain or pound of structural Formula IV. branched chain alkynyl hetero substituted with silicon, US 2015/0265555 A1 Sep. 24, 2015 11
C-Co straight chain or branched chain alkynyl hetero -continued Substituted with Sulphur, C-Co straight chain or branched chain alkynyl substituted with OH, C-Co straight chain or branched chain alkynyl substituted with O-alkyl, C-Co straight chain or branched chain alkynyl substituted with SH, C-C straight chain or branched chain alkynyl Substituted with S-alkyl, C-Co straight chain or branched chain alkynyl substituted with NH, C-Co straight chain or branched chain alkynyl substi tuted with NH-alkyl, I0121 substituted or unsubstituted aryl selected from phenyl, Substituted phenyl, naphthyl, Substituted naph thyl, 0.122 substituted or unsubstituted alkylaryl selected from alkylphenyl, alkylsubstituted phenyl, alkylnaph thyl, alkylsubstituted naphthyl, I0123 substituted or unsubstituted heteroaryl selected from substituted or unsubstituted pyridyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrrolyl, substi tuted or unsubstituted oxazolyl, substituted or unsubsti tuted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted diazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, and 0.124 substituted or unsubstituted alkyl heteroaryl selected from substituted or unsubstituted alkylpyridyl, Substituted or unsubstituted alkyl furanyl, substituted or unsubstituted alkylthiophenyl, substituted or unsubsti tuted alkyl pyrrolyl, substituted or unsubstituted alkyl oxazolyl, substituted or unsubstituted alkyl isoxazolyl, substituted or unsubstituted alkyl diazolyl, substituted or unsubstituted alkyl pyrazolyl, and substituted or unsubstituted alkyl triazolyl. 0.125. In some embodiments, a compound of Formula IV is selected from the following structures,
OMe US 2015/0265555 A1 Sep. 24, 2015 12
-continued 0.132 O-cycloalkyl selected from O (C-C)
Hg HO cycloalkyl, : 0.133 O-alkylcycloalkyl selected from O (C-C) HO alkylcycloalkyl, 0.134 O-acyl selected from O-ester and O-thioester, 0.135 S-alkyl selected from S (C-C) straight chain or branched chain alkyl, 0.136 S-cycloalkyl selected from S (C-C) cycloalkyl, 0.137 S-alkylcycloalkyl selected from S (C-C) alkylcycloalkyl, 0.138 S-acyl selected from S-ester and S-thioester, 0.139 C-C straight chain or branched chain alkyl, CN C-Co straight chain or branched chain alkyl hetero Substituted with oxygen, C-C straight chain or branched chain alkyl hetero substituted with silicon, C-Co straight chain or branched chain alkyl hetero NO. Substituted with Sulphur, C-Co straight chain or branched chain alkyl substituted with OH, C-Co straight chain or branched chain alkyl substituted with O-alkyl, C-Co straight chain or branched chain alkyl substituted with SH, C-C straight chain or branched chain alkyl Substituted with S-alkyl, C-Co straight chain or branched chain alkyl substituted with NH, C-Co straight chain or branched chain alkyl Substituted 0126. In another aspect, the compositions described with NH-alkyl, herein comprise a bitter receptor ligand selected from a com 0140 C-C straight chain or branched chain alkenyl, pound of structural Formula V. C-Co straight chain or branched chain alkenyl hetero Substituted with oxygen, C-C straight chain or branched chain alkenyl hetero substituted with silicon, (V) C-Co straight chain or branched chain alkenyl hetero Substituted with Sulphur, C-Co straight chain or branched chain alkenyl substituted with OH, C-Co NH straight chain or branched chain alkenyl substituted with O-alkyl, C-Co straight chain or branched chain alkenyl
R1 1s. s substituted with SH, C-C straight chain or branched H chain alkenyl Substituted with S-alkyl, C-Co straight chain or branched chain alkenyl substituted with NH, 0127 R is selected from: C-Co straight chain or branched chain alkenyl Substi I0128 H, OH, O-alkyl, O-cycloalkyl, O-alkylcy tuted with NH-alkyl, cloalkyl, O-acyl, S-alkyl, S-cycloalkyl, S-alkylcy 0141 C-C straight chain or branched chain alkynyl. cloalkyl, S-acyl, C-Co straight chain or branched chain C-Co straight chain or branched chain alkynyl hetero alkyl, C-Co straight chain or branched chain alkenyl, Substituted with oxygen, C-C straight chain or C-Co straight chain or branched chain alkynyl, C-C, branched chain alkynyl hetero substituted with silicon, cycloalkyl, C-C heterocycloalkyl, where the hetero C-Co straight chain or branched chain alkynyl hetero cycle contains one or two hetero atoms selected from O, Substituted with Sulphur, C-Co straight chain or S, and N.C.-Co alkylcycloalkyl, C-C alkylheterocy branched chain alkynyl substituted with OH, C-Co cloalkyl, where the heterocycle contains one or two het straight chain or branched chain alkynyl substituted with eroatoms selected from O, S, and Nand in the case of the O-alkyl, C-Co straight chain or branched chain alkynyl presence of NH in the heterocyclic ring, the nitrogen substituted with SH, C-C straight chain or branched atom is in the form of an amide, carbamate or urea, chain alkynyl Substituted with S-alkyl, C-Co straight substituted or unsubstituted aryl, substituted or unsub chain or branched chain alkynyl substituted with NH, stituted alkylaryl, substituted or unsubstituted het C-Co straight chain or branched chain alkynyl substi eroaryland substituted or unsubstituted alkylheteroaryl; tuted with NH-alkyl, and 0.142 substituted or unsubstituted aryl selected from phenyl, Substituted phenyl, naphthyl, Substituted naph wherein the composition is adapted to release a therapeuti thyl, cally effective amount of the ligand to one or more regions of 0.143 substituted or unsubstituted alkylaryl selected the intestine of a subject. from alkylphenyl, alkylsubstituted phenyl, alkylnaph 0129 In some embodiments, for a compound of Formula thyl, alkylsubstituted naphthyl, V. 0.144 substituted or unsubstituted heteroaryl selected 0130 R is selected from: from substituted or unsubstituted pyridyl, substituted or I0131 O-alkyl selected from O (C-C) straight chain unsubstituted furanyl, substituted or unsubstituted or branched chain alkyl, thiophenyl, substituted or unsubstituted pyrrolyl, substi US 2015/0265555 A1 Sep. 24, 2015
tuted or unsubstituted oxazolyl, substituted or unsubsti chain or branched chain alkyl substituted with NH, tuted isoxazolyl, substituted or unsubstituted thiazolyl, C-Co straight chain or branched chain alkyl substituted substituted or unsubstituted diazolyl, substituted or with NH-alkyl, unsubstituted pyrazolyl, substituted or unsubstituted 0152 C-C straight chain or branched chain alkenyl, triazolyl, and C-Co straight chain or branched chain alkenyl hetero 0145 substituted or unsubstituted alkyl heteroaryl Substituted with oxygen, C-Co straight chain or selected from substituted or unsubstituted alkylpyridyl, branched chain alkenyl hetero substituted with silicon, substituted or unsubstituted alkyl furanyl, substituted or C-Co straight chain or branched chain alkenyl hetero unsubstituted alkylthiophenyl, substituted or unsubsti Substituted with Sulphur, C-Co straight chain or tuted alkyl pyrrolyl, substituted or unsubstituted alkyl branched chain alkenyl substituted with OH, C-Co oxazolyl, substituted or unsubstituted alkyl isoxazolyl, straight chain or branched chain alkenyl substituted with substituted or unsubstituted alkyl diazolyl, substituted O-alkyl, C-Co straight chain or branched chain alkenyl or unsubstituted alkyl pyrazolyl, and substituted or substituted with SH, C-C straight chain or branched unsubstituted alkyl triazolyl. chain alkenyl Substituted with S-alkyl, C-Co straight 0146 In another aspect, the compositions described chain or branched chain alkenyl substituted with NH, herein comprise a bitter receptor ligand selected from a com C-Co straight chain or branched chain alkenyl Substi pound of structural Formula VI, tuted with NH-alkyl, 0153 C-C straight chain or branched chain alkynyl, C-Co straight chain or branched chain alkynyl hetero (VI) S Substituted with oxygen, C-Co straight chain or branched chain alkynyl hetero substituted with silicon, l R2, C-Co straight chain or branched chain alkynyl hetero R4 Substituted with Sulphur, C-Co straight chain or branched chain alkynyl substituted with OH, C-Co straight chain or branched chain alkynyl substituted with O-alkyl, C-Co straight chain or branched chain alkynyl 0147 R. R. and R are each independently selected Substituted with SH, C-Co straight chain or branched from: chain alkynyl Substituted with S-alkyl, C-Co straight 0148 H, C-C straight chain or branched chain alkyl, chain or branched chain alkynyl substituted with NH, C-Co straight chain or branched chain alkenyl, C-Co C-Co straight chain or branched chain alkynyl Substi straight chain or branched chain alkynyl, C-C, tuted with NH-alkyl, cycloalkyl, C-C heterocycloalkyl, where the hetero cycle contains one or two hetero atoms selected from O, 0154 substituted or unsubstituted aryl selected from S, and N. Ca-Co alkylcycloalkyl, C-C alkylheterocy phenyl, Substituted phenyl, naphthyl, Substituted naph cloalkyl, where the heterocycle contains one or two het thyl, eroatoms selected from O, S, and Nand in the case of the 0.155 substituted or unsubstituted alkylaryl selected presence of NH in the heterocyclic ring, the nitrogen from alkylphenyl, alkylsubstituted phenyl, alkylnaph atom is in the form of an amide, carbamate or urea, thyl, alkylsubstituted naphthyl, substituted or unsubstituted aryl, substituted or unsub stituted alkylaryl, substituted or unsubstituted het 0156 substituted or unsubstituted heteroaryl selected eroaryland substituted or unsubstituted alkylheteroaryl; from substituted or unsubstituted pyridyl, substituted or and unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrrolyl, substi wherein the composition is adapted to release a therapeuti tuted or unsubstituted oxazolyl, substituted or unsubsti cally effective amount of the ligand to one or more regions of tuted isoxazolyl, substituted or unsubstituted thiazolyl, the intestine of a subject. substituted or unsubstituted diazolyl, substituted or 0149. In some embodiments, for a compound of Formula unsubstituted pyrazolyl, substituted or unsubstituted VI, triazolyl, and 0150. R. R. and R are each independently selected 0157 substituted or unsubstituted alkyl heteroaryl from: selected from substituted or unsubstituted alkylpyridyl, 0151 C-C straight chain or branched chain alkyl, substituted or unsubstituted alkyl furanyl, substituted or C-Co straight chain or branched chain alkyl hetero unsubstituted alkylthiophenyl, substituted or unsubsti Substituted with oxygen, C-Co straight chain or tuted alkyl pyrrolyl, substituted or unsubstituted alkyl branched chain alkyl hetero substituted with silicon, oxazolyl, substituted or unsubstituted alkyl isoxazolyl, C-Co straight chain or branched chain alkyl hetero substituted or unsubstituted alkyl diazolyl, substituted Substituted with Sulphur, C-Co straight chain or or unsubstituted alkyl pyrazolyl, and substituted or branched chain alkyl substituted with OH, C-Co unsubstituted alkyl triazolyl. straight chain or branched chain alkyl substituted with O-alkyl, C-Co straight chain or branched chain alkyl 0158. In another aspect, the compositions described substituted with SH, C-C straight chain or branched herein comprise a bitter receptor ligand selected from a com chain alkyl Substituted with S-alkyl, C-Co straight pound of structural Formula VII, US 2015/0265555 A1 Sep. 24, 2015 14
-continued (VII)
O HO
O HO O R2( O R1, wherein O O 0159 RandR are each independently selected from: O 0160 H, CO-alkyl, CO-cycloalkyl, CO-alkylcy- 21 N cloalkyl, O OH 0.161 substituted or unsubstituted CO-aryl selected from CO-phenyl, CO-substituted phenyl, CO-naphthyl, OH substituted CO-naphthyl, OH 0162 substituted or unsubstituted CO-alkylaryl selected from CO-alkylphenyl, CO-alkylsubstituted OH phenyl, CO-alkylnaphthyl, CO-alkylsubstituted naph thyl, 0163 substituted or unsubstituted CO-alkenylaryl selected from CO-alkenyl phenyl, CO-alkenyl substi O tuted phenyl, CO-alkenyl naphthyl, CO-alkenyl substi O HO tuted naphthyl, CO-cinnamoyl, CO-coumaroyl, CO-caffeoyl, and CO-ferruloyl; and HO O O wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of HO the intestine of a subject. O O O 0164. In some embodiments, for a compound of Formula O H VII, 21 O 0.165 R and R are independently selected from: 0166 CO-alkyl selected from CO (C-C) straight chain or branched chain alkyl, (0167 CO-cycloalkyl selected from CO (C-C) OH cycloalkyl, and OH OH 0168 CO-alkylcycloalkyl selected from CO (C-C) O H alkylcycloalkyl. 0169. In some embodiments, a compound of Formula VII is selected from the following structures,
HO O
HO O
O O O O O O 21 O N OH 21 O N OH OMe
OMe
OH
OH US 2015/0265555 A1 Sep. 24, 2015 15
-continued -continued O
O
O OH
OMe
OH
OH O O HO
HO O O
HO
O O O OH 21 O wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of the intestine of a subject.
OH 0171 In another aspect, the compositions described herein comprise a bitter receptor ligand selected from a com pound of structural Formula VIII, OH O OH O (VIII) O OMe HO \ O OH
OH
OMe.
O HO 2.HO wherein R and Rare independently selected from: (0172 R and R are independently selected from: 0170 In another aspect, the compositions described (0173 H, beta-Glc, beta-Glc-beta-Glc(2->1), beta-Glc herein comprise a bitter receptor ligand selected from the beta-Glc(3->1)-beta-Glc(2-> 1), beta-Glc-alpha-Rha following structures, (2-> 1), beta-Glcbeta-Glc(3->1)-alpha-Rha(2->1), beta-Glcbeta-Glc(3->1)-alpha-Xyl(2->1) wherein Glc is glucose, Rha is rhamnose and Xyl is Xylose; and wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of HO How HO the intestine of a subject. 0.174. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from a com pound of structural Formula IX, US 2015/0265555 A1 Sep. 24, 2015 16
0188 C-C straight chain or branched chain alkenyl, (IX) C-Co straight chain or branched chain alkenyl hetero R4 N R1 Substituted with oxygen, C-Co straight chain or branched chain alkenyl hetero substituted with silicon, N C-Co straight chain or branched chain alkenyl hetero R3 DOCN R2, Substituted with Sulphur, C-C straight chain or branched chain alkenyl substituted with OH, C-Co (0175 R. R. R. and Ra are each independently selected straight chain or branched chain alkenyl substituted with from: O-alkyl, C-C straight chain or branched chain alkenyl substituted with SH, C-C straight chain or branched 0176 H, OH, O-alkyl, O-cycloalkyl, O-alkylcy chain alkenyl substituted with S-alkyl, C-Co straight cloalkyl, O-acyl, acyl, C-Co straight chain or branched chain or branched chain alkenyl substituted with NH, chain alkyl, C-Co straight chain or branched chain C-Co straight chain or branched chain alkenyl substi alkenyl, C-Co straight chain or branched chain alky tuted with NH-alkyl, nyl, C-C cycloalkyl, C-C heterocycloalkyl, where 0189 C-C straight chain or branched chain alkynyl, the heterocycle contains one or two hetero atoms C-Co straight chain or branched chain alkynyl hetero selected from O, S, and N, C-C alkylcycloalkyl, Substituted with oxygen, C-Co straight chain or C-C alkylheterocycloalkyl, where the heterocycle branched chain alkynyl hetero substituted with silicon, contains one or two hetero atoms selected from O, S, and C-Co straight chain or branched chain alkynyl hetero N and in the case of the presence of NH in the hetero Substituted with Sulphur, C-Co straight chain or cyclic ring, the nitrogenatom is in the form of an amide, branched chain alkynyl substituted with OH, C-Co carbamate or urea, Substituted or unsubstituted aryl, Sub straight chain or branched chain alkynyl substituted with stituted or unsubstituted alkylaryl, substituted or unsub O-alkyl, C-C straight chain or branched chain alkynyl stituted heteroaryland substituted or unsubstituted alkyl substituted with SH, C-C straight chain or branched heteroaryl; chain alkynyl substituted with S-alkyl, C-Co straight 0177 or chain or branched chain alkynyl substituted with NH, 0.178 R and R or R and Ra are joined together to form: C-Co straight chain or branched chain alkynyl Substi 0179 a substituted or unsubstituted 3-10 membered tuted with NH-alkyl, cyclic ring, a substituted or unsubstituted 5-6 membered 0.190 substituted or unsubstituted aryl selected from aryl ring, a substituted or unsubstituted 3-10 membered phenyl, Substituted phenyl, naphthyl, Substituted naph heterocyclic ring where the heterocycle contains one or thyl, two hetero atoms selected from O, S, and N, a substi 0191 substituted or unsubstituted alkylaryl selected tuted or unsubstituted 5-6 membered heteroaryl ring from alkylphenyl, alkylsubstituted phenyl, alkylnaph where the heterocycle contains one or two hetero atoms thyl, alkylsubstituted naphthyl, selected from O, S, and N; and 0.192 substituted or unsubstituted heteroaryl selected wherein the composition is adapted to release a therapeuti from substituted or unsubstituted pyridyl, substituted or cally effective amount of the ligand to one or more regions of unsubstituted furanyl, substituted or unsubstituted the intestine of a subject. thiophenyl, substituted or unsubstituted pyrrolyl, substi 0180. In some embodiments, for a compound of Formula tuted or unsubstituted oxazolyl, substituted or unsubsti IX, tuted isoxazolyl, substituted or unsubstituted thiazolyl, 0181. R. R. R. and Ra are independently selected from substituted or unsubstituted diazolyl, substituted or 0182 O-alkyl selected from O (C-C) straight chain unsubstituted pyrazolyl, substituted or unsubstituted or branched chain alkyl, triazolyl, and 0183 O-cycloalkyl selected from O (C-C-7) 0193 substituted or unsubstituted alkyl heteroaryl cycloalkyl, selected from substituted or unsubstituted alkylpyridyl, 0.184 O-alkylcycloalkyl selected from O (C-C) substituted or unsubstituted alkyl furanyl, substituted or alkylcycloalkyl, unsubstituted alkylthiophenyl, substituted or unsubsti tuted alkyl pyrrolyl, substituted or unsubstituted alkyl 0185 O-acyl selected from O-ester and O-thioester, oxazolyl, substituted or unsubstituted alkyl isoxazolyl, 0186 acyl selected from carboxylic acid, aldehyde, substituted or unsubstituted alkyl diazolyl, substituted ketone, ester and thioester, or unsubstituted alkyl pyrazolyl, and substituted or 0187 C-C straight chain or branched chain alkyl, unsubstituted alkyl triazolyl. C-Co straight chain or branched chain alkyl hetero 0194 In some embodiments, a compound of Formula IX Substituted with oxygen, C-C straight chain or is selected from the following structures, branched chain alkyl hetero substituted with silicon, C-Co straight chain or branched chain alkyl hetero Substituted with Sulphur, C-Co straight chain or branched chain alkyl substituted with OH, C-Co straight chain or branched chain alkyl substituted with O-alkyl, C-Co straight chain or branched chain alkyl substituted with SH, C-C straight chain or branched chain alkyl Substituted with S-alkyl, C-Co straight chain or branched chain alkyl substituted with NH, C-Co straight chain or branched chain alkyl Substituted with NH-alkyl, US 2015/0265555 A1 Sep. 24, 2015 17
-continued -continued
0.195. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from the following structures, US 2015/0265555 A1 Sep. 24, 2015 18
-continued -continued O / N N N r NH Oall? N N H wherein the composition is adapted to release a therapeuti 0200. In another aspect, the compositions described cally effective amount of the ligand to one or more regions of herein comprise a bitter receptor ligand selected from a com the intestine of a subject. pound of structural Formula XI, 0196. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from a com (XI) pound of structural Formula X,
(X) O 3. Rin N
Oul-2 N R2 wherein
0197) R, R and R are independently selected from: wherein (0198 H, C-C straight chain or branched chain alkyl, 0201 R. R. R. R. and Rs are each independently C-C, cycloalkyl and C-C alkylcycloalkyl, selected from: 0202 H, OH, O-alkyl, O-cycloalkyl, O-alkylcy and cloalkyl, O-acyl, C-Co straight chain or branched wherein the composition is adapted to release a therapeuti chain alkyl, C-Co straight chain or branched chain cally effective amount of the ligand to one or more regions of alkenyl, C-Co straight chain or branched chain alky the intestine of a subject. nyl, C-C cycloalkyl, C-C heterocycloalkyl, where the heterocycle contains one or two hetero atoms 0199. In some embodiments, a compound of Formula X is selected from O, S, and N, C-C alkylcycloalkyl, selected from the following structures, C-C alkylheterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N and in the case of the presence of NH in the hetero O cyclic ring, the nitrogenatom is in the form of an amide, carbamate or urea, Substituted or unsubstituted aryl, Sub stituted or unsubstituted alkylaryl, substituted or unsub NN S stituted heteroaryland substituted or unsubstituted alkyl 1s, / heteroaryl; 0203 X is selected from: 0204 O, S, NH, and NR where R is C-C straight chain or branched chain alkyl, and / wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of the intestine of a subject. els-- 0205. In some embodiments, for a compound of Formula XI, 0206 R. R. R. R. and Rs are each independently selected from: 0207 O-alkyl selected from O—(C-C) straight chain NN y or branched chain alkyl, 0208 O-cycloalkyl selected from O (C-C) cycloalkyl, es / 0209 O-alkylcycloalkyl selected from O (C-C) alkylcycloalkyl, US 2015/0265555 A1 Sep. 24, 2015
0210 O-acyl selected from O-ester and O-thioester, substituted or unsubstituted alkyl diazolyl, substituted 0211 C-C straight chain or branched chain alkyl, or unsubstituted alkyl pyrazolyl, and substituted or C-Co straight chain or branched chain alkyl hetero unsubstituted alkyl triazolyl; and Substituted with oxygen, C-C straight chain or 0218 R is selected from: branched chain alkyl hetero substituted with silicon, 0219) C-C straight chain or branched chain alkyl, C-Co straight chain or branched chain alkyl hetero C-Co straight chain or branched chain alkyl hetero Substituted with Sulphur, C-Co straight chain or Substituted with oxygen, C-Co straight chain or branched chain alkyl substituted with OH, C-Co branched chain alkyl hetero substituted with silicon, straight chain or branched chain alkyl substituted with C-Co straight chain or branched chain alkyl hetero O-alkyl, C-Co straight chain or branched chain alkyl Substituted with Sulphur, C-Co straight chain or substituted with SH, C-C straight chain or branched branched chain alkyl substituted with OH, C-Co chain alkyl Substituted with S-alkyl, C-Co straight straight chain or branched chain alkyl substituted with chain or branched chain alkyl substituted with NH, O-alkyl, C-Co straight chain or branched chain alkyl C-Co straight chain or branched chain alkyl Substituted substituted with SH, C-C straight chain or branched with NH-alkyl, chain alkyl Substituted with S-alkyl, C-Co straight 0212 C-C straight chain or branched chain alkenyl, chain or branched chain alkyl substituted with NH, C-Co straight chain or branched chain alkenyl hetero C-Co straight chain or branched chain alkyl Substituted Substituted with oxygen, C-Co straight chain or with NH-alkyl. branched chain alkenyl hetero substituted with silicon, 0220. In some embodiments, a compound of Formula XI C-Co straight chain or branched chain alkenyl hetero is selected from the following structures, Substituted with Sulphur, C-C straight chain or branched chain alkenyl substituted with OH, C-Co straight chain or branched chain alkenyl substituted with O-alkyl, C-Co straight chain or branched chain alkenyl substituted with SH, C-C straight chain or branched chain alkenyl Substituted with S-alkyl, C-Co straight chain or branched chain alkenyl substituted with NH, C-Co straight chain or branched chain alkenyl substi tuted with NH-alkyl, 0213 C-C straight chain or branched chain alkynyl, C-Co straight chain or branched chain alkynyl hetero Substituted with oxygen, C-Co straight chain or branched chain alkynyl hetero substituted with silicon, C-Co straight chain or branched chain alkynyl hetero Substituted with Sulphur, C-C straight chain or branched chain alkynyl substituted with OH, C-Co straight chain or branched chain alkynyl substituted with O-alkyl, C-Co straight chain or branched chain alkynyl substituted with SH, C-C straight chain or branched chain alkynyl substituted with S-alkyl, C-Co straight chain or branched chain alkynyl substituted with NH, C-Co straight chain or branched chain alkynyl substi tuted with NH-alkyl, 0214) substituted or unsubstituted aryl selected from phenyl, Substituted phenyl, naphthyl, Substituted naph thyl, 0215 substituted or unsubstituted alkylaryl selected from alkylphenyl, alkylsubstituted phenyl, alkylnaph thyl, alkylsubstituted naphthyl, 0216) substituted or unsubstituted heteroaryl selected from substituted or unsubstituted pyridyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrrolyl, substi tuted or unsubstituted oxazolyl, substituted or unsubsti tuted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted diazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, and 0217 substituted or unsubstituted alkyl heteroaryl selected from substituted or unsubstituted alkylpyridyl, substituted or unsubstituted alkyl furanyl, substituted or unsubstituted alkylthiophenyl, substituted or unsubsti tuted alkyl pyrrolyl, substituted or unsubstituted alkyl oxazolyl, substituted or unsubstituted alkyl isoxazolyl, US 2015/0265555 A1 Sep. 24, 2015 20
-continued -continued
US 2015/0265555 A1 Sep. 24, 2015 21
-continued (XII)
0221. In another aspect, the compositions described wherein herein comprise a bitter receptor ligand selected from the 0223 R. R. R. R. R. R. and R, are each indepen following structures, dently selected from: 0224 H, OH, O-alkyl, O-cycloalkyl, O-alkylcy cloalkyl, O-acyl, C-Co straight chain or branched chain alkyl, C-Co straight chain or branched chain alkenyl, C-Co straight chain or branched chain alky nyl, C-C cycloalkyl, C-C heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N, C-C alkylcycloalkyl, C-C alkylheterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and HO N and in the case of the presence of NH in the hetero cyclic ring, the nitrogenatom is in the form of an amide, carbamate or urea, Substituted or unsubstituted aryl, Sub HO stituted or unsubstituted alkylaryl, substituted or unsub stituted heteroaryland substituted or unsubstituted alkyl heteroaryl; 0225 with the proviso that 0226 when one of R or R is substituted the other of R and R must be hydrogen or 0227 R and R combine to represent a carbonyl (C=O) group, a thiocarbonyl (C=S) group, an imino (C—NH) group or a substituted imino C=NR) group: and wherein the bond adjacent to R may be a either a single CC bond or a double CC bond; and wherein the composition is adapted to release a therapeutically effective amount of the ligand to one or more regions of the intestine of a subject. HO 0228. In some embodiments, for a compound of Formula XII, 0229 R. R. R. R. R. R. and R2 are each indepen HO dently selected from: 0230 O-alkyl selected from O—(C-C) straight chain or branched chain alkyl, 0231 O-cycloalkyl selected from O (C-C) cycloalkyl, 0232 O-alkylcycloalkyl selected from O (C-C) alkylcycloalkyl, 0233 O-acyl selected from O-ester and O-thioester, 0234 C-C straight chain or branched chain alkyl, wherein the composition is adapted to release a therapeuti C-Co straight chain or branched chain alkyl hetero cally effective amount of the ligand to one or more regions of Substituted with oxygen, C-C straight chain or the intestine of a subject. branched chain alkyl hetero substituted with silicon, 0222. In another aspect, the compositions described C-Co straight chain or branched chain alkyl hetero herein comprise a bitter receptor ligand selected from a com Substituted with Sulphur, C-Co straight chain or pound of structural Formula XII, branched chain alkyl substituted with OH, C-Co US 2015/0265555 A1 Sep. 24, 2015 22
straight chain or branched chain alkyl substituted with 0241. In some embodiments, a compound of Formula XII O-alkyl, C-C straight chain or branched chain alkyl is selected from the following structures, substituted with SH, C-C straight chain or branched chain alkyl Substituted with S-alkyl, C-Co straight chain or branched chain alkyl substituted with NH, C-Co straight chain or branched chain alkyl Substituted with NH-alkyl, 0235 C-C straight chain or branched chain alkenyl, C-Co straight chain or branched chain alkenyl hetero Substituted with oxygen, C-C straight chain or branched chain alkenyl hetero substituted with silicon, C-Co straight chain or branched chain alkenyl hetero Substituted with Sulphur, C-C straight chain or branched chain alkenyl substituted with OH, C-Co straight chain or branched chain alkenyl substituted with O-alkyl, C-Co straight chain or branched chain alkenyl substituted with SH, C-C straight chain or branched chain alkenyl substituted with S-alkyl, C-Co straight chain or branched chain alkenyl substituted with NH, C-Co straight chain or branched chain alkenyl Substi tuted with NH-alkyl, 0236 C-C straight chain or branched chain alkynyl, C-Co straight chain or branched chain alkynyl hetero Substituted with oxygen, C-C straight chain or branched chain alkynyl hetero substituted with silicon, C-Co straight chain or branched chain alkynyl hetero Substituted with Sulphur, C-Co straight chain or branched chain alkynyl substituted with OH, C-Co straight chain or branched chain alkynyl substituted with O-alkyl, C-Co straight chain or branched chain alkynyl substituted with SH, C-C straight chain or branched chain alkynyl substituted with S-alkyl, C-Co straight chain or branched chain alkynyl substituted with NH, C-Co straight chain or branched chain alkynyl Substi tuted with NH-alkyl, 0237 substituted or unsubstituted aryl selected from phenyl, Substituted phenyl, naphthyl, Substituted naph thyl, 0238 substituted or unsubstituted alkylaryl selected from alkylphenyl, alkylsubstituted phenyl, alkylnaph thyl, alkylsubstituted naphthyl, 0239 substituted or unsubstituted heteroaryl selected from substituted or unsubstituted pyridyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrrolyl, substi tuted or unsubstituted oxazolyl, substituted or unsubsti tuted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted diazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, and 0240 substituted or unsubstituted alkyl heteroaryl selected from substituted or unsubstituted alkylpyridyl, substituted or unsubstituted alkyl furanyl, substituted or unsubstituted alkylthiophenyl, substituted or unsubsti tuted alkyl pyrrolyl, substituted or unsubstituted alkyl oxazolyl, substituted or unsubstituted alkyl isoxazolyl, substituted or unsubstituted alkyl diazolyl, substituted or unsubstituted alkyl pyrazolyl, and substituted or unsubstituted alkyl triazolyl. US 2015/0265555 A1 Sep. 24, 2015 23
-continued -continued
US 2015/0265555 A1 Sep. 24, 2015 24
-continued (0251 R, is selected from: 0252 C, to C straight chain or branched chain alkyl, C, to C2 straight chain or branched chain alkenyl, and C, to C straight chain or branched chain alkynyl; and wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of the intestine of a subject. 0253) In some embodiments, for a compound of Formula XIII, 0254 R. R. and Rs are each independently selected from: 0255 substituted or unsubstituted aryl selected from phenyl, Substituted phenyl, naphthyl, Substituted naph thyl: (0256 R is selected from: 0257 O-alkyl selected from O (C-C) straight chain or branched chain alkyl, 0258 O-cycloalkyl selected from O (C-C) cycloalkyl, and 0259 O-alkylcycloalkyl selected from O (C-C) alkylcycloalkyl. 0260. In some embodiments, a compound of Formula XIII is selected from the following structures, 0242. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from a com pound of structural Formula XIII,
X R3 N R2 O
R7 O
0243 R and R are each independently selected from: 0244 H. C-C straight chain or branched chain alkyl, N C-C, cycloalkyl, and C-C alkylcycloalkyl; O 0245 X and Y are independently is selected from: O / ( 0246 O and S: H 0247 R. R. and Rs are each independently selected from: 0248 C-C straight chain or branched chain alkyl, C-C, N-te / cycloalkyl, C-C alkylcycloalkyl and substituted or O unsubstituted aryl; 0249 R is selected from: 0261. In another aspect, the compositions described 0250 H, OH, O-alkyl, O-cycloalkyl and O-alkylcy- herein comprise a bitter receptor ligand selected from a com cloalkyl: pound of structural Formula XIV. US 2015/0265555 A1 Sep. 24, 2015 25
Substituted with Sulphur, C-Co straight chain or
(XIV) branched chain alkyl substituted with OH, C-Co straight chain or branched chain alkyl substituted with O-alkyl, C-Co straight chain or branched chain alkyl substituted with SH, C-C straight chain or branched chain alkyl Substituted with S-alkyl, C-Co straight chain or branched chain alkyl substituted with NH, C-Co straight chain or branched chain alkyl Substituted with NH-alkyl, 0271 substituted or unsubstituted aryl selected from phenyl, Substituted phenyl, naphthyl, Substituted naph thyl, 0272 substituted or unsubstituted alkylaryl selected wherein from alkylphenyl, alkylsubstituted phenyl, alkylnaph 0262 R is selected from: thyl, alkylsubstituted naphthyl, 0263 H, 6-deoxy carbohydrate residue, a polymer of 0273 substituted or unsubstituted heteroaryl selected 2-206-deoxycarbohydrate residues, 2,6-dideoxycarbo from substituted or unsubstituted pyridyl, substituted or hydrate residue, a polymer of 2-20 2.6-dideoxy carbo unsubstituted furanyl, substituted or unsubstituted hydrate residues, glucose residue, a polymer of 2-20 thiophenyl, substituted or unsubstituted pyrrolyl, substi glucose residues and a 2-20 Subunit polymer consisting tuted or unsubstituted oxazolyl, substituted or unsubsti of a combination of 6-deoxycarbohydrate residues, 2,6- tuted isoxazolyl, substituted or unsubstituted thiazolyl, dideoxy carbohydrate residues, and glucose residues; substituted or unsubstituted diazolyl, substituted or 0264 R is selected from: unsubstituted pyrazolyl, substituted or unsubstituted 0265 H. C-C straight chain or branched chain alkyl, triazolyl, and C-C cycloalkyl, C-C heterocycloalkyl, where the 0274 substituted or unsubstituted alkyl heteroaryl heterocycle contains one or two hetero atoms selected from O, S, and N. Ca-Co alkylcycloalkyl, C-C alkyl selected from substituted or unsubstituted alkylpyridyl, heterocycloalkyl, where the heterocycle contains one or substituted or unsubstituted alkyl furanyl, substituted or two hetero atoms selected from O, S, and N, substituted unsubstituted alkylthiophenyl, substituted or unsubsti or unsubstituted aryl, substituted or unsubstituted alky tuted alkyl pyrrolyl, substituted or unsubstituted alkyl laryl, Substituted or unsubstituted heteroaryland substi oxazolyl, substituted or unsubstituted alkyl isoxazolyl, tuted or unsubstituted alkyl heteroaryl, tigloyl, substi substituted or unsubstituted alkyl diazolyl, substituted tuted or unsubstituted aroyl and alkoyl; and or unsubstituted alkyl pyrazolyl, and substituted or 0266 R is selected from: unsubstituted alkyl triazolyl, 0267 C-C straight chain or branched chain alkyl, 0275 substituted or unsubstituted aroyl selected from C-C cycloalkyl, C-C heterocycloalkyl, where the substituted or unsubstituted benzoyl; and heterocycle contains one or two hetero atoms selected (0276 R is selected from: from O, S, and N. Ca-Co alkylcycloalkyl, C-C alkyl 0277 C-C straight chain or branched chain alkyl, heterocycloalkyl, where the heterocycle contains one or C-Co straight chain or branched chain alkyl hetero two hetero atoms selected from O, S, and N: Substituted with oxygen, C-Co straight chain or and wherein the dotted lines indicate the optional presence of branched chain alkyl hetero substituted with silicon, either a C4-C5 double bond or a C5-C6 double bond; and C-Co straight chain or branched chain alkyl hetero wherein the composition is adapted to release a therapeuti Substituted with Sulphur, C-C straight chain or cally effective amount of the ligand to one or more regions of branched chain alkyl substituted with OH, C-Co the intestine of a subject. straight chain or branched chain alkyl substituted with 0268. In some embodiments, for a compound of Formula O-alkyl, C-Co straight chain or branched chain alkyl XIV, substituted with SH, C-C straight chain or branched 0269 R is selected from: chain alkyl substituted with S-alkyl, C-Co straight 0270 C-C straight chain or branched chain alkyl, chain or branched chain alkyl substituted with NH, C-Co straight chain or branched chain alkyl hetero C-Co straight chain or branched chain alkyl substituted Substituted with oxygen, C-Co straight chain or with NH-alkyl. branched chain alkyl hetero substituted with silicon, 0278. In some embodiments, a compound of Formula XIV C-Co straight chain or branched chain alkyl hetero is selected from the following structures, O
O N O
OH O O HO O O O O MeO OH OMe OMe US 2015/0265555 A1 Sep. 24, 2015 26
-continued
O ~ O
OH O O
OMe MeO OH OMe OMe
O
O N O
OH O
MeO
OH O
MeO Zst: o o O
OH O US 2015/0265555 A1 Sep. 24, 2015 27
-continued
O -n. O
OH O O HO O O O MeO MeO OH OMe OMe
O ~ O
O O O O Zst: O O O O C MeO OMe OMe OMe OMe
0279. In another aspect, the compositions described 0283 substituted or unsubstituted CO-aryl selected herein comprise a bitter receptor ligand comprising a pino from CO-phenyl, CO-substituted phenyl, CO-naphthyl, lenic acid wherein the composition is adapted to release a substituted CO-naphthyl, therapeutically effective amount of the ligand to one or more regions of the intestine of a subject. In some embodiments, 0284 substituted or unsubstituted CO-alkylaryl the pinolenic acid is selected from CO-alkylphenyl, CO-alkylsubstituted phenyl, CO-alkylnaphthyl, CO-alkylsubstituted naph thyl, and 0285 substituted or unsubstituted CO-alkenylaryl 1-1-1 \-1 Y-1a1n-1-cool selected from CO-alkenyl phenyl, CO-alkenyl substi tuted phenyl, CO-alkenyl naphthyl, CO-alkenyl substi tuted naphthyl, CO-cinnamoyl, CO-coumaroyl, 0280. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from a com CO-caffeoyl, and CO-ferruloyl; and pound of structural Formula XV. wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of the intestine of a subject. (XV) 0286. In some embodiments, for a compound of Formula XV, 0287 R. R. and R are independently selected from: 0288 CO-alkyl selected from CO (C-C) straight chain or branched chain alkyl, 0289 CO-cycloalkyl selected from CO (C-C) cycloalkyl, and wherein 0290 CO-alkylcycloalkyl selected from CO (C-C) 0281 R, R and R are independently selected from: alkylcycloalkyl. 0282 H, CO-alkyl, CO-cycloalkyl, CO-alkylcy 0291. In some embodiments, a compound of Formula XV cloalkyl, is selected from the following structures, US 2015/0265555 A1 Sep. 24, 2015 28
-continued
HO,A. How
OH
OH OMe
HO How
OMe.
OH OMe
0292. In other embodiments, a compound of Formula XV is selected from the following structures,
COOH HO OH
OH
OH US 2015/0265555 A1 Sep. 24, 2015 29
-continued -continued COOH HO COOH COOH HO HO OH OH OH O O HO O O O OH O
O N OH O
OH 21 o OH OH
OH OH HO COOH HO COOH HO OH OH HOOC O OMe
O O HO HO \ O OH sOH SO 21 OH O
HO OMe.
HOOC o OH OH O OH OH HO HO O
0293. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from a com pound of structural Formula XVI, O
(XVI) 21 C- OH OMe
OMe
wherein 0294 X is selected from: 0295 O, S, NH, and NR where R is C-C straight O chain or branched chain alkyl, C-C cycloalkyl, Ca-Co alkylcycloalkyl or CO-alkyl: 0296 R and R are each independently selected from: 0297 H. C-C straight chain or branched chain alkyl, C-C, cycloalkyl, C-C heterocycloalkyl, where the OMe heterocycle contains one or two hetero atoms selected from O, S, and N, C-C alkylcycloalkyl, C-C alkyl OH heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N, substituted or unsubstituted aryl, substituted or unsubstituted alky laryl, substituted or unsubstituted heteroaryland substi US 2015/0265555 A1 Sep. 24, 2015 30
tuted or unsubstituted alkyl heteroaryl; CO-alkyl, CO 0310 CO-alkyl selected from CO (C-C) straight cycloalkyl, CO-alkylcycloalkyl, chain or branched chain alkyl, 0298 substituted or unsubstituted CO-aryl selected 0311 CO-alkenyl selected from CO (C-C) straight from CO-phenyl, CO-substituted phenyl, CO-naphthyl, chain or branched chain alkenyl, substituted CO-naphthyl, 0312 CO-cycloalkyl selected from CO (C-C) 0299 substituted or unsubstituted CO-alkylaryl cycloalkyl, and selected from CO-alkylphenyl, CO-alkylsubstituted 0313 CO-alkylcycloalkyl selected from CO (C-C) phenyl, CO-alkylnaphthyl, CO-alkylsubstituted naph alkylcycloalkyl. thyl, and 0314. In another aspect, the compositions described 0300 substituted or unsubstituted CO-alkenylaryl herein comprise a bitter receptor ligand selected from a com selected from CO-alkenyl phenyl, CO-alkenyl substi tuted phenyl, CO-alkenyl naphthyl, CO-alkenyl substi pound of structural Formula XVII, tuted naphthyl, CO-cinnamoyl, CO-coumaroyl, CO-caffeoyl, and CO-ferruloyl; and (XVII) wherein the bond adjacent to the heterocyclic ring is a single or a double bond; and wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of the intestine of a subject. 0301 In some embodiments, for a compound of Formula XVI, 0302 R is selected from: 0303 CO-alkyl selected from CO (C-C) straight chain or branched chain alkyl; wherein 0304 R and R are each independently selected from: 0315 X is selected from: 0305 C-C straight chain or branched chain alkyl, 0316 O, S, NH, and NR where R is C-C straight C-Co straight chain or branched chain alkyl hetero chain or branched chain alkyl, C-C cycloalkyl, Ca-Co Substituted with oxygen, C-Co straight chain or alkylcycloalkyl, or CO-alkyl; and branched chain alkyl hetero substituted with silicon, 0317. Y is selected from: C-Co straight chain or branched chain alkyl hetero 0318 CHO, COOH and COOZ where Z is C to Co Substituted with Sulphur, C-C straight chain or straight chain or branched chain alkyl, C. to C, branched chain alkyl substituted with OH, C-Co cycloalkyl, C to Co alkylcycloalkyl or CO-alkyl, straight chain or branched chain alkyl substituted with O-alkyl, C-Co straight chain or branched chain alkyl 0319 R is selected from: substituted with SH, C-C straight chain or branched 0320 H, C-C straight chain or branched chain alkyl, chain alkyl substituted with S-alkyl, C-C straight C-C cycloalkyl, C-C heterocycloalkyl, where the chain or branched chain alkyl substituted with NH, heterocycle contains one or two hetero atoms selected C-C straight chain or branched chain alkyl substituted from O, S, and N. Ca-Co alkylcycloalkyl, C-C alkyl with NH-alkyl, heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N, substituted 0306 substituted or unsubstituted aryl selected from or unsubstituted aryl, substituted or unsubstituted alky phenyl, Substituted phenyl, naphthyl, Substituted naph laryl, substituted or unsubstituted heteroaryland substi thyl, tuted or unsubstituted alkyl heteroaryl; CO-alkyl, CO 0307 substituted or unsubstituted alkylaryl selected cycloalkyl, CO-alkylcycloalkyl, from alkylphenyl, alkylsubstituted phenyl, alkylnaph 0321 substituted or unsubstituted CO-aryl selected thyl, alkylsubstituted naphthyl, from CO-phenyl, CO-substituted phenyl, CO-naphthyl, 0308 substituted or unsubstituted heteroaryl selected substituted CO-naphthyl, from substituted or unsubstituted pyridyl, substituted or 0322 substituted or unsubstituted CO-alkylaryl unsubstituted furanyl, substituted or unsubstituted selected from CO-alkylphenyl, CO-alkylsubstituted thiophenyl, substituted or unsubstituted pyrrolyl, substi phenyl, CO-alkylnaphthyl, CO-alkylsubstituted naph tuted or unsubstituted oxazolyl, substituted or unsubsti thyl, and tuted isoxazolyl, substituted or unsubstituted thiazolyl, 0323 substituted or unsubstituted CO-alkenylaryl substituted or unsubstituted diazolyl, substituted or selected from CO-alkenyl phenyl, CO-alkenyl substi unsubstituted pyrazolyl, substituted or unsubstituted tuted phenyl, CO-alkenyl naphthyl, CO-alkenyl substi triazolyl, and tuted naphthyl, CO-cinnamoyl, CO-coumaroyl, 0309 substituted or unsubstituted alkyl heteroaryl CO-caffeoyl, and CO-ferruloyl; and selected from substituted or unsubstituted alkylpyridyl, substituted or unsubstituted alkyl furanyl, substituted or and wherein the bond adjacent to the heterocyclic ring is a unsubstituted alkylthiophenyl, substituted or unsubsti single or a double bond; and tuted alkyl pyrrolyl, substituted or unsubstituted alkyl wherein the composition is adapted to release a therapeuti oxazolyl, substituted or unsubstituted alkyl isoxazolyl, cally effective amount of the ligand to one or more regions of substituted or unsubstituted alkyl diazolyl, substituted the intestine of a subject. or unsubstituted alkyl pyrazolyl, and substituted or 0324 In some embodiments, for a compound of Formula unsubstituted alkyl triazolyl, XVII, US 2015/0265555 A1 Sep. 24, 2015 31
0325 R is selected from:
0326 CO-alkyl selected from CO (C-C) straight chain or branched chain alkyl; 0327 Z is selected from: 0328 CO-alkyl selected from CO (C-C) straight chain or branched chain alkyl; 0329 R is selected from: 0330 C-C straight chain or branched chain alkyl, C-Co straight chain or branched chain alkyl hetero Substituted with oxygen, C-C straight chain or branched chain alkyl hetero substituted with silicon, C-Co straight chain or branched chain alkyl hetero Substituted with Sulphur, C-C straight chain or branched chain alkyl substituted with OH, C-Co straight chain or branched chain alkyl substituted with O-alkyl, C-C straight chain or branched chain alkyl substituted with SH, C-C straight chain or branched chain alkyl Substituted with S-alkyl, C-Co straight chain or branched chain alkyl substituted with NH, C-Co straight chain or branched chain alkyl Substituted with NH-alkyl, 0331 substituted or unsubstituted aryl selected from phenyl, Substituted phenyl, naphthyl, Substituted naph thyl, 0332 substituted or unsubstituted alkylaryl selected from alkylphenyl, alkylsubstituted phenyl, alkylnaph thyl, alkylsubstituted naphthyl, 0333 substituted or unsubstituted heteroaryl selected from substituted or unsubstituted pyridyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrrolyl, substi tuted or unsubstituted oxazolyl, substituted or unsubsti tuted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted diazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, and 0334 substituted or unsubstituted alkyl heteroaryl selected from substituted or unsubstituted alkylpyridyl, substituted or unsubstituted alkyl furanyl, substituted or unsubstituted alkylthiophenyl, substituted or unsubsti tuted alkyl pyrrolyl, substituted or unsubstituted alkyl oxazolyl, substituted or unsubstituted alkyl isoxazolyl, substituted or unsubstituted alkyl diazolyl, substituted or unsubstituted alkyl pyrazolyl, and substituted or unsubstituted alkyl triazolyl, 0335 CO-alkyl selected from CO (C-C) straight chain or branched chain alkyl, 0336 CO-alkenyl selected from CO (C-C) straight chain or branched chain alkenyl, 0337 CO-cycloalkyl selected from CO (C-C) cycloalkyl, and 0338 CO-alkylcycloalkyl selected from CO (C-C) alkylcycloalkyl. 0339. In some embodiments, a compound of Formula XVI or Formula XVII is selected from the following structures, US 2015/0265555 A1 Sep. 24, 2015 32
-continued -continued
0340. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from a com pound of structural Formula XVIII,
(XVIII) O
21 O1 R1,
S. X R2
wherein 0341 X is an organic or inorganic anion; 0342 or 0343 X is an internal Zwitterion when R is H; (0344 R is selected from: (0345 H. C-C straight chain or branched chain alkyl, C-C cycloalkyl, C-C heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N. Ca-Co alkylcycloalkyl, C-C alkyl heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N, substituted or unsubstituted aryl, substituted or unsubstituted alky laryl, substituted or unsubstituted heteroaryland substi tuted or unsubstituted alkyl heteroaryl; CO-alkyl, CO cycloalkyl, CO-alkylcycloalkyl, substituted or unsubstituted CO-aryl, substituted or unsubstituted CO alkylaryl, and substituted or unsubstituted CO-alkeny laryl; and 0346 R is selected from: 0347 C-C straight chain or branched chain alkyl, C-C cycloalkyl, C-C heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N. Ca-Co alkylcycloalkyl, C-C alkyl heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N; and wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of the intestine of a subject. 0348. In some embodiments, for a compound of Formula XVIII, 0349 X is selected from: 0350 F, Cl, Br, acetate or sulphate: 0351 R is selected from: 0352 C-C straight chain or branched chain alkyl, C-Co straight chain or branched chain alkyl hetero Substituted with oxygen, C-C straight chain or branched chain alkyl hetero substituted with silicon, C-Co straight chain or branched chain alkyl hetero Substituted with Sulphur, C-Co straight chain or branched chain alkyl substituted with OH, C-Co US 2015/0265555 A1 Sep. 24, 2015
straight chain or branched chain alkyl substituted with -continued O-alkyl, C-C straight chain or branched chain alkyl COOH COOH COOH substituted with SH, C-C straight chain or branched chain alkyl Substituted with S-alkyl, C-Co straight r r r chain or branched chain alkyl substituted with NH, s X S. X s X C-Co straight chain or branched chain alkyl Substituted with NH-alkyl, 0353 substituted or unsubstituted aryl selected from phenyl, Substituted phenyl, naphthyl, Substituted naph COOM COOM s COOMe thyl, 0354 substituted or unsubstituted alkylaryl selected from alkylphenyl, alkylsubstituted phenyl, alkylnaph cr"Cric thyl, alkylsubstituted naphthyl, N. X X C X 0355 substituted or unsubstituted heteroaryl selected from substituted or unsubstituted pyridyl, substituted or unsubstituted furanyl, substituted or unsubstituted cr" 21 COOMe 21 COOMe thiophenyl, substituted or unsubstituted pyrrolyl, substi s X s X- N tuted or unsubstituted oxazolyl, substituted or unsubsti tuted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted diazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, and 21 COOE ea COOEt 21 COOEt 0356 substituted or unsubstituted alkyl heteroaryl selected from substituted or unsubstituted alkylpyridyl, s X X X substituted or unsubstituted alkylfuranyl, substituted or unsubstituted alkylthiophenyl, substituted or unsubsti tuted alkyl pyrrolyl, substituted or unsubstituted alkyl COOE COOEt COOEt. oxazolyl, substituted or unsubstituted alkyl isoxazolyl, 21 ea 21 substituted or unsubstituted alkyl diazolyl, substituted or unsubstituted alkyl pyrazolyl, and substituted or unsubstituted alkyl triazolyl; and 0357 R is selected from: 0358 C-C straight chain or branched chain alkyl, C-C straight chain or branched chain alkyl hetero Substituted with oxygen, C-Co straight chain or branched chain alkyl hetero substituted with silicon, 0360. In another aspect,p the compositionsp described C-C straight chain or branched chain alkyl hetero herein comprise a bitter receptor ligand selected from a com Substituted with Sulphur, C-Co straight chain or pound of structural Formula XIX, branched chain alkyl substituted with OH, C-Co straight chain or branched chain alkyl substituted with O-alkyl, C-Co straight chain or branched chain alkyl (XIX) substituted with SH, C-C straight chain or branched chain alkyl Substituted with S-alkyl, C-Co straight chain or branched chain alkyl substituted with NH, C-C straight chain or branched chain alkyl substituted with NH-alkyl. 0359. In some embodiments, a compound of Formula XVIII is selected from the following structures, O R3 R2 1. 21 COOH 21 COOH 21 COOH wherein r" or 0361 R, RandR are each independently selected from: s! s! s! . 0362 H, C-Co straight chain or branched chain alkyl, C-C cycloalkyl, C-C heterocycloalkyl, where the 1s heterocycle contains one or two hetero atoms selected from O, S, and N. Ca-Co alkylcycloalkyl, C-C alkyl US 2015/0265555 A1 Sep. 24, 2015 34
heterocycloalkyl, where the heterocycle contains one or 0375 substituted or unsubstituted alkylaryl selected two hetero atoms selected from O, S, and N, substituted from alkylphenyl, alkylsubstituted phenyl, alkylnaph or unsubstituted aryl, substituted or unsubstituted alky thyl, alkylsubstituted naphthyl, laryl, substituted or unsubstituted heteroaryland substi tuted or unsubstituted alkyl heteroaryl, CO-alkyl, CO 0376 substituted or unsubstituted heteroaryl selected alkenyl, CO-cycloalkyl, CO-alkylcycloalkyl, from substituted or unsubstituted pyridyl, substituted or 0363 substituted or unsubstituted CO-aryl selected unsubstituted furanyl, substituted or unsubstituted from CO-phenyl, CO-substituted phenyl, CO-naphthyl, thiophenyl, substituted or unsubstituted pyrrolyl, substi substituted CO-naphthyl, tuted or unsubstituted oxazolyl, substituted or unsubsti 0364 substituted or unsubstituted CO-alkylaryl tuted isoxazolyl, substituted or unsubstituted thiazolyl, selected from CO-alkylphenyl, CO-alkylsubstituted substituted or unsubstituted diazolyl, substituted or phenyl, CO-alkylnaphthyl, CO-alkylsubstituted naph unsubstituted pyrazolyl, substituted or unsubstituted thyl, triazolyl, and 0365 substituted or unsubstituted CO-alkenylaryl selected from CO-alkenyl phenyl, CO-alkenyl substi 0377 substituted or unsubstituted alkyl heteroaryl tuted phenyl, CO-alkenyl naphthyl, CO-alkenyl substi selected from substituted or unsubstituted alkylpyridyl, tuted naphthyl, CO-cinnamoyl, CO-coumaroyl, substituted or unsubstituted alkyl furanyl, substituted or CO-caffeoyl, and CO-ferruloyl; and unsubstituted alkylthiophenyl, substituted or unsubsti 0366 R. Rs and Rare each independently selected from: tuted alkyl pyrrolyl, substituted or unsubstituted alkyl 0367 H, OH, O (C-C) straight chain or branched oxazolyl, substituted or unsubstituted alkyl isoxazolyl, chain alkyl, O—(C-C) cycloalkyl, O—(C-C) het substituted or unsubstituted alkyl diazolyl, substituted erocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N, O (C- or unsubstituted alkyl pyrazolyl, and substituted or Co) alkylcycloalkyl, O—(C-C) alkylheterocy unsubstituted alkyl triazolyl, cloalkyl, where the heterocycle contains one or two het 0378 CO-alkyl selected from CO (C-C) straight ero atoms selected from O, S, and N, O CO-alkyl, O CO-alkenyl, O CO-cycloalkyl, O CO-alkylcy chain or branched chain alkyl, cloalkyl, O CO-alkylcycloalkyl, 0379 CO-alkenyl selected from CO (C-C) straight 0368 substituted or unsubstituted O CO-aryl selected chain or branched chain alkenyl, from O CO-phenyl, O CO-substituted phenyl, 0380 CO-cycloalkyl selected from CO (C-C) O CO-naphthyl, substituted O CO-naphthyl, cycloalkyl, and 0369 substituted or unsubstituted O CO-alkylaryl selected from O CO-alkylphenyl, O CO-alkylsub 0381 CO-alkylcycloalkyl selected from CO (C-C) stituted phenyl, O CO-alkylnaphthyl, O CO-alkyl alkylcycloalkyl, and substituted naphthyl, 0370 substituted or unsubstituted O CO-alkenylaryl 0382 R. Rs and Rare each independently selected from: selected from O CO-alkenyl phenyl, O CO-alkenyl 0383 O—(C-C) straight chain or branched chain substituted phenyl, O CO-alkenyl naphthyl, O CO alkyl, O-(C-C) straight chain or branched chain alkenyl substituted naphthyl, O CO-cinnamoyl, alkyl hetero Substituted with oxygen, O—(C-C) O CO-coumaroyl, O CO-caffeoyl, and O CO-fer straight chain or branched chain alkylhetero substituted ruloyl; and with silicon, O—(C-C) straight chain or branched wherein the composition is adapted to release a therapeuti chain alkyl hetero substituted with sulphur, O (C- cally effective amount of the ligand to one or more regions of Co) straight chain or branched chain alkyl Substituted the intestine of a subject. with OH, O (C-C) straight chain or branched chain 0371. In some embodiments, for a compound of Formula alkyl substituted with O-alkyl, O (C-C) straight XIX, chain or branched chain alkyl substituted with SH, 0372 R. RandR are each independently selected from: O—(C-C) straight chain or branched chain alkyl sub 0373 C-C straight chain or branched chain alkyl, C-Co straight chain or branched chain alkyl hetero stituted with S-alkyl, O—(C-C) straight chain or Substituted with oxygen, C-Co straight chain or branched chain alkyl substituted with NH, O—(C- branched chain alkyl hetero substituted with silicon, Co) straight chain or branched chain alkyl substituted C-Co straight chain or branched chain alkyl hetero with NH-alkyl, Substituted with Sulphur, C-C straight chain or 0384 O CO-alkyl selected from O CO (C-C) branched chain alkyl substituted with OH, C-Co straight chain or branched chain alkyl, straight chain or branched chain alkyl substituted with O-alkyl, C-Co straight chain or branched chain alkyl 0385) O CO-alkenyl selected from O CO (C- substituted with SH, C-C straight chain or branched Co) straight chain or branched chain alkenyl, chain alkyl substituted with S-alkyl, C-Co straight 0386 O CO-cycloalkyl selected from O CO (C- chain or branched chain alkyl substituted with NH, C.) cycloalkyl, and C-Co straight chain or branched chain alkyl substituted (0387 O CO-alkylcycloalkyl selected from O CO with NH-alkyl, (C-Cs) alkylcycloalkyl. 0374 substituted or unsubstituted aryl selected from phenyl, Substituted phenyl, naphthyl, Substituted naph 0388. In some embodiments, a compound of Formula XIX thyl, is selected from the following structures,
US 2015/0265555 A1 Sep. 24, 2015 36
-continued 0393 substituted or unsubstituted CO-alkylaryl selected from CO-alkylphenyl, CO-alkylsubstituted phenyl, CO-alkylnaphthyl, CO-alkylsubstituted naph HO thyl, 0394 substituted or unsubstituted CO-alkenylaryl selected from CO-alkenyl phenyl, CO-alkenyl substi tuted phenyl, CO-alkenyl naphthyl, CO-alkenyl substi tuted naphthyl, CO-cinnamoyl, CO-coumaroyl, CO-caffeoyl, and CO-ferruloyl; and 0395 R. Rs and R are independently selected from: 0396 H, OH, O (C-C) straight chain or branched chain alkyl, O—(C-C) cycloalkyl, O—(C-C) het erocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N, O (C- Co) alkylcycloalkyl, O—(C-C) alkylheterocy cloalkyl, where the heterocycle contains one or two het ero atoms selected from O, S, and N, O CO-alkyl, O CO-alkenyl, O CO-cycloalkyl, O CO-alkylcy HO cloalkyl, O CO-alkylcycloalkyl, 0397) substituted or unsubstituted O CO-aryl selected from O CO-phenyl, O CO-substituted phenyl, O CO-naphthyl, substituted O CO-naphthyl, 0398 substituted or unsubstituted O CO-alkylaryl selected from O CO-alkylphenyl, O CO-alkylsub stituted phenyl, O CO-alkylnaphthyl, O CO-alkyl substituted naphthyl, 0399 substituted or unsubstituted O CO-alkenylaryl selected from O CO-alkenyl phenyl, O CO-alkenyl Substituted phenyl, O—CO-alkenyl naphthyl, O CO alkenyl substituted naphthyl, O CO-cinnamoyl, 0389. In another aspect, the compositions described O CO-coumaroyl, O CO-caffeoyl, and O CO-fer herein comprise a bitter receptor ligand selected from a com ruloyl; and pound of structural Formula XX, wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of the intestine of a subject. (XX) R4 0400. In some embodiments, for a compound of Formula XX, R5 04.01 R, RandR are each independently selected from: 0402 C-C straight chain or branched chain alkyl, C-Co straight chain or branched chain alkyl hetero O O O Substituted with oxygen, C-C straight chain or R11 O R6, branched chain alkyl hetero substituted with silicon, C-Co straight chain or branched chain alkyl hetero O Substituted with Sulphur, C-Co straight chain or -O O R3 branched chain alkyl substituted with OH, C-Co straight chain or branched chain alkyl substituted with O-alkyl, C-Co straight chain or branched chain alkyl substituted with SH, C-C straight chain or branched wherein chain alkyl Substituted with S-alkyl, C-Co straight 0390 R, R and R are independently selected from: chain or branched chain alkyl substituted with NH, C-Co straight chain or branched chain alkyl Substituted 0391 H, C-C straight chain or branched chain alkyl, with NH-alkyl, C-C cycloalkyl, C-C heterocycloalkyl, where the 0403 substituted or unsubstituted aryl selected from heterocycle contains one or two hetero atoms selected phenyl, Substituted phenyl, naphthyl, Substituted naph from O, S, and N. Ca-Co alkylcycloalkyl, C-C alkyl thyl, heterocycloalkyl, where the heterocycle contains one or 0404 substituted or unsubstituted alkylaryl selected two hetero atoms selected from O, S, and N, substituted from alkylphenyl, alkylsubstituted phenyl, alkylnaph or unsubstituted aryl, substituted or unsubstituted alky thyl, alkylsubstituted naphthyl, laryl, substituted or unsubstituted heteroaryland substi tuted or unsubstituted alkyl heteroaryl, CO-alkyl, CO 04.05 substituted or unsubstituted heteroaryl selected alkenyl, CO-cycloalkyl, CO-alkylcycloalkyl, from substituted or unsubstituted pyridyl, substituted or unsubstituted furanyl, substituted or unsubstituted 0392 substituted or unsubstituted CO-aryl selected thiophenyl, substituted or unsubstituted pyrrolyl, substi from CO-phenyl, CO-substituted phenyl, CO-naphthyl, tuted or unsubstituted oxazolyl, substituted or unsubsti substituted CO-naphthyl, tuted isoxazolyl, substituted or unsubstituted thiazolyl, US 2015/0265555 A1 Sep. 24, 2015 37
substituted or unsubstituted diazolyl, substituted or -continued unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, and 0406 substituted or unsubstituted alkyl heteroaryl selected from substituted or unsubstituted alkylpyridyl, substituted or unsubstituted alkyl furanyl, substituted or unsubstituted alkylthiophenyl, substituted or unsubsti tuted alkyl pyrrolyl, substituted or unsubstituted alkyl oxazolyl, substituted or unsubstituted alkyl isoxazolyl, substituted or unsubstituted alkyl diazolyl, substituted or unsubstituted alkyl pyrazolyl, and substituted or unsubstituted alkyl triazolyl, 0407 CO-alkyl selected from CO (C-C) straight OH chain or branched chain alkyl, 0408 CO-alkenyl selected from CO (C-C) straight chain or branched chain alkenyl, OH 04.09 CO-cycloalkyl selected from CO (C-C) cycloalkyl, and 0410 CO-alkylcycloalkyl selected from CO (C-C) alkylcycloalkyl; and OMe 0411 RRs and Rare each independently selected from: 0412 O—(C-C) straight chain or branched chain HO O alkyl, O—(C-C) straight chain or branched chain alkyl hetero Substituted with oxygen, O—(C-C) straight chain or branched chain alkylhetero substituted OH with silicon, O—(C-C) straight chain or branched chain alkyl hetero substituted with sulphur, O (C- HOO O Co) straight chain or branched chain alkyl Substituted OMe with OH, O (C-C) straight chain or branched chain alkyl substituted with O-alkyl, O (C-C) straight HO O O chain or branched chain alkyl substituted with SH, O—(C-C) straight chain or branched chain alkyl sub O OMe stituted with S-alkyl, O—(C-C) straight chain or OH branched chain alkyl substituted with NH, O—(C- Co) straight chain or branched chain alkyl Substituted OH O with NH-alkyl, OMe 0413 O CO-alkyl selected from O CO (C-C) OMe straight chain or branched chain alkyl, 0414 O CO-alkenyl selected from O CO (C- HO O O Co) straight chain or branched chain alkenyl, 0415 O CO-cycloalkyl selected from O CO (C- O OMe C.) cycloalkyl, and OH 0416 O CO-alkylcycloalkyl selected from O—CO OH (C-C) alkylcycloalkyl. 0417. In some embodiments, a compound of Formula XX is selected from the following structures,
US 2015/0265555 A1 Sep. 24, 2015 38
-continued -continued
OH.
OH
0418. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from a com pound of structural Formula XXI,
(XXI)
wherein
0419 R and R are independently selected from: 0420 H, C-Co straight chain or branched chain alkyl, C-C cycloalkyl, C-C heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N. Ca-Co alkylcycloalkyl, C-C alkyl heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N, substituted or unsubstituted aryl, substituted or unsubstituted alky laryl, substituted or unsubstituted heteroaryland substi tuted or unsubstituted alkyl heteroaryl, CO-alkyl, CO alkenyl, CO-cycloalkyl, CO-alkylcycloalkyl, 0421 substituted or unsubstituted CO-aryl selected from CO-phenyl, CO-substituted phenyl, CO-naphthyl, substituted CO-naphthyl, 0422 substituted or unsubstituted CO-alkylaryl selected from CO-alkylphenyl, CO-alkylsubstituted phenyl, CO-alkylnaphthyl, CO-alkylsubstituted naph thyl, 0423 substituted or unsubstituted CO-alkenylaryl selected from CO-alkenyl phenyl, CO-alkenyl substi tuted phenyl, CO-alkenyl naphthyl, CO-alkenyl substi tuted naphthyl, CO-cinnamoyl, CO-coumaroyl, CO-caffeoyl, and CO-ferruloyl; and 0424 R. R. and Rs are independently selected from: 0425 H, OH, O (C-C) straight chain or branched chain alkyl, O—(C-C) cycloalkyl, O—(C-C) het erocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N, O (C- Co) alkylcycloalkyl, O—(C-C) alkylheterocy US 2015/0265555 A1 Sep. 24, 2015 39
cloalkyl, where the heterocycle contains one or two het 0437 CO-cycloalkyl selected from CO (C-C) ero atoms selected from O, S, and N, O CO-alkyl, cycloalkyl, and O CO-alkenyl, O CO-cycloalkyl, O CO-alkylcy cloalkyl, O CO-alkylcycloalkyl, 0438 CO-alkylcycloalkyl selected from CO (C-C) 0426 substituted or unsubstituted O CO-aryl selected alkylcycloalkyl, and from O CO-phenyl, O CO-substituted phenyl, 0439 R. R. and Rs are each independently selected from: O CO-naphthyl, substituted O CO-naphthyl, 0427 substituted or unsubstituted O CO-alkylaryl 0440 O—(C-C) straight chain or branched chain selected from O CO-alkylphenyl, O CO-alkylsub alkyl, O-(C-C) straight chain or branched chain stituted phenyl, O CO-alkylnaphthyl, O CO-alkyl alkyl hetero Substituted with oxygen, O—(C-C) substituted naphthyl, straight chain or branched chain alkylhetero substituted 0428 substituted or unsubstituted O CO-alkenylaryl with silicon, O—(C-C) straight chain or branched selected from O CO-alkenyl phenyl, O CO-alkenyl chain alkyl hetero substituted with sulphur, O—(C- substituted phenyl, O CO-alkenyl naphthyl, O CO Co) straight chain or branched chain alkyl Substituted alkenyl substituted naphthyl, O CO-cinnamoyl, with OH, O (C-C) straight chain or branched chain O CO-coumaroyl, O CO-caffeoyl, and O CO-fer alkyl substituted with O-alkyl, O (C-C) straight ruloyl; and chain or branched chain alkyl substituted with SH, wherein the composition is adapted to release a therapeuti O—(C-C) straight chain or branched chain alkyl sub cally effective amount of the ligand to one or more regions of stituted with S-alkyl, O—(C-C) straight chain or the intestine of a subject. branched chain alkyl substituted with NH, O (C- 0429. In some embodiments, for a compound of Formula Co) straight chain or branched chain alkyl Substituted XXI, with NH-alkyl, 0430 R and R are each independently selected from: 0441 O CO-alkyl selected from O CO (C-C) 0431 C-C straight chain or branched chain alkyl, straight chain or branched chain alkyl, C-Co straight chain or branched chain alkyl hetero Substituted with oxygen, C-Co straight chain or 0442 O CO-alkenyl selected from O CO (C- branched chain alkyl hetero substituted with silicon, Co) straight chain or branched chain alkenyl, C-Co straight chain or branched chain alkyl hetero 0443 O CO-cycloalkyl selected from O CO (C- Substituted with Sulphur, C-C straight chain or C.) cycloalkyl, and branched chain alkyl substituted with OH, C-Co straight chain or branched chain alkyl substituted with 0444 O CO-alkylcycloalkyl selected from O CO O-alkyl, C-Co straight chain or branched chain alkyl (C-C) alkylcycloalkyl. substituted with SH, C-C straight chain or branched 0445. In some embodiments, a compound of Formula XXI chain alkyl Substituted with S-alkyl, C-Co straight is selected from the following structures, chain or branched chain alkyl substituted with NH, C-Co straight chain or branched chain alkyl substituted with NH-alkyl, OH 0432 substituted or unsubstituted aryl selected from phenyl, Substituted phenyl, naphthyl, Substituted naph OH thyl, substituted or unsubstituted alkylaryl selected from alkylphenyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubstituted naphthyl, HO O 0433 substituted or unsubstituted heteroaryl selected O N OH from substituted or unsubstituted pyridyl, substituted or unsubstituted furanyl, substituted or unsubstituted OH thiophenyl, substituted or unsubstituted pyrrolyl, substi OH tuted or unsubstituted oxazolyl, substituted or unsubsti tuted isoxazolyl, substituted or unsubstituted thiazolyl, OH substituted or unsubstituted diazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, and HO N O 0434 substituted or unsubstituted alkyl heteroaryl selected from substituted or unsubstituted alkylpyridyl, substituted or unsubstituted alkyl furanyl, substituted or unsubstituted alkylthiophenyl, substituted or unsubsti OH tuted alkyl pyrrolyl, substituted or unsubstituted alkyl OH oxazolyl, substituted or unsubstituted alkyl isoxazolyl, substituted or unsubstituted alkyl diazolyl, substituted or unsubstituted alkyl pyrazolyl, and substituted or HO N O unsubstituted alkyl triazolyl, 0435 CO-alkyl selected from CO (C-C) straight chain or branched chain alkyl, 0436 CO-alkenyl selected from CO (C-C) straight OH chain or branched chain alkenyl, US 2015/0265555 A1 Sep. 24, 2015
-continued -continued N OMe
OMe HO O O N OMe
OH
OMe
OMe HO N O
OH
OMe HO O N O OH
0446. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from the following structures,
N H US 2015/0265555 A1 Sep. 24, 2015 41
-continued
HO
O Y/\ O Y/\ ... I OH ... I OH O O
Q\ /O Q\ /O OES OES . I I IOH ... I IOMe O O
wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of the intestine of a subject. O O 0447. In another aspect, the compositions described OESV/ OESV/9 herein comprise a bitter receptor ligand selected from a com- IIIOH IIIOMe pound of structural Formula XXII,
(XXII)
wherein 0448 R, and R are each independently selected from: 0449 H. C-C substituted or unsubstituted straight chain or branched chain alkyl, C-Co Substituted or unsubstituted Straight chain or branched chain alkenyl, C-Co Substituted or unsubstituted Straight chain or branched chain alkynyl, substituted or unsubstituted O—C-Co straight chain or branched chain alkyl. Substituted or unsubstituted O-C-Cio Straight chain or branched chain alkenyl, substituted or unsubstituted O—C to Costraight chain or branched chain alkynyl: and wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of the intestine of a subject. 0450. In some embodiments, a compound of Formula XXII is selected from the following structures, US 2015/0265555 A1 Sep. 24, 2015 42
-continued -continued
HO HO
HG OH HG OH
0451. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from a com pound of structural Formula XXIII,
wherein 0452 R, and R are each independently selected from: 0453 H, C-C substituted or unsubstituted straight chain or branched chain alkyl, C-Co Substituted or unsubstituted Straight chain or branched chain alkenyl, C-Co Substituted or unsubstituted Straight chain or branched chain alkynyl, alpha or beta glucosyl, alpha or beta fructosyl, alpha or beta mannosyl, alpha or beta galactosyl, alpha or beta fucosyl; and wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of the intestine of a subject. 0454. In some embodiments, a compound of Formula XXIII is selected from the following structures,
US 2015/0265555 A1 Sep. 24, 2015 43
-continued -continued
0455. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from a com pound of structural Formula XXIV.
(XXIV)
wherein 0456 X is C-O or CHOH; and 0457. R. RandR are each independently selected from: 0458 C-C substituted or unsubstituted straight chain or branched chain alkyl, C-Co Substituted or unsubsti tuted Straight chain or branched chain alkenyl, C-Co substituted or unsubstituted straight chain or branched chain alkynyl; and wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of the intestine of a subject. 0459. In some embodiments, a compound of Formula XXIV is selected from the following structures,
O2 OH US 2015/0265555 A1 Sep. 24, 2015 44
-continued -continued
US 2015/0265555 A1 Sep. 24, 2015 45
-continued -continued
US 2015/0265555 A1 Sep. 24, 2015 46
-continued -continued
0460. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from a com pound of structural Formula XXV.
(XXV)
wherein 0461) R. R. R. and Ra are each independently selected from: 0462 H, C-C substituted or unsubstituted straight chain or branched chain alkyl, C-Co Substituted or unsubstituted Straight chain or branched chain alkenyl, C-Co Substituted or unsubstituted Straight chain or branched chain alkynyl; and US 2015/0265555 A1 Sep. 24, 2015 47 wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of the intestine of a subject. 0463. In some embodiments, a compound of Formula XXV is selected from the following structures,
0464. In some embodiments, the composition comprising a compound of Formula XXIV further comprises turmeric extract compounds, beta-carotene, saw palmetto extract com pounds, fermented noni juice compounds., L-ascorbic acid, aloe vera compounds, Solanum Dulcamara extract com pounds, Celastrol, Garcinia mangostana L (Guttiterae) peri carp extract compounds, rutin, quercetin, ginko billboa extract compounds, Ocimum sanctum extract compounds, rosemary extract compounds, blueberry extract compounds, Withania somnifera Dunal extract compounds, Rhodiola extract com pounds, Schizandra berry extract compounds, astralagus root, Coenzyme Q10, cinnamon oil (flavor), plant derived glycerine (solubilizer), or a combination thereof 0465. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from the following structures, US 2015/0265555 A1 Sep. 24, 2015 48
-continued -continued
HO HO
wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of the intestine of a subject. 0466. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from the following structures, US 2015/0265555 A1 Sep. 24, 2015 49
-continued -continued OH
OH HO
US 2015/0265555 A1 Sep. 24, 2015 50
-continued -continued
HO HO
wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of the intestine of a subject. 0467 In another aspect, the compositions described herein comprise a bitter receptor ligand selected from the following structures, US 2015/0265555 A1 Sep. 24, 2015 51
-continued -continued O O
OH
O O E H OH OH O
OH wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of O O the intestine of a subject. O O 0468. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from the following structures, O OH O OH OH -, O O O O O O
OH O OH OH OH
O O wherein the composition is adapted to release a therapeuti O O cally effective amount of the ligand to one or more regions of the intestine of a subject. 0469. In another aspect, the compositions described OH O herein comprise a bitter receptor ligand selected from the following structures, US 2015/0265555 A1 Sep. 24, 2015 52
-continued
l HO OH HO O s
HO O w
OMe O
OMe O
MeO OMe
HO OH
OMe O HO O w
HO O MeO OMe
HO O w
HO O HO OH
MeO O w
HO OH
HO O HO O
OMe O MeO OH
MeO OH HO O OMe
HO O w O O k HO OH
HO OMe OMe O US 2015/0265555 A1 Sep. 24, 2015 53
-continued -continued MeO OMe
MeO OMe
HO OH
O O
HO OH O
MeO c c OMe O O O
HO OMe
HO OH MeO OMe O O OH HO OH
HO OH
O O MeO OH O O OH MeO OMe OH O O MeO OMe O O wherein the composition is adapted to release a therapeuti HO OMe cally effective amount of the ligand to one or more regions of the intestine of a subject. O O 0470. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from a com pound of structural Formula XXVI or XXVII, (XXVI) R1 O OH O.
HO ''' OH w O OH OH CH HO HO OH HO On & HO OH O HO CH2 CH "wo no' O O R2 HO O
O HO O H -5 R3 OO HH US 2015/0265555 A1 Sep. 24, 2015
-continued (XXVII) R1 M HO O
HO II . . .
HO HO CH OH OH OH O R2 OH OH, V Oil II. S -O CH, O S IO V HO HO R3 O
HO OH
OH
... I III OH
% OH
wherein -continued 0471) R. R. R. and R are each independently selected from: 0472 H, C-C substituted or unsubstituted straight chain or branched chain alkyl, —C(O)—(C-C substi tuted or unsubstituted Straight chain or branched chain OH alkyl), —C(O)— (substituted or unsubstituted aryl) with particular preference for the esters of gallic acid; and wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of the intestine of a subject. 0473. In another aspect, the compositions described herein comprise a bitter receptor ligand selected from the following structures, OH
OH OH
HO OH US 2015/0265555 A1 Sep. 24, 2015 55
-continued wherein a a.e 2. 0475 R. R. R. and R, are each independently selected from: 0476 H, CN, F, Cl, Br, I, OH, C-C substituted or unsubstituted Straight chain or branched chain alkyl, C-C substituted or unsubstituted straight chain or branched chain alkenyl, C-Co. Substituted or unsubsti tuted straight chain or branched chain alkynyl, COOH, COOalkyl, COO(substituted or unsubstituted aryl); 0477 R. R. Rs. Rs. Ro, and Ro are each independently selected from: 0478 H, CN, F, Cl, Br, I, OH, C-C substituted or unsubstituted Straight chain or branched chain alkyl, C-C substituted or unsubstituted straight chain or branched chain alkenyl, C-Co. Substituted or unsubsti tuted Straight chain or branched chain alkynyl, —O— (C-C substituted or unsubstituted straight chain or branched chain alkyl, COOH, COOalkyl, COO(substi tuted or unsubstituted aryl); and 0479 R is selected from: 0480 H, C-C substituted or unsubstituted straight chain or branched chain alkyl, C-Co Substituted or unsubstituted Straight chain or branched chain alkenyl, C-C substituted or unsubstituted straight chain or branched chain alkynyl, —C (O)—(C-C substi tuted or unsubstituted Straight chain or branched chain alkyl, —C (O)-(substituted or unsubstituted aryl); and wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of the intestine of a subject. 0481. In some embodiments, a compound of Formula XXVIII is selected from the following structures,
HOOC O O COOH 21 OH N O N-- O How OH wherein the composition is adapted to release a therapeuti MeOOC O O COOMe cally effective amount of the ligand to one or more regions of 21 OH n the intestine of a subject. 0474) In another aspect, the compositions described O --- O herein comprise a bitter receptor ligand selected from a com pound of structural Formula XXVIII, HOOC O O COOH (XXVIII) 21 n O N O N-- O R11 O1 N
O N-- MeOOC 21 O No O n COOMe
R5 R1O O --- O US 2015/0265555 A1 Sep. 24, 2015 56
-continued unsubstituted Straight chain or branched chain alkenyl, C-Co Substituted or unsubstituted Straight chain or HOOC O l O COOH branched chain alkynyl, -C (O)—(C-C substi 21 O N tuted or unsubstituted Straight chain or branched chain O N-- O alkyl, —C (O)-(substituted or unsubstituted aryl); and 0487 Ro and Rare each independently selected from: 0488 H, C-C substituted or unsubstituted straight chain or branched chain alkyl, C-Co Substituted or unsubstituted Straight chain or branched chain alkenyl, HOOC O C O COOH C-Co Substituted or unsubstituted Straight chain or 21 O N branched chain alkynyl: O --- O Or Ro and R taken together with the nitrogen to which they are attached form a 3 to 8 membered saturated heterocycle optionally containing a further 1 to 2 heteroatoms selected HOOC O O COOH from N, O, and S; and 21 OH N wherein the composition is adapted to release a therapeuti cally effective amount of the ligand to one or more regions of O --- O the intestine of a subject. 0489. In some embodiments, a compound of Formula XXIX is selected from the following structures, OH OH HOOC O O COOH. 21 OH N O N-- O HO
OH OH O) 0482 In another aspect, the compositions described herein comprise a bitter receptor ligand selected from a com pound of structural Formula XXIX,
(XXIX) O)
HO
wherein 0483 R. R. R. R. R. R. R., and Rs are each indepen dently selected from: 0484 H, CN, F, Cl, Br, I, OH, C-C substituted or unsubstituted Straight chain or branched chain alkyl, C-Co Substituted or unsubstituted Straight chain or branched chain alkenyl, C-C substituted or unsubsti tuted Straight chain or branched chain alkynyl, —O— (C-C substituted or unsubstituted straight chain or branched chain alkyl, COOH, COOalkyl, COO(substi tuted or unsubstituted aryl); 0485 R. is selected from: 0486 H, C-C substituted or unsubstituted straight chain or branched chain alkyl, C-Co Substituted or US 2015/0265555 A1 Sep. 24, 2015 57
-continued -continued
HO
O
HO c O 0490. In any of the embodiments, in certain instances, wherein the bitter receptor ligand comprises a compound having an asymmetric center or centers, the compound is a racemic mixture, a diastereoisomeric mixture, a single enan tiomer, an enantiomeric diastereomer, a meso compound, a pure epimer, or a mixture of epimers thereof 0491. In any of the embodiments, in certain instances, wherein the bitter receptor ligand comprises a compound having one or more double bonds, the compound is a cis/ trans, E/Z or geometric isomer thereof 0492. In another aspect, the compositions described herein comprise a bitter receptor ligand comprising a plant extract selected from the group consisting of Gentian (Gen tiana lutea), Bitterroot (Lewisia rediviva), Saffron Flowers (Crocus sativus), Senna leaves (Cassia Senna), Manna (Fraxinus Ornus), Myrrh (Commiphora molmol), Angelica Root (Angelica archanelica), Dwarf elder root (Sambucus ebulus), Camphor (Cinnamomum camphora), Japanese Gen tium (Gentiana scabra), Chinese rhubarb root (Rheum pal matum), Burnet-saxifrage root (Theriac venezian), Zedoary root (Curcuma Zedoaria), Carline thistle root (Carlina acau lis) and combinations thereof, wherein the composition is adapted to release a therapeutically effective amount of the ligand to one or more regions of the intestine of a Subject. In Some embodiments, the plant extract is a root extract. 0493. In another aspect, the compositions described herein comprise a bitter receptor ligand comprising Fennel fruit, Rhubarb, Licorice, Phellodendron, Zedoary, Japanese O bitter wood, Chamomile, Cranesbill, Carrot, Dried orange O peel, Scutellaria root, Magnolia bark, Borei, Cyperus rhi Zome, Platycodon, Chinaberry bark, and Cnidium, wherein US 2015/0265555 A1 Sep. 24, 2015 the composition is adapted to release a therapeutically effec Tetrahydro-Cyclopent(b)azepin-8(1H)-one, 2,3,6,7-tetrahy tive amount of the ligand to one or more regions of the dro-7-hydroxy-7-methyl-Cyclopent-2-en-1-one, 2.5- intestine of a Subject. dihydroxy-5-methyl-3-(1-piperidinyl)-Cyclopent-2-en-1- 0494. In another aspect, the compositions described one, 2,5-dihydroxy-5-methyl-3-(1-pyrrolidinyl)Cyclopent hereincomprise a bitter receptor ligand comprising cinnamon 2-en-1-one, 2,3-di-1-pyrrolidinyl-Cyclopent-2-en-1-one, (Cinnamomum verum) and bitter melon (Momordica charan 5-hydroxy-5-methyl-2,3-di-1-piperidinyl-Cyclopent-2-en tia), wherein the composition is adapted to release a thera 1-one, 5-hydroxy-5-methyl-2,3-di-1-pyrrolidinyl-Cyclo peutically effective amount of the ligand to one or more pent-2-en-1-one, 5-methyl-2,3-di-1-pyrrolidinyl-Cyclopent regions of the intestine of a subject. In some embodiments, 2-en-1-one, 5-methylene-2,3-di-1-pyrrolidinyl-Cyclopent-2- the composition further comprises maltitol, cocoa butter, en-1-one, 3-methyl-2-(1-pyrrolidinyl)-Cyclo Phenyalanine cocoa powder, milk fat, chocolate liquor, Soya lecithin, aspartic acid, Cyclo Proline-alanine, Cyclo Proline Vanilla extract, calcium carbonate and/or Omega-3-fatty acid. asparagine, Cyclo Proline-glycine, Cyclo Proline-isolucine, 0495. In another aspect, the compositions described Cyclo Proline-leucine, Cyclo Proline-methionine, Cyclo Pro herein comprise a bitter receptor ligand selected from the line-phenylalanine, Cyclo Proline-proline, Cyclo Proline-va group consisting of Thiamin, Chromium, Vanadium, Alpha line, Cyclo Valine-phenylalanine, Cynaratriol, Cynaropicrin, lipoic acid, L-carnosine, Cinnamon Bark extract, Banana Cynaropicrin, Daidzein, Daidzin, Dhurrin, Dihydroxyben Leaf extract, Boswellic acid, Miracle fruit (Gymnema Sylves Zoic Acid, 2,3-Dihydroxybenzoic Acid, 2,4-Ethyl b-L-arabi tre) leaf extract, Bitter melon (Momordica charantia) extract noside, Ethyl alpha-D-Glucoside, Ethyl beta-D-Glucoside, and combinations thereof, wherein the composition is Eustomoroside, Eustomoside, Gallic Acid, Gaudichaudio adapted to release a therapeutically effective amount of the side F, Gelidoside, Genistein, Genistin, Gentiopicroside, ligand to one or more regions of the intestine of a Subject. Gentistic Acid, Gentomoside, Geshoidin, 6'-O-beta-D-Glu 0496. In another aspect, the compositions described cosylgentiopicroside, ucoZaluzanin C. Glutamyl Aspartic herein comprise a bitter receptor ligand selected from the Acid, Glutamyl Glutamic Acid, Glycyl Leucine, Goitrin, group consisting of Jiaogulan (Gynostemma pentaphyllum) Gramine, Grosshemin, Haematoxylin Tetramethyl Ether extract, Green tea (Camellia sinensis) extract, Chinese Haw Helicin, Heptadeca-16-ene, 1-Acetoxy-2,4-Dihydroxy-Hep thorn (Crataegus pinnatifida) extract, Bitter melon (Mo tadeca-16-ene, 1,2,4-Trihydroxy-Histidine, L-Hulupone, mordica charantia) extract, Mulberry (Morus species) extract Humulinone, Humulone, Hydroxybenzoic Acid, 4-Hymeno and combinations thereof, wherein the composition is side A, Hymenoside B, Hymenoside C, Hymenoside D, adapted to release a therapeutically effective amount of the Hymenoside E, Hyrnenoside F, Isohumulone, cis-Isohumu ligand to one or more regions of the intestine of a Subject. lone, trans-Isoleucine, L-1solupanine, IsoSparteine, beta 0497. In another aspect, the compositions described Isosparteine, 10,17-Dioxo-beta-Isosparteine, 10-oxo-beta herein comprise a bitter receptor ligand selected from the Lactucin, L-Leucine, L-alanyl-L-alanyl-L-Leucine, N-(2R)- group consisting of dextromorphan, chlorhexidine, guaifen 6-amino-2-(4S)-2,5-dioxo-4-(phenylme-thyl)-1- esin, pseudoephedrine, caffeine, peroxide, atorvastatin, aspi imidazolidinyl-1-oxohexyl-L-leucyl-L-methionyl-N- rin, acetaminophen, diphenhydramine, doxylamine, sildena methyl-L-phenyl-alanyl-, (4-1)-lactam, L-Leucine, glycyl-L- fil citrate, loperamide and combinations thereof, wherein the alanyl-Leucine, L-L-Leucine, N—(N-2-L-leucyl-L- composition is adapted to release a therapeutically effective glutaminyl)-L-Leucine, N-(N-L-leucyl-L-a-glutamyl)-L- amount of the ligand to one or more regions of the intestine of Leucine, N—N2-N2-N-(1-L-leucyl-L-prolyl)-L- a subject. phenylalanyl-L-asparaginyl-L-gluta-minyl-L-Leucine, 0498. In another aspect, the compositions described N—N2-N-N-(1-L-leucyl-L-prolyl)-L-phenylalanyl-L- herein comprise a bitter receptor ligand selected from the seryl-L-glutaminyl-L-Leucine, L-leucyl-L-Valyl-Leucy group consisting of Acteoside, Adhumulone, Adlupulone, Leucine, Leucyl Phenylalanine, Limonin, Limoninmonolac Aesculetin, Aesculin, L-Alanine, L-alanyl-L-alanyl-L-Ala tone, Unamarin, Lotaustralin, Lupine, Lupanine, 13-Hy nine, L-alanyl-L-isoleucyl-Alanine L-, L-Valyl-L-Valyl droxy-Lupanine, 7-hydroxy-Lupinine, Epilupinine Lupoxes Amarogentin, Amaropanin Amaroswerin, Amygdalin, B. Lupoxes C. Lupulone, Luputrione, Mellein, 6-Methoxy Angustifoline, Antiacetylhumulone, Antiisohumulone, Argi Methionine, L-Methyl alpha-L-arabinoside, Methyl beta-L- nine, L-Arginyl Leucine, Arginyl Leucy Leucine, Arginyl arabinoside, Methyl beta-D-Glucoside, Methyl alpha-D-Glu Proline, Asaronaldehyde, Aspartyl Aspartic acid, Asparasa coside 2,3-Di-isoleucine, Methyl alpha-D-Glucoside 2,3-Di ponin I, Atropine, Benzyl beta-D-arabinoside, Benzyl beta leucine, Methyl alpha-D-Glucoside 2,3-Di-L-phenylalanine, L-arabinoside, Benzyl beta-D-fructoside, Benzyl beta-D-ga Methyl alpha-D-Glucoside 2,3-Di-threonine, Methyl alpha lactoside, Benzyl alpha-D-glucoside, Benzyl beta-D- D-Glucoside 2,3-Di-tyrosine, Methyl a-D-mannoside, glucoside, Benzyl alpha-D-mannoside, Bitter Peptides, Bitter Methyl beta-L-xylopyranoside, Methyl alpha-D-xyloside, Peptides from Soy Proteins, Butyl alpha-D-glucoside. Butyl Naringin, Neochlorogenic Acid, gamma-Lactone, Neohespe beta-D-glucoside, Caffeine, Carnosifloside II, Camosifloside ridin, Nuezhenide, Oleonuezhenide, Oleuropein, Oliviero III, Camosifloside IV. Catechin, Epicatechin, Epicatechin side A, Olivieroside B, Olivieroside C. Perrottetin H, Pheny gallate, Chaconine, alpha-Chaconine, beta2-Chlorampheni lalanine, L-Phenyl alpha-D-galactoside, Phenyl alpha-D- col, Cholic Acid, Cichoriin, Cohumulone, Colupulone, Cryp glucoside, Phenyl beta-D-glucoside, Phenylthiourea, tochlorogenic Acid, gamma-lactone, Cucurbitacin B, Cucur Phlomisoside II, Piperidine-2-carboxylic acid, 4-(2-car bitacin D, Cyclo Alanine-glycine, Cyclo Alanine boxy-2-hydroxyethyl)thio-Piperidinecarboxylic acid-2.4 phenylanaline, Cyclo Alanine-Valine, Cyclo(L- (2-carboxy-2-hydroxyethyl)thio-Prehumulone, Prelupu arginylglycyl-L-prolyl-L-prolyl-L-phenylalanyl-L- lone, Propyl beta-D-fructoside, Propyl alpha-D-glucoside, isoleucyl-L-Valy-1), Cyclo Asparagine-phenylalanine, Cyclo Propyl beta-D-glucoside, Protocatechuic Acid, Prunasin, Glycine-phenylalanine, Cycloheximide Cyclo Lucine-Tryp Pulcherrimine, Quinidine, Quinine, Quinolizinium-7-olate, tophan, Cyclopent(b)azepin-8(1H)-one, 7-Methyl-2,3,6,7- Ranitidine, Rebaudioside C, Salicin, Salidroside, Scabraside, US 2015/0265555 A1 Sep. 24, 2015 59
Scandenoside R5, Sclareolide, Scopolin, Septemfidoside, Angostura Orange Bitters, Bittermens (including Xocolatl Seryl Lysyl Glycyl Leucine. Sinapine, Solanine, alpha Mole Bitters, Grapefruit Bitters, Elemakule Tiki Bitters, Sparteine, Sparteine, 17-oxo-Stevisalioside A, Strychnine, Boston “Bittahs'), The Bitter Truth bitters (including Aro Suavioside C1, Suavioside D2, Suavioside F. Sucrose Octaac matic Bitters, Orange Bitters, Lemon Bitters, Celery Bitters, etate, Sweroside, Swertiamarin, Swertiapunimarin, Taxi Creole Bitters. Grapefruit Bitters, Chocolate Bitters, and phyllin, TFI (Furostan, beta-D-galactopyranoside). Theafla Jerry Thomas Bitters), Fee Brothers bitters (aromatic, orange, vin, Theaflavin Gallate A, Theaflavin Gallate B, Tomatidine, mint, lemon and peach), aromatic bitters containing Angos Tomatine, alpha-Tricyclodehydroisohumulone, Trifloroside, tura bark and/orcontains glycerin; Dr. Adam Elmegirab's Trihydroxybenzoic Acid, 2.4.6-Tryptophan, L-Uracil, 6-pro Boker's Bitters, Dandelion & Burdock Bitters, Limited Edi pyl-2-thio-L-Valine, L-arginylglycyl-L-prolyl-L-prolyl-L- tion Spanish Bitters, Hermes Orange. Hermes Regular, Pey phenylalanyl-L-isoleucyl-(BPla)Valine-, L-Yohimbin and chaud's Bitters, Regans’ Orange Bitters No. 6, Urban Moon combinations thereof, wherein the composition is adapted to shine (citrus and maple bitters), Appenzeller, Bokers, release atherapeutically effective amount of the ligand to one Calisaya bitters, Gordon & Co. Pale Orange Bitters, Hartwig or more regions of the intestine of a subject. Kantorowicz, Hostetter's, Malort, Kabanes, Kina Lillet, 0499. In another aspect, the compositions described Maraschino bitters, Meinhard's Bitters, Dr. Teodoro Mein herein comprise a bitter receptor ligand selected from the hards Angostura Bitters, Meyer's Bitter, Flimms, Reichs group consisting of acesulfame K, acetaminophen, Post Bitter, West Indies Bitters, New York Bitters, Boston 2"acetylpyrazine, aloin, amino-2-norbornane-carboxylic Bitters, St Louis Bitters, Frisco Bitters, Lupulins Bitters, Dr acid, amygadalin, andrographolide. p-Arbutin, aristolochic Grants Bitters, Philadelphia Bitters, Kent Bitters, Dixons Bit acid, atropine, brucine, 4-benzylpiperidine, caffeine, ters, Milwaukee Bitters, Gippsland Bitters, Utica Bitters, Ste chloramphenicol, chloroquine, ciprofloxacin, clarithromy anes Bitters, Ralays, Bairnsdale, McDonalds, Weisflog Bitter, cin, clindamycin, cycloheximide, cyclooctanone, dexmetha Bradley's Bitters, Bitter KAs, Chino, Crodino, Fanta Chi sone, diltiazem hydrochloride, diisobutylamine, dimethyl notto, Gioia, Sanbitter, and Stirrings Blood Orange, wherein biguanide, 2,6-dimethylpiperidine, doxepin, enalapril the composition is adapted to release a therapeutically effec maleate, edrophonium, enoxacin, (-) epicatechin, (-) eryth tive amount of the ligand to one or more regions of the romycin, ethylpyrazine, famotidine, gabapentin, Ginkgolide intestine of a Subject. A, goitrin, guaiacol glyceryl ether, labetalol HCl, linamarin, 0501. In another aspect, the compositions described lomefloxacin, (-) lupinine, N-methylthiourea, 1-methyl-2- herein comprise a bitter receptor ligand comprising a quinolinone, methylprednisone, nitrophthalene, nitrosaccha polyphenol selected from anthocyanins, anthroquinones, rin, ofloxacin, oleuropein, omeprazole, oxybutynin chloride, chalcones, lignans, napthoguinones, neolignans, pyroantho oxyphenomium HBr, peptide-LPFSQL, Peptide-YQEPV cyanins, pigmented tannins, tannins, Xanthones, or combina LGPVRGVRGPFPIIV, peptide-PVLGPVRGFPIIV, pep tions thereof, wherein the composition is adapted to release a tide-PVRGPFPHV, peptide-RGPFPIIV, N'-ethyl-N'5-pheny therapeutically effective amount of the ligand to one or more lurea, 2-picoline, picric acid, pirenzepine dihydrochloride, regions of the intestine of a subject. prednisone, procainamide-HCl, Quassin, Quinacrine, qui 0502. In another aspect, the compositions described nine, ranitidine, Saccharin, Salicin, Spartein sulfate pentahy herein comprise a bitter receptor ligand comprising an herbal, drate. Sucrose octaacetate, Strychnine, Sulfamethoxazole, plant, flower, fruit, vegetable, root or algal extract or combi theobromine, thioacetanilide, thiocarbanilide, tolazoline nations thereof that provides a bitter taste and wherein the tolylurea, trapidil, trimethoprim, L-tryptophan and combina composition is adapted to release a therapeutically effective tions thereof, wherein the composition is adapted to release a amount of the ligand to one or more regions of the intestine of therapeutically effective amount of the ligand to one or more a Subject. In some embodiments, the amount of the ligand is regions of the intestine of a subject. at least 100 fold lower than an NOAEL amount. 0500. In another aspect, the compositions described 0503. In another aspect, the compositions described herein comprise a bitter receptor ligand comprising a bitters herein comprise a bitter receptor ligand comprising phenylth selected from the group consisting of Alomo Bitters, Appen iocarbamide wherein the composition is adapted to release a Zeller Alpenbitter, Amargo Vallet, Amaro Cora, Amaro Erbes, therapeutically effective amount of the ligand to one or more Amaro Jannamico, Amaro Lucano, Amaro Montenegro, regions of the intestine of a subject. Amer Picon, Amaro Quintessentia, Aperol, Araucano, Arn 0504. In another aspect, the compositions described bitter, Averna, Becherovka, Beerenburg, Old Men Bitters, herein comprise a bitter receptor ligand comprising a fla Boonekamp's, Borsci San Marzano, Cappellano Chinato, Vanone, a flavone, a flavonol, a flavan, a phenolic flavonoid, Campari, Carpano Antica, Cio Ciara, Cocchi Chinato, Cock an isoflavone, a limonoid aglycone, a glucosinolate or Drops, Collins Orange, Cynar, Demänovka, Dimitri, China hydrolysis product thereof and an organic isothiocyanate. Martini, Echt Stonsdorfer, Fernet Branca, Fernet Stock, Fer net 1882, Gammel Dansk, Gran Classico Bitter, Hoppe 0505. In another aspect, the compositions described Orange, Killepitsch, Kuemmerling, Lauterbacher Tropfen, herein comprise a bitter receptor ligand comprising a mixture Licor Beirao, Luxardo Amaro, Luxardo Bitters, Luxardo Fer of gentian root (Gentiana scabra) extract and bitter melon net, Marcarini Chinato, Meletti, Nardini Amaro, Nijmeegs (Momordica charantia) extract wherein the composition is Neutje, Par-D-Schatz, Pelinkovac, Pimm's No. 1, Quinquina, adapted to release a therapeutically effective amount of the RamaZZotti, Ratzeputz, Riemerschmid Angostura, Riga ligand to one or more regions of the intestine of a subject. Black Balsam, Santa Maria al Monte Amaro, Schrobbeler, 0506. In another aspect, the compositions described Schwartzhog, St. Vitus, Sirop de Picon, Sommer, Suze, herein comprise a bitter receptor ligand comprising an extract Swedish bitters, Tilus, Torani, Underberg, Unicum, Versinthe from Salacia Oblonga wherein the composition is adapted to La Blanche, Wurzelpeter, Wurzelpeter Bitter Orange, Weis release atherapeutically effective amount of the ligand to one flog Bitter, Zucca, Amargo Chuncho, Angostura bitters, or more regions of the intestine of a Subject. US 2015/0265555 A1 Sep. 24, 2015 60
0507. In another aspect, the compositions described atherapeutically effective amount of the ligand to one or more hereincomprise a bitter receptor ligand comprising a hop acid regions of the intestine of a subject. selected from the group consisting of (+)-tetrahydro-O-acids, 0515. In another aspect, the compositions described (+)-trans-tetrahydro-iso-O-acids, (-)-cis-tetrahydro-iso-C.- herein comprise a bitter receptor ligand comprising an extract acids, (+)-transhexahydro-iso-O-acids, (-)-cis-hexahy selected from Andrographis paniculata, Curcuna longa, droiso-O-acids, and mixtures thereof wherein the composi Glycyrrhiza glabra and Terminalia chebula wherein the com tion is adapted to release atherapeutically effective amount of position is adapted to release a therapeutically effective the ligand to one or more regions of the intestine of a Subject. amount of the ligand to one or more regions of the intestine of 0508. In another aspect, the compositions described a Subject. herein comprise a bitter receptor ligand selected from 3-Epi 0516. In another aspect, the compositions described 11,13-dihydrodeacylcynaropicrin, Subexpinnatin, 11,13-Di herein comprise a bitter receptor ligand comprising an extract hydrodeacylcynaropicrin, 11 beta, 13-Dihydrocynaropicrin, selected from Garcinia mangostana L. Myristica fragrams, lsoamberboin, 3,11,13-Trihydroxy-1014)-guaien-12,6- Zizyphus Jazeiro and combinations thereof wherein the com olide, Dehydrocynaropicrin, Sibthorpin, 8-Deoxy-11,13-di position is adapted to release a therapeutically effective hydroxygrosheimin, Isolipidiol, 8-Hydroxy-3-oxo-4{15), amount of the ligand to one or more regions of the intestine of 10{14)guaiadien-12,6-olide, 3.8-Dihydroxy-1014), 11 a Subject. In some embodiments, the composition further (13)-guaiadien-12,6-olide, Grossheimin, Integrifolin, 8.beta comprises an extract of oregano, magnolia, cranberry, rose Hydroxydehydrozaluzanin C, Muricatin, Cynaropicrin, mary, Camellia, morin, Zingiber officinale, Myristica fra 13-Chloro-3,11-dihydroxy-4(15), 1014)-guaiadien-12,6- grams, Punica granatum, Zizyphus Joazeiro, Jabara, Aza olide, 3-Acetyl-13-chloro-13-deoxysolstitialin, Cynaroside dirachta indica, Acacia, olong tea, Juglans regia, A 8-Deoxy-11-hydroxy-13-chlorogrosheimin, Cynarascolo Zanthoxylum alantum, Mimusops elengi, Hibiscus abelmos side A Cynarascoloside 8, Cynarascoloside C, Cynarinin A, chus, yurvedic, Carapa procera, Khaya Senegalensis, Salva and Cynarinin 8 wherein the composition is adapted to dora persica, Cucurbitaceae (Citrullus Olocynthis), Acacia release atherapeutically effective amount of the ligand to one catechu, Acacia nilotica, Achyrathes aspera, Azadirachta or more regions of the intestine of a subject. indica, ristolochia bracteolate, Cinnamomum camphora, 0509. In another aspect, the compositions described Cinnamomum verum, Curcuna Zanga, ucalyptus globulus, herein comprise a bitter receptor ligand selected from Dena Ficus bengalensis, Juglans regia, Madhuca longifolia, Mimu tonium benzoate, Denatonium saccharide, glycyrrhizic acid Sops elengi, cinum sanctum, Oolonga tea, Piper betel leaves, ammonium salt, Epigallocatechin, Epigallocatechin gallate, Piper longum, Piper nigrum, Potentilla ulgens, Syzygium hyperforin, coptisine chloride, allyl methyl sulfide, rotterlin, curcumin, elagic acid and embelin wherein the composition aromaticum, Spilanthes calva, Vaccinium macrocarpon, Zan is adapted to release a therapeutically effective amount of the thoxylum rmatum, and mixtures thereof ligand to one or more regions of the intestine of a Subject. 0517. In another aspect, the compositions described 0510. In another aspect, the compositions described herein comprise a bitter receptor ligand comprising an herb herein comprise a bitter receptor ligand comprising is a quer selected from Asparagus, Gossypium, Foeniculum, Lepi cetin-rich apple peel extract (QAE) or a triterpene-rich apple dium, Chlorophytum, Ipomoea, Withania and Leptadenia. In peel extract (TAE) wherein the composition is adapted to Some embodiments, a bitter receptor ligand is an herb release atherapeutically effective amount of the ligand to one selected Asparagus racemosus, Gossypium arboretum (her or more regions of the intestine of a subject. baceum), Foeniculum vulgare, Lepidium sativum, Chloro 0511. In another aspect, the compositions described phytum borivilianum, Ipomoea digitata, Withania somnifera herein comprise a bitter receptor ligand comprising an extract and Leptadenia reticulate wherein the composition is adapted selected from Artemisia absinthium, Acer tegmentosum to release a therapeutically effective amount of the ligand to Maxim, Crinum asiaticum and Ganoderma Lucidum wherein one or more regions of the intestine of a subject. the composition is adapted to release a therapeutically effec 0518. In another aspect, the compositions described tive amount of the ligand to one or more regions of the herein comprise a bitter receptor ligand comprising a mixture intestine of a Subject. of extracts selected from Emblica officinalis, Tinospora 0512. In another aspect, the compositions described cordifolia, Embelia basaal, Cyperus rotunduns, Asparagus herein comprise a bitter receptor ligand comprising an extract racemosus and Lepidium sativum wherein the composition is selected from fruit of Vitis vinifera, fruit of Emblica officina adapted to release a therapeutically effective amount of the lis, fruit of Phoenix dactylifera, any part of Cichorium inty ligand to one or more regions of the intestine of a subject. bus, haulm of Andrographis paniculata and haulm of Phyl 0519 In another aspect, the compositions described lantus amarus wherein the composition is adapted to release herein comprise a bitter receptor ligand comprising a mixture atherapeutically effective amount of the ligand to one or more of extracts selected from Acanthopanax sessiliflorum, Cervi regions of the intestine of a subject. cornu, garlic, Cassia tora L., Rehmannia glutinosa, Cornus 0513. In another aspect, the compositions described officinalis, Ganoderma lucidum, Schizandra chinensis Baill, herein comprise a bitter receptor ligand comprising an extract Zizyphus jujuba Var and Chinese yam wherein the composi selected from Andrographis paniculata, Curcuna longa, tion is adapted to release atherapeutically effective amount of Glycyrrhiza glabra and Terminalia chebula wherein the com the ligand to one or more regions of the intestine of a Subject. position is adapted to release a therapeutically effective 0520. In another aspect, the compositions described amount of the ligand to one or more regions of the intestine of herein comprise a bitter receptor ligand comprising a juice, a subject. oil, puree, or extract of Morinda citrifolia wherein the com 0514. In another aspect, the compositions described position is adapted to release a therapeutically effective herein comprise a bitter receptor ligand comprising an extract amount of the ligand to one or more regions of the intestine of of olive leaves wherein the composition is adapted to release a Subject. US 2015/0265555 A1 Sep. 24, 2015
0521. In another aspect, the compositions described 0532. In another aspect, the compositions described herein comprisea bitter receptor ligand is selected from the herein comprise a bitter receptor ligand comprising an extract group consisting of isoxanthohumol. Xanthohumol, chlor of Colocasia antiquorum varstems wherein the composition pheniramine, dapsone, diphenidol, falcarindiol, helicon, sac is adapted to release a therapeutically effective amount of the charin, cromolyn, cnicin, crispolide, hydrocortisone and ligand to one or more regions of the intestine of a subject. orphenadrine wherein the composition is adapted to release a 0533. In another aspect, the compositions described therapeutically effective amount of the ligand to one or more herein comprise a bitter receptor ligand comprising an extract regions of the intestine of a subject. of a plant of the Scophulariaceae family wherein the compo 0522. In another aspect, the compositions described sition is adapted to release a therapeutically effective amount herein comprise a bitter receptor ligand comprising an extract of the ligand to one or more regions of the intestine of a of Coptidis Rhizoma, Pharbitidis Semen or mixtures thereof Subject. wherein the composition is adapted to release a therapeuti 0534. In another aspect, the compositions described cally effective amount of the ligand to one or more regions of herein comprise a bitter receptor ligand comprising bitter the intestine of a subject. buckwheat powder wherein the composition is adapted to 0523. In another aspect, the compositions described release atherapeutically effective amount of the ligand to one herein comprise a bitter receptor ligand comprising an extract or more regions of the intestine of a Subject. of Muscari comosum, Aloe Vera barbadensis, or mixtures 0535 In another aspect, the compositions described thereof wherein the composition is adapted to release a thera herein comprise a bitter receptor ligand comprising an extract peutically effective amount of the ligand to one or more selected from Chrysanthemum zawadski, Artemisia capillar regions of the intestine of a subject. ies, and Maitake mushroom wherein the composition is 0524. In another aspect, the compositions described adapted to release a therapeutically effective amount of the herein comprise a bitter receptor ligand comprising an extract ligand to one or more regions of the intestine of a subject. of dried Du-Zhong leaves (Eucommia ulmoides) wherein the 0536. In another aspect, the compositions described composition is adapted to release a therapeutically effective herein comprise a bitter receptor ligand comprising Makkoli amount of the ligand to one or more regions of the intestine of wherein the composition is adapted to release a therapeuti a subject. cally effective amount of the ligand to one or more regions of 0525. In another aspect, the compositions described herein comprise a bitter receptor ligand comprising an extract the intestine of a subject. of Auklandia (Costus Root) wherein the composition is 0537. In another aspect, the compositions described adapted to release a therapeutically effective amount of the herein comprise a bitter receptor ligand comprising an extract ligand to one or more regions of the intestine of a Subject. of Momordica charantia or Sohporae tonkinesis radix 0526 In another aspect, the compositions described wherein the composition is adapted to release a therapeuti herein comprise a bitter receptor ligand comprising an extract cally effective amount of the ligand to one or more regions of of a plant of genus Hemerocallis wherein the composition is the intestine of a subject. adapted to release a therapeutically effective amount of the 0538. In another aspect, the compositions described ligand to one or more regions of the intestine of a Subject. herein comprise a bitter receptor ligand comprising an extract 0527. In another aspect, the compositions described of Guarana, Paraguay, Kola, Buchu, Vervain, Damiana and herein comprise a bitter receptor ligand comprising a hop Ginseng wherein the composition is adapted to release a extract from cones of hop plants of the genus Humulus therapeutically effective amount of the ligand to one or more wherein the composition is adapted to release a therapeuti regions of the intestine of a subject. cally effective amount of the ligand to one or more regions of 0539. In another aspect, the compositions described the intestine of a subject. herein comprise a bitter receptor ligand comprising an extract 0528. In another aspect, the compositions described of bitter melon, Sesame seed lignans and mixtures thereof herein comprise a bitter receptor ligand comprising deox wherein the composition is adapted to release a therapeuti ynojirimycin, fagomine or combinations thereof wherein the cally effective amount of the ligand to one or more regions of composition is adapted to release a therapeutically effective the intestine of a subject. amount of the ligand to one or more regions of the intestine of 0540. In another aspect, the compositions described a subject. herein comprise a bitter receptor ligand comprising an extract 0529. In another aspect, the compositions described of fenugreek seeds wherein the composition is adapted to herein comprise a bitter receptor ligand comprising pterostil release atherapeutically effective amount of the ligand to one bene wherein the composition is adapted to release a thera or more regions of the intestine of a Subject. peutically effective amount of the ligand to one or more 0541. In another aspect, the compositions described regions of the intestine of a subject. herein comprise a bitter receptor ligand comprising an extract 0530. In another aspect, the compositions described of fenugreek seeds wherein the composition is adapted to herein comprise a bitter receptor ligand comprising an extract release atherapeutically effective amount of the ligand to one of black pepper, cumin, ginger, turmeric, cinnamon, rose hip or more regions of the intestine of a Subject. and Saffron wherein the composition is adapted to release a 0542. In another aspect, the compositions described therapeutically effective amount of the ligand to one or more herein comprise a bitter receptor ligand comprising a humu regions of the intestine of a subject. lone wherein the composition is adapted to release a thera 0531. In another aspect, the compositions described peutically effective amount of the ligand to one or more herein comprise a bitter receptor ligand comprising an extract regions of the intestine of a subject. of a plant of genus Gynostemma wherein the composition is 0543. In another aspect, the compositions described adapted to release a therapeutically effective amount of the herein comprise a bitter receptor ligand comprising an extract ligand to one or more regions of the intestine of a Subject. from a plant used in Ayurvedic medicine wherein the compo US 2015/0265555 A1 Sep. 24, 2015 62 sition is adapted to release a therapeutically effective amount ments, the chemosensory receptor enhancer is an umami of the ligand to one or more regions of the intestine of a receptor enhancer that enhances the effect of food on umami Subject. receptors in the intestine. 0544. In another aspect, the compositions described 0551 Also provided herein are compositions comprising herein comprise a bitter receptor ligand comprising agmatine bitter receptor ligands that further comprise one or more wherein the composition is adapted to release a therapeuti chemosensory receptor ligands is selected from a Sweet cally effective amount of the ligand to one or more regions of receptor ligand, an umami receptor ligand, a fat receptor the intestine of a subject. ligand, a bile acid receptor ligand, or any combination 0545. In another aspect, the compositions described thereof. In some embodiments, the composition futher com herein comprise a bitter receptor ligand comprising met prises a Sweet receptor ligand. In other embodiments, the forminor salt thereof wherein the composition is adapted to composition futher comprises an umami receptor ligand. In release atherapeutically effective amount of the ligand to one other embodiments, the composition futher comprises a or more regions of the intestine of a subject. In a further Sweet receptor ligand and an umami receptor ligand. aspect, the compositions described herein comprise a met 0552 Sweet receptor ligands include glucose, sucralose, forminor salt thereof wherein the composition is adapted to aspartame, Stevioside, Rebaudioside, Neotame, acesulfame release atherapeutically effective amount of the metforminor K, and saccharin. Umami receptor ligands include glutamate salt thereof to one or more regions of the intestine of a subject. salts, glutamines, acetylglycines, or aspartame. Fat receptor In some embodiments, the metformin Salt is metformin ligands include linoleic acids, oleic acids, palmitates, ole hydrochloride. In other embodiments, the therapeutically oylethanolamides, mixed fatty acid emulsion, omega-3 fatty effective amount of metforminor salt thereof is about 1 mg to acids and N-acylphosphatidylethanolamine (NAPE). Sour about 2000 mg. In yet other embodiments, the therapeutically receptor ligands include citric acid and hydroxycitric acid. effective amount of metformin or salt thereof is about 10 mg Bile acids include deoxycholic acids, taurocholic acids and to about 1500 mg. In further embodiments, the therapeuti chenodeoxycholic acids. In certain embodiments, the cally effective amount of metforminor salt thereof is about 50 chemosensory receptor ligand is nonmetabolized. In certain mg to about 1000 mg. In yet further embodiments, the thera embodiments, the chemosensory receptor ligand is an ago peutically effective amount of metformin or salt thereof is nist. In certain embodiments, the chemosensory receptor about 100 mg to about 500 mg. In other embodiments, the ligand is an enhancer. composition further comprises a DPP-IV inhibitor. 0553. The compositions described herein can be formu 0546. In some embodiments, the compositions described lated with an enteric coating. In some embodiments, the com herein are adapted to release a therapeutically effective position has an enteric coating. In another aspect, the com amount of a bitter receptor ligand to one or more regions of positions described herein can be formulated with a modified the intestine. In some embodiments, the compositions release system. In yet another aspect, the compositions described herein further release at least some of the bitter described herein can be formulated with a timed release sys receptor ligand in the stomach. In certain instances, the com tem. In a further aspect, the compositions described herein positions release about 10%, about 20%, about 30%, about can beformulated with a modified release and enteric coating. 40%, about 50%, about 60%, about 70%, about 80% or about In yet a further aspect, the compositions described herein can 90% bitter receptor ligand in the stomach. be formulated with a timed release and enteric coating. 0547. In some embodiments, the compositions are 0554 Provided herein is a method of treating a condition adapted to release in the duodenum, jejunum, ileum, caecum, associated with a chemosensory receptor in a subject com colon and/or rectum. In other embodiments, the compositions prising administering a composition described herein to the are adapted to release in the jejunum, ileum, caecum, colon Subject. In one aspect, the composition comprises a bitter and/or rectum. In some embodiments, the composition is receptor ligand selected from any of the compounds previ formulated for release in the lower intestine. In further ously described herein to the subject and wherein the com embodiments, the composition is formulated for release in the position is adapted to release a therapeutically effective upper intestine. In still further embodiments, the composition amount of a bitter receptor ligand to one or more regions of is formulated for release in the upper intestine and lower the gastrointestinal tract. intestine. 0555 Provided herein is a method of treating a condition associated with a chemosensory receptor in a Subject by 0548. In one embodiment, a composition releases a bitter administering a composition comprising at least two bitter receptor ligand at an onset of about 5 to about 45 minutes, receptor ligands to the Subject. about 105 to about 135 minutes, about 165 to about 195 minutes or about 225 to about 255 minutes, or a combination 0556 Provided herein is a method of treating a condition of times thereof following oral administration to a subject. associated with a chemosensory receptor in a Subject by administering a composition comprising at least one bitter 0549. In other embodiments, a composition releases a bit receptor ligand and a cognate metabolite. In some embodi ter receptor ligand at an onset of about pH 5.0, about pH 5.5, ments, the metabolite is administered after the administration about pH 6.0, about pH 6.5, about pH 7.0, or combination of the bitter receptor ligand. In another embodiment, the thereof following oral administration to a Subject. metabolite is co-administered with the bitter receptor ligand. 0550 Also provided herein are compositions comprising In further embodiments, the bitter receptor ligand is co-ad bitter receptor ligands that further comprise a chemosensory ministered with the ingestion of food by the subject or the receptor enhancer selected from the group consisting of a bitter ligand is administered before the subject ingests food. Sweet receptor enhancer, a bitter receptor enhancer, an umami In certain instances, food itself may comprise one or more receptor enhancer, a fat receptor enhancer, a Sour receptor bitter receptor ligands. In certain instances, food itself may enhancer and abile acid receptor enhancer. In certain embodi serve as a metabolite. US 2015/0265555 A1 Sep. 24, 2015
0557. Provided herein is a method of treating a condition one or more bitter receptor ligand compositions that has an associated with a chemosensory receptor by administering a onset of release at about pH 5.5, about pH 6.0, about pH 6.5. composition having at least one bitter receptor ligand to the and/or about pH 7.0. lower intestine of a subject. In another embodiment, the com 0562 Provided herein is a method of treating a condition position comprising at least one bitter receptor ligand is associated with a chemosensory receptor by administering administered to the upper intestine of a subject. In yet another one or more compositions having at least one bitter receptor embodiment, the composition comprising at least one bitter ligand wherein the compositions release at an onset of two receptor ligand is administered to the upper intestine and different pH ranges, wherein said two pH ranges are selected lower intestine of a subject. In certain instances, bitter recep from about pH 5.0 to about pH 6.0, about pH 6.0 to about pH torligand in the upper intestine and lower intestine is the same 7.0 and about pH 7.0 to about pH 8.0. bitter receptor ligand. In certain instances, a bitter receptor 0563 Provided herein are methods of modulating circu ligand in the upper intestine and lower intestine are different lating concentrations of one or more hormones, including but chemosensory receptor ligands. not limited to GLP-1, GLP-2, GIP, oxyntomodulin, PYY. 0558 Provided herein is a method of treating a condition CCK, glycentin, insulin, glucagon, ghrelin, amylin, insulin, associated with a chemosensory receptor by administering a C-peptide and uroguanylin, by administering a composition composition having at least one bitter receptor ligand to the comprising at least one bitter ligand described herein to a duodenum, jejunum, ileum, caecum, colon and/or rectum. In subject. Provided herein are methods of modulating the hor other embodiments, the composition comprising at least one monal profile of lower intestine by administering a composi bitter receptor ligand is administered to the duodenum of a tion having at least one bitter receptor ligand to the lower subject. In another embodiment, the composition comprising intestine of a subject. In one embodiment, the hormonal pro at least one bitter receptor ligand is administered to the file is that of GLP-1, oxyntomodulin, and PYY. jejunum of a subject. In another embodiment, the composi 0564) Provided herein are methods of modulating the hor tion comprising at least one bitter receptor ligand is admin monal profile of upper intestine by administering a composi istered to the ileum of a subject. In another embodiment, the tion having at least one bitter receptor ligand to the upper composition comprising at least one bitter receptor ligand is intestine of a subject. In one embodiment, the hormonal pro administered to the caecum of a subject. In another embodi file is that of GLP-1, GLP-2, oxyntomodulin, PYY. GIP. ment, the composition comprising at least one bitter receptor C-peptide, glucagon, insulin, CCK, or any combination ligand is administered to the colon of a subject. In another thereof embodiment, the composition comprising at least one bitter 0565. Further provided herein are methods to sensitize receptor ligand is administered to the rectum of a subject. In lower intestinal chemosensory receptors by stimulating bitter another embodiment, the composition comprising at least one receptors in the upper intestine. bitter receptor ligand is administered to the duodenum, 0566 Provided herein are methods of treating conditions jejunum, ileum, caecum, colon and/or rectum of a subject. In associated with a chemosensory receptor with the composi yet another embodiment, the composition releases at least tions described herein. Conditions associated with a some of the bitter receptor ligand into the stomach. chemosensory receptor include metabolic syndrome, diabe 0559) Provided herein is a method of treating a condition tes type I, diabetes type II, obesity, binge eating, undesired associated with a chemosensory receptor by administering food cravings, food addiction, a desire to reduce food intake one or more bitter receptor ligand compositions that release at or to lose weight or maintain weight loss, desire to maintain an onset about 5 to about 45 minutes, about 105 to about 135 healthy weight, desire to maintain normal blood glucose minutes, about 165 to about 195 minutes, about 225 to about metabolism, anorexia, pre-diabetes, glucose intolerance, ges 255 minutes or a combination of times thereof following oral tational diabetes mellitus (GDM), impaired fasting glycemia administration to a subject. (IFG), post-prandial hyperglycemia, accelerated gastric emp 0560 Provided herein is a method of treating a condition tying, dumping syndrome, delayed gastric emptying, dyslipi associated with a chemosensory receptor by administering demia, post-prandial dyslipidemia, hyperlipidemia, hyper one or more bitter receptor ligand compositions that have an triglyceridemia, post hypertriglyceridemia, insulin onset of release at about 10 minutes, about 30 minutes, about resistance, bone loss disorders, osteopenia, osteoporosis, 120 minutes, about 180 minutes, about 240 minutes or a muscle wasting disease, muscle degenerative disorders, poly combination of times thereof following oral administration to cystic ovary syndrome (PCOS), non-alcoholic fatty liver dis a subject. In one embodiment, the composition releases at an ease (NAFL), non-alcoholic steatohepatitis (NASH). onset of about 10 minutes following administration to a Sub immune disorders of the gut, (e.g., celiac disease), bowel ject. In one embodiment, the composition releases at an onset irregularity, irritable bowel syndrome (IBS), inflammatory of about 30 minutes following administration to a subject. In bowel disease (IBD), including, e.g., ulcerative colitis, one embodiment, the composition releases at an onset of Crohn's disease, short bowel syndrome and peripheral neur about 120 minutes following administration to a subject. In opathy, e.g., diabetic neuropathy. In some embodiments, the one embodiment, the composition releases at an onset of condition is obesity. In other embodiments, the condition is about 180 minutes following administration to a subject. In diabetes. In further embodiments, the subject has undergone one embodiment, the composition releases at an onset of bariatric surgery. In yet other embodiments, methods pro about 240 minutes following administration to a subject. In vided herein further include administering a drug for diabetes one embodiment, the composition releases at an onset of or obesity. about 10 minutes, 30 minutes, about 120 minutes, about 180 0567. In certain embodiments, the condition or disorder minutes and about 240 minutes following oral administration associated with a chemosensory receptor in is sadness, stress, to a subject. grief, anxiety, anxiety disorder (e.g., generalized anxiety dis 0561 Provided herein is a method of treating a condition order, obsessive-compulsive disorder, panic disorder, post associated with a chemosensory receptor by administering a traumatic stress disorder or social anxiety disorder or a mood US 2015/0265555 A1 Sep. 24, 2015 64 disorder (e.g., depression, bipolar disorder, dysthymic disor release component comprising metformin hydrochloride and der and cyclothymic disorder). In certain embodiments, the a pharmaceutically acceptable excipient; and (b) a pH 6.5 compositions described herein may be used for inducing feel enterically coated extended release component comprising ings of happiness, well-being or contentment. metformin hydrochloride and a pharmaceutically acceptable 0568 Additionally, the compositions described herein excipient; and wherein the combined amount of metformin may be used for the dietary management of the conditions from both components is less than 400 mg and wherein the associated with a chemosensory receptor listed above. For metformin has sub-therapeutic plasma AUC and sub-thera example, disorders such as frailty, anorexia, cachexia, loss of peutic plasma Cmax. lean body mass, food associated or food-induced nausea and 0580. In some embodiments, the proportion of metformin Vomiting, food allergies, food associated aversive reactions hydrochloride in the immediate release component to the may be treated with chemosensory receptor antagonists. metforminhydrochloride in the delayed release component is 0569. Also provided herein are methods for treating a about 20/80, 30/70, 35/65, 40/60, 45/55 or 50/50. In other disease, disorder or defect in energy homeostasis in a subject embodiments, the dosage form exhibits a dissolution release comprising administering a composition described herein. In profile of 20-50% amount of metformin hydrochloride in one aspect, the composition is adapted to release a therapeu about 30 to about 60 minutes after oral administration and tically effective amount of a bitter receptor ligand to one or 80-100% amount of metformin hydrochloride after 60 min more regions of the intestine. utes after oral administration. 0570 Also provided herein are methods for treating over 0581. In some embodiments, the sub-therapeutic plasma weight in a Subject comprising administering a composition AUC and Sub-therapeutic plasma Cmax resulting from described herein. In one aspect, the composition is adapted to administration of the dosage form is 50% or less than the release a therapeutically effective amount of a bitter receptor plasma AUC and Cmax resulting from administration of a ligand to one or more regions of the intestine. single dose of GLUMETZA 500 mg. 0571 Also provided herein are methods for treating obe 0582. In some embodiments, the dosage form further sity in a Subject comprising administering a composition comprises a DPP-IV inhibitor in (a), (b) or both. In other described herein. In one aspect, the composition is adapted to embodiments, the dosage form further comprises an antidia release a therapeutically effective amount of a bitter receptor betic or antiobesity agent. ligand to one or more regions of the intestine. 0583. In some embodiments, the dosage form further 0572 Also provided herein are methods for reducing food comprises (c) an immediate release component comprising intake in a subject comprising administering a composition metformin hydrochloride. In some instances, the (c) imme described herein. In one aspect, the composition is adapted to diate release component has a pH 5.0 enteric coating. In some release a therapeutically effective amount of a bitter receptor instances, the combined amount of metformin from compo ligand to one or more regions of the intestine. nents (a)-(c) is less than 600 mg. 0573 Also provided herein are methods for treating type 0584. In some embodiments, the excipient in the extended II diabetes in a Subject comprising administering a composi release component is selected from the group consisting of tion described herein. In one aspect, the composition is ethylcellulose, hydroxypropylmethylcellulose, hydroxypro adapted to release a therapeutically effective amount of a pylcellulose, polyvinylpyrrolidone, Xanthan gum, Sodium bitter receptor ligand to one or more regions of the intestine. alginate, polysorbate-80 and mixtures thereof 0574 Also provided herein are methods for maintaining 0585. In some embodiments, the combined amount of healthy body weight in a Subject comprising administering a metformin hydrochloride is about 250 mg. composition described herein. In one aspect, the composition 0586. In some embodiments, the dosage form is a bi-layer is adapted to release a therapeutically effective amount of a tablet. In other embodiments, the dosage form is a capsule bitter receptor ligand to one or more regions of the intestine. with the two components as encapsulated mini-tablets. 0575 Also provided herein are methods for treating pre 0587. Also provided herein are pharmaceutical dosage diabetes in a subject comprising administering a composition forms comprising (a) a pH 6.5 enterically coated immediate described herein. In one aspect, the composition is adapted to release component comprising metformin hydrochloride and release a therapeutically effective amount of a bitter receptor a pharmaceutically acceptable excipient; and (b) a pH 6.5 ligand to one or more regions of the intestine. enterically coated extended release component comprising 0576 Also provided herein are methods for increasing metformin hydrochloride and a pharmaceutically acceptable GLP-1 concentration in a Subject comprising administering a excipient; and wherein the metformin hydrochloride has composition described herein. In one aspect, the composition reduced average bioavailability. is adapted to release a therapeutically effective amount of a 0588. In some embodiments, the average bioavailability is bitter receptor ligand to one or more regions of the intestine. less than the average bioavailability of an immediate release 0577 Also provided herein are methods for increasing metformin formulation having an equivalent amount of met PYY concentration in a subject comprising administering a formin. In other embodiments, the average bioavailability is composition described herein. In one aspect, the composition less than 15%. is adapted to release a therapeutically effective amount of a 0589. In some embodiments, the combined amount of bitter receptor ligand to one or more regions of the intestine. metformin hydrochloride is less than 400 mg. 0578. In some embodiments of the methods provided herein, prior to administration of the composition, the Subject INCORPORATION BY REFERENCE is prescreened for endogenous chemosensory receptor levels 0590 All publications, patents, and patent applications and types for use in adjusting the amount of the composition mentioned in this specification are herein incorporated by for administration. reference to the same extent as if each individual publication, 0579. Also provided herein are pharmaceutical dosage patent, or patent application was specifically and individually forms comprising (a) a pH 6.5 enterically coated immediate indicated to be incorporated by reference. US 2015/0265555 A1 Sep. 24, 2015
BRIEF DESCRIPTION OF THE FIGURES Chemosensory Receptors 0591 FIG. 1 shows plasma hormone concentrations, PYY 0597 Mammalian chemosensory receptors and ligands (total) and GLP-1 (active) in response to gastric infusion of are discussed, e.g., in U.S. Pat. App. Pub. Nos. 2008/0306053 bitter receptor ligands. and 2008/0306093, both titled “Modulation of Chemosen sory Receptors and Ligands Associated Therewith and U.S. 0592 FIG. 2 shows L-cell index of the infusion of bitter Pat. No. 7,105,650, titled “T2R taste receptors and genes receptor ligands as compared to water control. encoding same. Complete or partial sequences of numerous human and other eukaryotic chemosensory receptors are cur DETAILED DESCRIPTION OF THE INVENTION rently known (see, e.g., Pilpel, Y. et al., Protein Science, 8:969 0593. The present invention relates to methods and com 77 (1999); Mombaerts, P., Annu. Rev. Neurosci., 22:487 50 positions for treating conditions associated with a chemosen (1999); EP0867508A2; U.S. Pat. No. 5,874,243: WO sory receptor, for example, metabolic conditions including 92/17585; WO95/18140; WO 97/17444; WO99/67282). obesity and diabetes, using a ligand or combination of ligands 0598 Sweet and Umami Receptors: In humans, different that stimulates chemosensory receptors present on cells lin combinations of the T1Rs, a family of class C G-protein ing the gut. Binding of ligand(s) to these chemosensory coupled receptors, respond to Sweet and umami taste stimuli. receptors modulates the synthesis, secretion and/or storage of T1R2 and T1 R3 reportedly recognize sweet tastestimuli. The hormones, e.g., GLP-1, GLP-2, oxyntomodulin, PYY. GIP. T1R subunits that comprise the heteromeric sweet and umami insulin, C-peptide, glycentin, glucagon, amylin, ghrelin, taste receptors are described by, e.g., Xu, et al., 2004, Proc uroguanylin and/or CCK that are key regulators of energy and Natl AcadSci USA 101: 14258-14263. Xu, et al., report that metabolic processes Such as glucose metabolism. The spe aspartame and neotame require the N-terminal extracellular cific hormone(s) produced vary depending on the receptor(s) domain of T1R2, G protein coupling requires the C-terminal stimulated. Chemosensory receptor ligands include receptor half of T1R2, and that cyclamate and lactisole, a sweet recep ligands that are metabolizable or can be metabolized as an tor inhibitor, require the transmembrane domain of T1R3. energy source, e.g. food or metabolites, as well as receptor Their results suggest the presence of multiple Sweetenerinter ligands that are nonmetabolized, e.g. tastants. Nonmetabo action sites on this receptor. lized chemosensory receptor ligands, as used herein, include 0599 T1R1 and T1R3 recognize umami taste stimulus ligands that are not Substantially metabolized, i.e., ligands L-glutamate. This response is reportedly enhanced by 5' ribo having insignificant caloric value. nucleotides (Xu, et al., 2004). 0600 Bitter Receptors: Bitter chemicals are detected by 0594. In some embodiments, one or more nonmetabolized around 50 T2R receptor (GPCR) family members (Adler et chemosensory receptor ligands are used to modulate the al., 2000, Cell 100:693-702: Chandrashekar et al., 2000, Cell secretion of hormone molecules and regulate metabolic pro 100:703-711; Matsunami et al., 2000, Nature 404:601-604). cesses. In other embodiments, a nonmetabolized chemosen Certain T2Rs and methods for expressing them are described sory receptor ligand(s) is combined with a metabolized or in, e.g., U.S. Pat. App. Pub. No. 2008/0306053 and U.S. Pat. metabolizable chemosensory receptor ligand(s). It is contem No. 7,105,650. Haplotypes of many of the bitter receptor have plated that the addition of one or more metabolized also been identified which confer differences in the sensitivity chemosensory receptor ligands along with activation of the of individuals to particular bitter tastant (Pronin et al., 2007, enteroendocrine cell chemosensory receptors by a nonme Current Biology 17(6): 1403-1408). tabolized chemosensory receptor ligand(s), may result in 0601 Bile Receptors: There are multiple bile acid recep enhanced stimulation of hormone release. tors. The bile acid receptor having subunits Gpbar1 and 0595. The present embodiments described herein addi M-Bar is reportedly involved in the influence of bile acids on tionally contemplate targeting administration of chemosen fat solubilization, cholesterol maintenance, and bile acid sory receptor ligands to specific sites throughout the gut. homeostasis (Maruyama, et al., 2006, J. Endocrinol. 191, Enteroendocrine cells, e.g., L cells, K cells, and I cells, that 197-205). Maruyama, et al., report a possible role for Gpbar each Secrete a different set of metabolic hormones in response in energy homeostasis. Kawamata, et al. (A G protein to chemosensory stimulation, occur throughout the length of coupled receptor responsive to bile acids' J. Biol. Chem. 278, the intestine. The concentrations and proportions of these 9435-9440, 2003), report a possible role for bile acid receptor enteroendocrine cell types are different in the various intes TGRS in the Suppression of macrophage function. tinal segments, and, as noted above, each cell type has a 0602 Sour and Salty Taste Receptors: A number of can different metabolic hormone expression profile. Targeted didate receptors and transduction mechanisms for sensing administration of the compositions of the invention to specific Sour and salty taste have been proposed (Miyamoto et al., intestinal segments, for example, through the use of formu 2000, Prog. Neurobiol. 62:135-157). For example, acid-sens lations designed for release within one or more desired seg ing ion channel-2 (ASIC2) is proposed to function as a Sour ments of the stomach and/or intestine, provides an additional receptor in the rat (Ugawa et al., 2003, J. Neurosci. 23:3616 level of control over the effect of such compositions, e.g., in 3622; Ugawa et al., 1998, Nature 395:555-556). HCN1 and the modulation of hormones involved in metabolism. HCN4, members of hyperpolarization-activated cyclic nucle 0596. The present embodiments described herein thus otide gated channels (HCNs) are also candidate sour receptor include a novel approach to treating important chemosensory channels (Stevens et al., 2001, Nature 413:631-635). Among receptor-associated conditions by, for example, modulating TRP channel families, members of the PKD family (polycys the secretion of metabolic hormones through enteroendocrine tic kidney disease, also called TRPP or polycystins) have chemosensory receptor activation. The embodiments further been reported to possess unique properties (Delmas et al., include the capability to select combination therapies tailored 2004, Biochem. Biophys. Res. Commun 322:1374-1383: to the specific needs of individuals having varying hormone Nauli and Zhou, 2004, Bioessays 26:844-856). Two TRP profiles. channel members, PKD1 L3 (Genbank Accession Nos. AY1 US 2015/0265555 A1 Sep. 24, 2015 66
64486, murine, nucleic acid, AAO32799 murine, amino acid, 687-698; Satiel, Cell 142(5): 672-674; also see Matsumura et AY164485, human, nucleic acid, and AAO32798, human, al., 2009, Neurosci Lett 450: 186-190). amino acid), and PKD2L1 (Genbank Accession Nos. NM 181422, murine, nucleic acid, NP 852087, murine, Hormones amino acid, NM 016112, human, nucleic acid and 0605. The embodiments described herein include compo NP 057 196, human, amino acid, are reportedly specifically sitions and methods for modulating the concentrations of expressed in a Subset of taste receptor cells that do not corre circulating enteroendocrine cell hormones, including, but not spond to bitter, Sweet or umami sensing cells. The proteins are limited to, GLP-1, GLP-2, GIP. Oxyntomodulin, PYY. CCK, localized at the apical tip of taste cells where tastants are glycentin, insulin, glucagon, C-peptide, ghrelin, amylin, detected. PKD1 L3 and PKD2L1 heteromer formation is uroguanylin, etc., such compositions and methods compris required for functional cell Surface expression and whenever ing administering at least one chemosensory receptor ligand PKD1 L3 and PKD2L1 are expressed in heterologous cells to a subject to treat a condition associated with a chemosen they are activated by sour solutions. Therefore, it is contem sory receptor. Hormone modulation can be achieved by plated PKD1 L3 and PKD2L1 function together as sour taste administering a composition comprising a chemosensory receptors in mammals, although an understanding of the receptor ligand, including an agonist, antagonist, modifier, mechanism is not necessary to practice the present invention enhancer or combination thereof acting on a Sweet-taste and the present invention is not limited to any particular receptor, an umami receptor, a bitter receptor, a fatty acid mechanism of action. receptor, and/or a bile acid receptor. 0606. In particular embodiments, a combination of one or 0603 Fat Receptors: Fat receptor or fatty acid receptor as more agonists of the Sweet, umami, bitter, free fatty acid, and used herein means any transporter receptor or other molecule bile acid receptors will simulate the synchronous release of that binds to fats and/or fatty acids that are ingested. important hormones and neural signals from the enteroendo Chemosensory receptors for fat have not been well charac crine cells and thus facilitate the assimilation and disposition terized, though there is possible involvement of fatty acid of meal nutrients. In additional embodiments, a combination transport proteins known to be present in the gastrointestinal of one or more agonists of the Sweet, umami, bitter, free fatty tract. The mouse fatty acid transporter protein CD36 has been acid, and bile acid receptors Suppresses ghrelin synthesis, reported to be a potential fat taste receptor (Laugerette, et al., activity or action, or its post-translational modification (Ghre 2005, “CD36 involvement in orosensory detection of dietary lin Octonoyl Acyl Transferase activity or GOAT) and/or ghre lipids, spontaneous fat preference, and digestive secretions.” lin secretion or release from oxyntic cells in the stomach. It is Journal of Clinical Investigation 115(11): 3177-84). In rat, important to note that some of these hormones may not CD36 has been found to be expressed at higher levels in exhibit major effects when administered alone but may per proximal than distal intestinal mucosa (Chen, et al., 2001, form additively and/or synergistically when released “Gut expression and regulation of FAT/CD36: possible role in together. For example, PYY 3-36 as a single therapy has fatty acid transport in rat enterocytes. Am J Physiol Endo disappointed in the clinic (Nastech Press Release). Therefore, crinol Metab. 281 (5):E916-23). More recently, a number of in embodiments the invention provides coordinate and Syn GPCRs which were previously classified as orphan receptors chronous release of guthormones in concert while not ascrib have been shown to respond to lipid ligands, including fatty ing a specific activity to merely a single hormone. Enteroen acids and several have been identified as candidates for fat docrine cell (e.g., L cells, K cells and I cells) stimulation by receptors in taste. nutrients reportedly alters release of one or more of the fol 0604. When a ligand binds to a GPCR, the receptor pre lowing known hormones: GLP-1, GLP-2, GIP. Oxyntomodu Sumably undergoes a conformational change leading to acti lin, PYY. CCK, insulin, glucagon, C-peptide, glycentin, ghre vation of the G Protein. G Proteins are comprised of three lin, amylin and uroguanylin. Nutrients may also alter release Subunits: a guanyl nucleotide binding a subunit, a B subunit, of yet-to-be-characterized hormones released from enteroen and a Y subunit. G Proteins cycle between two forms, depend docrine cells. This modulation in hormone release can result ing on whether GDP or GTP is bound to the a subunit. When in beneficial therapeutic effects, for example, better glucose GDP is bound, the G Protein exists as a heterotrimer: the control in the treatment of diabetes and related disorders GO?3y complex. When GTP is bound, the a subunit dissociates (prediabetes, polycystic ovary disease), inflammatory bowel from the heterotrimer, leaving a G|By complex. When a Golfy disorders, bowel damage and osteoporosis (e.g., through the complex operatively associates with an activated G Protein release of GLP-2), lowering of circulating lipids in the treat Coupled Receptor in a cell membrane, the rate of exchange of ment of hyperlipidemia, fatty liver disease, and reduced food GTP for bound GDP is increased and the rate of dissociation intake and the regulation of energy homeostasis in the treat of the bound Go. Subunit from the GCfBy complex increases. ment of obesity (weight loss). Administering a combination The free GC. subunit and Gfy complex are thus capable of of one or more agonists of the Sweet, umami, bitter, free fatty transmitting a signal to downstream elements of a variety of acid, and bile acid receptors components along with a DPP signal transduction pathways. These events form the basis for IV inhibitor can increase the therapeutic effect, since GLP-1. a multiplicity of different cell signaling phenomena, includ PYY. GLP-2 and GIP are rapidly eliminated by DPP-IV. ing for example the signaling phenomena that are identified as 0607. In vivo results consistent with the use of Sweet, neurological sensory perceptions such as taste and/or Smell. umami, free fatty acid, and bile acid receptors to increase (See, e.g., U.S. Pat. No. 5,691,188.) GP120, a GPCR corre GLP-1 concentrations include: sponding to an fatty acid receptor, has also been identified in 0608. The release of GLP-1 was reported during the taste buds of mice and, furthermore, omega-3 fatty acids intraduodenal glucose delivery in humans. (See, e.g., Kuo, et have been shown to mediate anti-inflammatory effects and al., 2008, “Transient, early release of glucagon-like peptide-1 reverse insulin resistance in obese mice via their actions on during low rates of intraduodenal glucose delivery. Regul GP120 present in macrophages (Oh et al., 2010, Cell 142(5): Pept 146, 1-3.) US 2015/0265555 A1 Sep. 24, 2015 67
0609. An increase in post-prandial GLP-1 levels was after administration of Stevia or rebaudioside A, both of observed after administration of the alpha-glucosidase inhibi which are nonmetabolized Sweeteners. Gregersen, S., et al., tor miglitol in humans. (See, e.g., Lee, et al., 2002, “The "Antihyperglycemic Effects of Stevioside in type 2 diabetic effects of miglitol on glucagon-like peptide-1 secretion and subjects.” 73 Metabolism, Vol 53, No 1 (January), 2004; pp appetite sensations in obese type 2 diabetics.” Diabetes Obes 73-76. Metab 4, 329-335.) 0619. Additionally, reports in humans or animals have 0610. In rats, the increase in GLP-1 after administration of Suggested that non-nutritive Sweeteners may not cause weight miglitol was synergistic with administration of a DPP-IV loss, and may even result in weight gain. See e.g., Maki, K.C., inhibitor (Goto et al., 2008, Poster P-470 ADA). et al., “Chronic consumption of rebaudioside A, a steviol 0611) Inulin-type fructans (non-digestible fructose poly glycoside, in men and women.” Food Chem Toxicol. 2008 mers) reportedly stimulated GLP-1 secretion. (See, e.g., July; 46 Suppl 7:S47-53. Epub 2008 May 16; Yang, Q. “Gain Delzenne, et al., 2007, "Modulation of glucagon-like peptide weight by going diet?” Artificial sweeteners and the neuro 1 and energy metabolism by inulin and oligofructose: experi biology of sugar cravings. Neuroscience 2010. Yale J Biol mental data. J Nutr 137, 2547S-2551S and Niness, et al., Med. 2010 June: 83(2):101-8; Ludwig, DS, “Artificially 1999, "Inulin and oligofructose: what are they?” J. Nutr 129, Sweetened beverages: cause for concern.” JAMA. 2009 Dec. 1402S-1406S.) 9; 302(22):2477-8); Richard Mattes. Effects of Aspartame 0612 Administration of glutamate, an umami agonist, to and Sucrose on Hunger and Energy Intake in Humans. Physi rats resulted in decreased weight gain and reduced abdominal ology & Behavior, Vol. 47, pp. 1037-1044. Effects of Aspar fat. (See, e.g., Kondoh, et al., 2008, “MSG intake suppresses tame and Sucrose on Hunger and Energy Intake in Humans. weight gain, fat deposition, and plasma leptin levels in male Sprague-Dawley rats.” Physiol Behav 95, 135-144.) Chemosensory Receptor Ligands 0613 Oral administration of free fatty acids to mice 0620 Chemosensory receptor ligands include metabo resulted in increased portal and systemic GLP-1 concentra lized chemosensory receptor ligands that can be metabolized tions. (See, e.g., Hirasawa, et al., 2005, "Free fatty acids as an energy source, e.g. food or metabolites, as well as regulate gut incretin glucagon-like peptide-1 secretion nonmetabolized chemosensory receptor ligands that are not through GPR120.” Nat Med 11, 90-94.) metabolized as an energy source, e.g. tastants. The term non 0614 G protein-coupled bile acid receptor 1 deficient metabolized chemosensory receptor ligands, as used herein, mice showed significantly higher fat accumulation and includes chemosensory receptor ligands that are metabolized Weight gain relative to control mice. (See, e.g., Maruyama, et to a small degree but are not metabolized substantially. That al., 2006, cited above.) is, nonmetabolized chemosensory receptor ligand includes 0615. In vivo studies with rat jejunum perfused with ligands that have insignificant caloric value. Chemosensory Sucralose and glutamate showed that sweet and umami recep receptor ligands include agonists, antagonists, modifiers, and tors regulate glucose, peptide and glutamate absorption. (See, enhancers as well as other compounds that modulate e.g., Mace, et al., 2008, “An energy supply network of nutri chemosensory receptors. Many chemosensory receptor ent absorption coordinated by calcium and T1R taste recep ligands are known in the art and have been reported in the tors in rat small intestine.JPhysiol.) literature. 0616) Bile acids provided to humans via rectal adminis 0621 Non-limiting examples of umami receptor ligands tration caused release of PYY. (See, e.g., Adrian, et al., 1993, include glutamate salts, glutamines, acetyl glycines, and "Deoxycholate is an important releaser of peptide YY and aspartame. An exemplary umami receptor ligand is glutamic enteroglucagon from the human colon.” Gut 34(9): 1219-24.) acid monophosphate. Umami receptor ligands are not limited 0617 While there are reports of metabolized ligands to the to ligands with intrinsic umami quality but also include Various chemosensory receptors having effects to release gut ligands reported to be enhancers which enhance the signal hormones, it has been reported that nonmetabolized from an umami ligand without having any discernable taste chemosensory receptor ligands may not effect gut hormone properties in their own right. Such ligands are IMP (inosine release. Frank Reimann. Molecular mechanisms underlying monophosphate), GMP (guanosine monophosphate) and the nutrient detection by incretin-secreting cells.” Int Dairy J. like. Many more umami receptor ligands other than those 2010 April: 2004): 236-242. doi:10.1016/j.idairyj.2009.11. listed herein and in the cited manuscripts, are known to those O14. of skill in the art, and still more can be identified using 0618. For example, instillation of sucralose (a nonmetabo methods known in the art and described herein. lized Sweetener) into the duodenum of humans reportedly had 0622. In some embodiments, an umami receptor ligand is no effect on gut hormone release while instillation of metabo selected from tastant or flavor compounds described herein or lized Sugars did. Ma J, et al., “Effect of the artificial sweet known in the art. ener. Sucralose, on gastric emptying and incretin hormone 0623 Non-limiting examples of fat receptor ligands release in healthy subjects.” CKAm J Physiol Gastrointest include linoleic acids, oleic acids, palmitates, oleoylethano Liver Physiol. 2009 April; 296(4):G735-9. Epub 2009 Feb. lamides, omega-3 fatty acids, mixed fatty acid emulsion, and 12. Other studies in rats reportedly showed no effect of the N-acylphosphatidylethanolamine (NAPE), myristoleic acid, nonmetabolized sweeteners, sucralose and stevia, to cause palmitoleic acid, alpha-linolinic acid, arachidonic acid, guthormone release, while dextrose did have an effect. Fujita eicosapentaenoic acid, erucic acid, and docosahexaenoic Y. et al., “Incretin Release from Gut is Acutely Enhanced by acid. Many more fat receptor ligands other than those listed Sugar but Not by Sweeteners In Vivo.” Am J Physiol Endo herein and in the cited manuscripts, are known to those of skill crinol Metab. 2008 Dec. 23. Epub ahead of print: Reimann in the art, and still more can be identified using methods F., et al., “Glucose sensing in L-cells: a primary cell study.” known in the art and described herein. Cell Metabolism. 2008; 8:532–539. Other reports in humans 0624 Bile acids include cholic acids, deoxycholic acids, reported no alterations of gut hormones in the circulation taurocholic acids and chenodeoxycholic acids. Many more US 2015/0265555 A1 Sep. 24, 2015
bile acid receptor ligands other than those listed herein and in charantia (bitter melon), and isothiocyanates. Certain bitter the cited manuscripts, are known to those of skill in the art, tastants are described, e.g., in Drewnowski and Gomez-Carn and still more can be identified using methods known in the eros, American Journal of Nutrition, 72 (6): 1424 (2000). art and described herein. Many more bitter receptor ligands other than those listed herein and in the cited manuscripts, are knownto those of skill 0625 Non-limiting bitter receptor ligands include fla in the art, and still more can be identified using methods Vanones, flavones, flavonols, flavans, phenolic flavonoids, known in the art and described herein. Exemplary bitter phy isoflavones, limonoid aglycones, glucosinolates or hydroly tonutrients in common plant foods that can be bitter receptor sis product thereof, caffeine, quinine, extracts of Momordica ligands are listed in the following table.
Phytonutrient class Typical component Taste quality Food source Phenolic compounds Flavanones Naringin Bitter Grapefruit, flavedo Grapefruit, albedo Grapefruit, pith Grapefruit, seeds Immature grapefruit Grapefruit juice Oroblanco juice Melogold juice Flavones Tangeretin Bitter Orange fruit Orange juice uice from concentrate Nobiletin Bitter Orange fruit Orange juice uice from concentrate Sinensetin Bitter Orange fruit Orange juice (fresh) uice from concentrate (frozen) uice from concentrate Pure juice Flavonols Quercetin Bitter Grapefruit juice Lemon juice Endive Fresh hops Wine Black tea infusion Oolong tea infusion Green tea infusion Flavans Catechin Bitter Red wine Green tea infusion Oolong tea infusion Black tea infusion Epicatechin Bitter Red wine Low-fat cocoa powder instant cocoa powder Green tea infusion Oolong tea infusion Black tea infusion Epicatechin gallate Bitter and Green tea infusion astringent Oolong tea infusion Black tea infusion Epigallocatechin Bitter with Sweet Green tea infusion aftertaste Oolong tea infusion Black tea infusion Epigallocatechin Bitter with Sweet Green tea infusion gallate aftertaste Oolong tea infusion Black tea infusion Phenolic flavonoids Catechin mono- and Bitter Red wine polymers MW <500 Rosé wine Catechin polymers Astringent Red wine MW >500 (tannins) Apple cider Polyphenols Astringent and Low-fat cocoa power bitter instant cocoa powder Isoflavones Genistein and Bitter or Soybeans daidzein astringent Toasted, defatted soy flakes Textured soy protein Breakfast patties Tofu Genistin Astringent Soy seeds Daidzin US 2015/0265555 A1 Sep. 24, 2015 69
-continued
Phytonutrient class Typical component Taste quality Food source Triterpenes Limonoid aglycones Limonin Bitter Lemon juice Orange juice Grapefruit juice Tangerine juice Grapefruit, flavedo Grapefruit, albedo Grapefruit, pith Grapefruit, seeds Nomilin Bitter Grapefruit juice Oroblanco juice Melogold juice Limonin glucoside Tasteless Grapefruit juice Lemon juice Organosulfur compounds
Glucosinolates Sinigrin Bitter Cabbage Brussels sprouts Cauliflower Turnip or Swede Calabrese Broccoli Collards Kale Mustard greens Progoitrin Bitter Brussels sprouts Cabbage Cauliflower Turnip or Swede Calabrese Glucobrassicin Bitter Brussels sprouts Hydrolysis product Goitrin 5-vinyl-2- Bitter Aqueous extract of of glucosinolates oxazolidine thione Brussels sprouts Cabbage, pith Cabbage, cambia cortex Cabbage, lea Isothiocyanates Allyl-isothiocyanate Acrid mustard Cabbage, pith oils; pungent or Cabbage, cambia lachrymatory cortex Cabbage, lea 3-Methyl Acrid mustard Cabbage, pith Sulfinylpropyl oils Cabbage, cambia isothiocyanate cortex Cabbage, lea Benzyl isothiocyanate Acrid mustard Cabbage, cambia oils; garlic-like cortex Cabbage, lea 4-Methylsulfinyl butyl Acrid mustard Cabbage, pith isothiocyanate oils Cabbage, cambia cortex Cabbage, lea Phenylethyl Acrid, irritant, Cabbage, pith isothiocyanate or lachrymatory Cabbage, cambia cortex Cabbage, lea
0626. In some embodiments, a bitter receptor ligand is 12/996,670 (published as U.S. 2011/0311991), U.S. Pat. No. selected from tastant or flavor compounds described herein or 7,811,788; U.S. application Ser. No. 1 1/182,942 (published known in the art. as U.S. 2006/0019346); U.S. application Ser. No. 12/993,542 0627. In some embodiments, a bitter receptor ligand is (published as U.S. 2011/0086138), U.S. application Ser. No. selected from compounds described in U.S. application Ser. 12/373.235 (published as U.S. 2010/0055209); International No. 12/593,479 (published as U.S. 2010/0130498); U.S. Application Ser. No. PCT/IL2007/000454 (published as WO application Ser. No. 12/593,398 (published as U.S. 2010/ 2007/116404); U.S. application Ser. No. 10/472,056 (pub 0184796); U.S. Pat. No. 7,829,299; U.S. application Ser. No. lished as U.S. 2004/0138189); U.S. Pat. No. 5,891,919; U.S. 1 1/578,013 (published as U.S. 2010/0056621): U.S. Pat. No. Pat. No. 6,376,657; U.S. application Ser. No. 1 1/554,982 7,416,867; U.S. application Ser. No. 1 1/455,693 (published (published as U.S. 2007/0104805); U.S. application Ser. No. as U.S. 2007/0037212); U.S. application Ser. No. 13/059,730 11/926,745 (published as U.S. 2008/0108604): International (published as U.S. 2011/0143376), U.S. application Ser. No. Application Ser. No. PCT/CA2009/001688 (published as US 2015/0265555 A1 Sep. 24, 2015 70
WO 2010/060198): U.S. application Ser. No. 12/735,557 -continued (published as U.S. 2010/0330205); International Application
Ser. No. PCT/CA2007/001066 (published as WO 2008/ 000063); U.S. application Ser. No. 11/438.204 (published as U.S. 2006/0269617); U.S. application Ser. No. 10/563,713 (published as U.S. 2006/0172020); U.S. application Ser. No. 10/902,352 (published as U.S. 2006/0024335); U.S. applica tion Ser. No. 10/538,038 (published as U.S. 2006/0275765), U.S. application Ser. No. 1 1/555,617 (published as U.S. 2008/0187936); U.S. application Ser. No. 12/739,264 (pub lished as U.S. 2010/0316736); U.S. application Ser. No. 12/215,609 (published as U.S. 2009/0042813); U.S. applica tion Ser. No. 1 1/893,088 (published as U.S. 2008/0050499); U.S. Pat. No. 7,807.204; U.S. application Ser. No. 1 1/811,166 (published as U.S. 2008/0003268): U.S. Pat. No. 6,376,657; International Application Ser. No. PCT/US2011/041 183 (published as WO 2011/163183); International Application Ser. No. PCT/EP2011/059814 (published as WO 2011/ 157692); U.S. application Ser. No. 12/790.292 (published as U.S. 2011/0293753); International Application Ser. No. PCT/ JP2009/071700 (published as WO 2010/076879); U.S. appli cation Ser. No. 13/032,530 (published as U.S. 2011/ 0217394); International Application Ser. No. PCT/EP2011/ 000110 (published as WO 2011/085979); International Application Ser. No. PCT/US2010/058467 (published as WO 2011/068814); U.S. application Ser. No. 13/060,996 (pub lished as U.S. 2011/0152361): U.S. Application Ser. No. 12/09,253 (published as U.S. 2011/0124609); U.S. applica tion Ser. No. 12/687.962 (published as U.S. 2011/01 19499); and International Application Ser. No. PCT/EP2010/004623 (published as WO 2011/012298); each of which are incorpo rated by reference in their entirety. 0628. In some embodiments, a bitter receptor ligand is selected from absinthine, artemorine, amorogentine, arglab ine, azathioprine, azepinone, benzoin, brucine, camphor, cas carillin, chlorhexidine, N,N'-diethylthiourea, herbolide A, isohumulone, noscapine, papaverine, parthenolide, picro toxinin, arborescine, or (-)-C-thujone, including but not lim ited to suitable derivatives. The structural formulae of these compounds are shown below,
US 2015/0265555 A1 Sep. 24, 2015 71
-continued wherein 0630 X is O or S; 0631 Y is selected from: N 0632 O-, S-, NH- and N-alkyl (including but not lim ited to C-Cs straight chain or branched chain alkyl, 2 N C-C, cycloalkyl, C-C alkylcycloalkyl); 0633 R and R are joined together to form: 0634 a cycloalkyl ring (which may either be substituted or unsubstituted), 0635 a heterocycloalkyl ring (which may either be sub O o1l stituted or unsubstituted), where the heterocycle con tains one or more hetero atoms selected from O, S, and N, HN NH 0636 an alicyclic system (which may either be substi tuted or unsubstituted), HN )-\ HN NH 0637 an aryl ring (which may either be substituted or unsubstituted), or )-\ N-( 0638 aheteroaryl ring (which may either be substituted or unsubstituted) where the heterocycle contains one or more hetero atoms selected from O, S, and N: 0639 R is selected from: 0640 H, 0641 OH, C 0642 O-alkyl (including but not limited to C-Cs straight chain or branched chain alkyl). 0643 O-cycloalkyl (including but not limited to C-C, cycloalkyl). 0644 O-alkylcycloalkyl (including but not limited to C-C alkylcycloalkyl). 0.645 O-acyl (including but not limited to esters, thioesters), 0646 C-C straight chain or branched chain alkyl (in cluding but not limited to hetero substituted alkyl chains S with oxygen, silicon, Sulphur and Substituted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), 1N 1N 0647 C-C straight chain or branched chain alkenyl H H (including but not limited to hetero substituted alkyl chains with oxygen, silicon, Sulphur and Substituted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, N NO NHalkyl), 0648 C-C straight chain or branched chain alkynyl (including but not limited to hetero substituted alkyl CC OH. chains with oxygen, silicon, Sulphur and Substituted o alkyl chains with OH, Oalkyl, SH, Salkyl, NH, H NHalkyl), N1S-N 0649) C-C, cycloalkyl, IX 0650 C-C heterocycloalkyl, where the heterocycle 4N contains one or two hetero atoms selected from O, S, and N 0629. In other embodiments, a bitter receptor ligand is 0651 C-C alkylcycloalkyl, selected from a compounds structurally related to absinthine, 0652 C-C alkylheterocycloalkyl, where the hetero arglabine, arborescine, artemorine, noscapine, or partheno cycle contains one or two hetero atoms selected from O, lide having the structural Formula I: S, and N and in the case of the presence of NH in the heterocyclic ring, the nitrogen atom may be in the form of an amide, carbamate or urea,
(I) 0653 aryl (including but not limited to phenyl, substi tuted phenyl, naphthyl, Substituted naphthyl), 0654 alkylaryl (including but not limited to alkylphe nyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubsti tuted naphthyl), 0655 heteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thia zolyl, diazolyl pyrazolyl, triazolyl all of which may either unsubstituted or substituted), US 2015/0265555 A1 Sep. 24, 2015 72
0656 alkylheteroaryl (including but not limited to -continued pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isox azolyl, diazolyl pyrazolyl, triazolyl all of which may either unsubstituted or substituted); and 0657 wherein the bond adjacent to R is a single or a double bond. 0658. In some embodiments, a bitter receptor ligand is selected from andrographolide, antazoline, amorogentine, artemorine, berberine chloride, brucine, camphor, and cascar illin, including but not limited to suitable derivatives. The structural formulae of these compounds are shown below,
O
Ho O
O
OH
O
OH
O O O 0659. In other embodiments, a bitter receptor ligand is
ulu OH selected from a compound having a structural Formula II:
(II)
wherein 0660 X is O or S: 0661 Y is selected from: 0662 O-, S-, NH- and N-alkyl (including but not lim ited to C-Cs straight chain or branched chain alkyl, C-C cycloalkyl, Ca-Cs alkylcycloalkyl); 0663 Z is CRR in each instance wherein the bond adja cent to (Z), is a single or a double bond; 0664 R is selected from: 0665 H, 0.666 OH, 0667 O-alkyl (including but not limited to C-Cs straight chain or branched chain alkyl). 0668 O-cycloalkyl (including but not limited to C-C, cycloalkyl). US 2015/0265555 A1 Sep. 24, 2015
0669 O-alkylcycloalkyl (including but not limited to 0690 R is in each instance independently selected from: C-Cs alkylcycloalkyl). (0691 halogen, NO, CN, OR, NRR, COOR, 0670 O-acyl (including but not limited to esters, CONRR, NRCORs, NRCONRR, NRSOA, thioesters), COR SONRR, OOCR, CRROH, ROH and A: 0692 R. R. R. and R, are each independently selected 0671 C-C straight chain or branched chain alkyl (in from: cluding but not limited to hetero substituted alkyl chains 0693 H, with oxygen, silicon, Sulphur and Substituted alkyl 0694 C-C straight chain or branched chain alkyl (in chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), cluding but not limited to hetero substituted alkyl chains 0672 C-C straight chain or branched chain alkenyl with oxygen, silicon, Sulphur and Substituted alkyl (including but not limited to hetero substituted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), chains with oxygen, silicon, Sulphur and Substituted 0695 C-C straight chain or branched chain alkenyl alkyl chains with OH, Oalkyl, SH, Salkyl, NH, (including but not limited to hetero substituted alkyl NHalkyl), chains with oxygen, silicon, Sulphur and Substituted 0673 C-C, cycloalkyl, alkyl chains with OH, Oalkyl, SH, Salkyl, NH, 0674 C-C heterocycloalkyl, where the heterocycle NHalkyl), contains one or two hetero atoms selected from O, S, and 0696 C-C straight chain or branched chain alkynyl N, (including but not limited to hetero substituted alkyl 0675 C-C alkylcycloalkyl, chains with oxygen, silicon, Sulphur and Substituted 0676 C-C alkylheterocycloalkyl, where the hetero alkyl chains with OH, Oalkyl, SH, Salkyl, NH, cycle contains one or two hetero atoms selected from O, NHalkyl), S, and N and in the case of the presence of NH in the (0697 C-C cycloalkyl, heterocyclic ring, the nitrogen atom may be in the form 0.698 an alicyclic system, of an amide, carbamate or urea; 0.699) C-C, heterocycloalkyl, where the heterocycle 0677 R is selected from: contains one or two hetero atoms selected from O, S, and 0678 C-C straight chain or branched chain alkyl (in N cluding but not limited to hetero substituted alkyl chains 0700 C-C alkylcycloalkyl, with oxygen, silicon, Sulphur and Substituted alkyl 0701 C-C alkylheterocycloalkyl, where the hetero chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), cycle contains one or two hetero atoms selected from O, S, and N and in the case of the presence of NH in the 0679) C-C straight chain or branched chain alkenyl heterocyclic ring, the nitrogen atom may be in the form (including but not limited to hetero substituted alkyl of an amide, carbamate or urea, chains with oxygen, silicon, Sulphur and Substituted 0702 aryl (including but not limited to phenyl, substi alkyl chains with OH, Oalkyl, SH, Salkyl, NH, tuted phenyl, naphthyl, Substituted naphthyl), NHalkyl), 0703 alkylaryl (including but not limited to alkylphe 0680 C-C straight chain or branched chain alkynyl nyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubsti (including but not limited to hetero substituted alkyl tuted naphthyl), chains with oxygen, silicon, Sulphur and Substituted 0704 heteroaryl (including but not limited to pyridyl, alkyl chains with OH, Oalkyl, SH, Salkyl, NH, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thia NHalkyl), zolyl, diazolyl pyrazolyl, triazolyl all of which may 0681 C-C cycloalkyl, either unsubstituted or substituted), 0682 an alicyclic system, 0705 alkylheteroaryl (including but not limited to 0683 C-C, heterocycloalkyl, where the heterocycle pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isox contains one or two hetero atoms selected from O, S, and azolyl, diazolyl pyrazolyl, triazolyl all of which may N either unsubstituted or substituted); 0684 C-C alkylcycloalkyl, 0706 or wherein, in some embodiments R and R, are 0685 C-C alkylheterocycloalkyl, where the hetero joined together to form a substituted or unsubstituted het cycle contains one or two hetero atoms selected from O, eroaryl or a substituted or unsubstituted heterocycloalkyl S, and N and in the case of the presence of NH in the system; heterocyclic ring, the nitrogen atom may be in the form 0707 A is selected from: 0708 O-alkyl (including but not limited to C-Cs of an amide, carbamate or urea, straight chain or branched chain alkyl). 0686 aryl (including but not limited to phenyl, substi 0709 O-cycloalkyl (including but not limited to C-C, tuted phenyl, naphthyl, Substituted naphthyl), cycloalkyl). 0687 alkylaryl (including but not limited to alkylphe 0710 O-alkylcycloalkyl (including but not limited to nyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubsti C-Cs alkylcycloalkyl). tuted naphthyl), 0711 O-acyl (including but not limited to esters, 0688 heteroaryl (including but not limited to pyridyl, thioesters), furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thia 0712 C-C straight chain or branched chain alkynyl Zolyl, diazolyl pyrazolyl, triazolyl all of which may (including but not limited to hetero substituted alkyl either unsubstituted or substituted), chains with oxygen, silicon, Sulphur and Substituted 0689 alkylheteroaryl (including but not limited to alkyl chains with OH, Oalkyl, SH, Salkyl, NH, pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isox NHalkyl), azolyl, diazolyl pyrazolyl, triazolyl all of which may 0713 C-C cycloalkyl, either unsubstituted or substituted); 0714 an alicyclic system, US 2015/0265555 A1 Sep. 24, 2015 74
0715 C-C, heterocycloalkyl, where the heterocycle -continued contains one or two hetero atoms selected from O, S, and N, 0716 C-C alkylcycloalkyl, 0717 C-C alkylheterocycloalkyl, where the hetero cycle contains one or two hetero atoms selected from O, S, and N and in the case of the presence of NH in the heterocyclic ring, the nitrogen atom may be in the form of an amide, carbamate or urea, 0718 aryl (including but not limited to phenyl, substi tuted phenyl, naphthyl, Substituted naphthyl), 0719 alkylaryl (including but not limited to alkylphe nyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubsti tuted naphthyl), 0720 heteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thia Zolyl, diazolyl pyrazolyl, triazolyl all of which may 0725. In some embodiments, a bitter receptor ligand is selected from 1.8-naphthaldehyde acid, 1-naphthoic acid, either unsubstituted or substituted), and 1-nitronaphthalene, picrotin, picrotoxinin, piperonylic acid, 0721 alkylheteroaryl (including but not limited to Sodium benzoate, (-)-C-thujone, parthenolide, herbolide A, pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isox herbolide D acetate, hydroxyl-8C.-parthenolide, pseudo-art azolyl, diazolyl pyrazolyl, triazolyl all of which may absine, including but not limited to suitable derivatives. The either unsubstituted or substituted); structural formulae of these compounds are shown below, 0722 m is an integer from 0 to 4; and 0723 n is an integer from 1 to 5. 0724. In some embodiments, a bitter receptor ligand is
selected from the following structures: US 2015/0265555 A1 Sep. 24, 2015
-continued 0746 C-C alkylheterocycloalkyl, where the hetero a. OH YY cycle contains one or two hetero atoms selected from O. 2. S. and N and in the case of the presence of NH in the heterocyclic ring, the nitrogen atom may be in the form of an amide, carbamate or urea, 0747 aryl (including but not limited to phenyl, substi tuted phenyl, naphthyl, substituted naphthyl), 0748 alkylaryl (including but not limited to alkylphe nyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubsti tuted naphthyl), 0749 heteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thia 0726. In other embodiments, a bitter receptor ligand is zolyl, diazolyl, pyrazolyl, triazolyl all of which may selected from a compound having a structural Formula III: either unsubstituted or substituted), and (0750 alkylheteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isox (III) azolyl, diazolyl pyrazolyl, triazolyl all of which may O O YR1. either unsubstituted or substituted); (0751 or R and R, and/or R and R can be joined R2 together in some embodiments to form: 0752 a 3-10 membered cyclic ring (which may either be substituted or unsubstituted), R3 0753 a 5-6 membered aryl ring (which may either be substituted or unsubstituted), R4 0754 a 3-10 membered heterocyclic ring (which may either be substituted or unsubstituted) where the hetero wherein cycle contains one or two hetero atoms selected from O, 0727 R is selected from: S, and N, or 0728 H, 0755 a 5-6 membered heteroaryl ring (which may or 0729) C-C straight chain or branched chain alkyl, may not be substituted) where the heterocycle contains (0730 C-C, cycloalkyl, one or two hetero atoms selected from O, S, and N. (0731 C-C alkylcycloalkyl, and 0756. In other embodiments, a bitter receptor ligand is 0732 M wherein M is a cation (including but not lim ited to Li", Na', K", NH, Ba, Ca", Mg" and Al"): selected from a compound having a structural Formula VI: (0733 R. R. and Ra are independently selected from:
0734 H, (IV) 0735, OH, (0736 O-alkyl (including but not limited to C-Cs straight chain or branched chain alkyl). (0737 O-cycloalkyl (including but not limited to C-C, cycloalkyl). (0738) O-alkylcycloalkyl (including but not limited to C-Cs alkylcycloalkyl). (0739 O-acyl (including but not limited to esters, thioesters), 0740 C-C straight chain or branched chain alkyl (in cluding but not limited to hetero substituted alkyl chains wherein R is selected from: with oxygen, silicon, sulphur and substituted alkyl (0757 acyl (including but not limited to esters, chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl). thioesters), (0741 C-Co straight chain or branched chain alkenyl 0758 C-C straight chain or branched chain alkyl (in (including but not limited to hetero substituted alkyl cluding but not limited to hetero substituted alkyl chains chains with oxygen, silicon, Sulphur and substituted with oxygen, silicon, Sulphur and substituted alkyl alkyl chains with OH, Oalkyl, SH, Salkyl, NH, chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl). NHalkyl). (0759) C-Co straight chain or branched chain alkenyl 0742 C-C straight chain or branched chain alkynyl (including but not limited to hetero substituted alkyl (including but not limited to hetero substituted alkyl chains with oxygen, silicon, Sulphur and substituted chains with oxygen, silicon, Sulphur and substituted alkyl chains with OH, Oalkyl, SH, Salkyl, NH. alkyl chains with OH, Oalkyl, SH, Salkyl, NH2, NHalkyl). NHalkyl). 0760 an alicyclic system, 0743 C-C, cycloalkyl, 0761 C-C straight chain or branched chain alkynyl (0744 C-C heterocycloalkyl, where the heterocycle (including but not limited to hetero substituted alkyl contains one or two hetero atoms selected from O, S, and chains with oxygen, silicon, Sulphur and substituted N alkyl chains with OH, Oalkyl, SH, Salkyl, NH2, 0745 C-C alkylcycloalkyl, NHalkyl). US 2015/0265555 A1 Sep. 24, 2015 76
0762 C-C, cycloalkyl, -continued
0763 C-C heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N,
0764 C-C alkylcycloalkyl,
0765 C-C alkylheterocycloalkyl, where the hetero cycle contains one or two hetero atoms selected from O, S, and N and in the case of the presence of NH in the heterocyclic ring, the nitrogen atom may be in the form of an amide, carbamate or urea, HO 0766 aryl (including but not limited to phenyl, substi tuted phenyl, naphthyl, Substituted naphthyl), HO, 0767 alkylaryl (including but not limited to alkylphe nyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubsti tuted naphthyl), 0768 heteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thia Zolyl, diazolyl pyrazolyl, triazolyl all of which may either unsubstituted or substituted), and 0769 alkylheteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isox azolyl, diazolyl pyrazolyl, triazolyl all of which may either unsubstituted or substituted).
0770. In some instances, a compound of Formula IV is selected from the following structures: US 2015/0265555 A1 Sep. 24, 2015
0771. In other embodiments, a bitter receptor ligand is zolyl, diazolyl pyrazolyl, triazolyl all of which may selected from a compound having a structural Formula V: either unsubstituted or substituted), and 0794 alkylheteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isox (V) azolyl, diazolyl pyrazolyl, triazolyl all of which may either unsubstituted or substituted). NH 0795. In other embodiments, a bitter receptor ligand is selected from a compound having a structural Formula VI:
R1 H 1s. s (VI) S wherein (0772 R is selected from: R4 ls (0773 H, 0774 OH, 0775 O-alkyl (including but not limited to C-C, straight chain or branched chain alkyl). 0776 O-cycloalkyl (including but not limited to C-C, wherein cycloalkyl). 0796 R. R. and R are each independently selected 0777 O-alkylcycloalkyl (including but not limited to from: C-C alkylcycloalkyl). 0778 O-acyl (including but not limited to esters, 0797 H, thioesters), 0798 C-C straight chain or branched chain alkyl (in 0779 SH, cluding but not limited to hetero substituted alkyl chains 0780 S-alkyl (including but not limited to C-Cs with oxygen, silicon, Sulphur and Substituted alkyl straight chain or branched chain alkyl). chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), 0781 S-cycloalkyl (including but not limited to C-C, 0799) C-C straight chain or branched chain alkenyl cycloalkyl). (including but not limited to hetero substituted alkyl 0782 S-alkylcycloalkyl (including but not limited to chains with oxygen, silicon, Sulphur and Substituted C-C alkylcycloalkyl). alkyl chains with OH, Oalkyl, SH, Salkyl, NH, 0783) S-acyl (including but not limited to esters, NHalkyl), thioesters), 0784 C-C straight chain or branched chain alkyl (in 0800 C-C straight chain or branched chain alkynyl cluding but not limited to hetero substituted alkyl chains (including but not limited to hetero substituted alkyl with oxygen, silicon, Sulphur and Substituted alkyl chains with oxygen, silicon, Sulphur and Substituted chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), alkyl chains with OH, Oalkyl, SH, Salkyl, NH, 0785 C-C straight chain or branched chain alkenyl NHalkyl), (including but not limited to hetero substituted alkyl 0801 C-C, cycloalkyl, chains with oxygen, silicon, Sulphur and Substituted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, 0802 C-C heterocycloalkyl, where the heterocycle NHalkyl), contains one or two hetero atoms selected from O, S, and 0786 C-C straight chain or branched chain alkynyl N, (including but not limited to hetero substituted alkyl 0803 C-C alkylcycloalkyl, chains with oxygen, silicon, Sulphur and Substituted 0804 C-C alkylheterocycloalkyl, where the hetero alkyl chains with OH, Oalkyl, SH, Salkyl, NH, cycle contains one or two hetero atoms selected from O, NHalkyl), S, and N and in the case of the presence of NH in the 0787 C-C, cycloalkyl, heterocyclic ring, the nitrogen atom may be in the form 0788 C-C heterocycloalkyl, where the heterocycle of an amide, carbamate or urea, contains one or two hetero atoms selected from O, S, and N, 0805 aryl (including but not limited to phenyl, substi 0789 C-C alkylcycloalkyl, tuted phenyl, naphthyl, Substituted naphthyl), 0790 C-C alkylheterocycloalkyl, where the hetero 0806 alkylaryl (including but not limited to alkylphe cycle contains one or two hetero atoms selected from O, nyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubsti S, and N and in the case of the presence of NH in the tuted naphthyl), heterocyclic ring, the nitrogen atom may be in the form of an amide, carbamate or urea, 0807 heteroaryl (including but not limited to pyridyl, 0791 aryl (including but not limited to phenyl, substi furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thia tuted phenyl, naphthyl, Substituted naphthyl), zolyl, diazolyl pyrazolyl, triazolyl all of which may 0792 alkylaryl (including but not limited to alkylphe either unsubstituted or substituted), and nyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubsti 0808 alkylheteroaryl (including but not limited to tuted naphthyl), pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isox 0793 heteroaryl (including but not limited to pyridyl, azolyl, diazolyl pyrazolyl, triazolyl all of which may furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thia either unsubstituted or substituted). US 2015/0265555 A1 Sep. 24, 2015 78
0809. In other embodiments, a bitter receptor ligand is -continued selected from a compound having a structural Formula VII:
O (VII) O HO O O
HO O O O y O R3 NR1. 21 \ O OH wherein OH 0810 R and R are independently selected from: OH
0811 H, OH 0812 CO-alkyl (including but not limited to C-C, straight chain or branched chain alkyl). 0813 CO-cycloalkyl (including but not limited to C-C cycloalkyl). O HO O 0814 CO-alkylcycloalkyl (including but not limited to C-Cs alkylcycloalkyl). HO O O 0815 CO-aryl (including but not limited to alkyl phe nyl, alkyl substituted phenyl, alkyl naphthyl, alkyl sub HO stituted naphthyl), O O O OH 0816 CO-alkylaryl (including but not limited to alkyl phenyl, alkyl Substituted phenyl, alkyl naphthyl, alkyl 21 O Substituted naphthyl), and 0817 CO-alkenylaryl (including but not limited to alk enyl phenyl, alkenyl Substituted phenyl, alkenyl naph thyl, alkenyl Substituted naphthyl, cinnamoyl, couma- OH OH royl, caffeoyl, ferruloyl). 0818. In some instances, a compound of Formula VII is OH OH selected from the following structures:
O
O HO O
HO O O O O O O O 21 \ O OH 21 \ O OH OMe OMe
OH
OH US 2015/0265555 A1 Sep. 24, 2015 79
-continued continued O
HO How How HO 1n 1a
OH
O O O O OMe 1N 1N
0820. In other embodiments, a bitter receptor ligand is selected from a compound having a structural Formula VIII:
(VIII)
OH wherein OMe 0821 RandR are residues independently selected from: H HO 0822 OH 0823 beta-Glc, 0824 beta-Glc-beta-Glc(2->1), 0825 beta-Glcbeta-Glc(3->1)-beta-Glc(2->1), 0826 beta-Glc-alpha-Rha(2->1), 0827 beta-Glcbeta-Glc(3->1)-alpha-Rha(2-> 1), and 0828 beta-Glcbeta-Glc(3->1)-alpha-Xyl(2-> 1); and 0829 wherein Glc is glucose, Rha is rhamnose and Xyl is Xylose. 0830. In other embodiments, a bitter receptor ligand is selected from a compound having a structural Formula XI:
(IX) R4 N R1 0819. In some instances, a bitter receptor ligand is selected 21 from the following structures: Sa R3 N R2,
wherein 0831 R. R. R. and Ra are each independently selected from HO HO 0832 H, 0833 OH, J. " 0834 O-alkyl (including but not limited to C-Cs straight chain or branched chain alkyl). US 2015/0265555 A1 Sep. 24, 2015
0835 O-cycloalkyl (including but not limited to C-C, 0855. In some instances, a compound of Formula IX is cycloalkyl). selected from the following structures: 0836 O-alkylcycloalkyl (including but not limited to C-Cs alkylcycloalkyl). 0837 O-acyl (including but not limited to esters, thioesters), 0838 acyl (including but not limited to carboxylic acids, aldehydes, ketones, esters, thioesters), 0839) C-C straight chain or branched chain alkyl (in cluding but not limited to hetero substituted alkyl chains with oxygen, silicon, Sulphur and Substituted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), 0840 C-C straight chain or branched chain alkenyl (including but not limited to hetero substituted alkyl chains with oxygen, silicon, Sulphur and Substituted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), 0841 C-C straight chain or branched chain alkynyl (including but not limited to hetero substituted alkyl chains with oxygen, silicon, Sulphur and Substituted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), 0842 C-C, cycloalkyl, 0843 C-C heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N, 0844 C-C alkylcycloalkyl, 0845 C-C alkylheterocycloalkyl, where the hetero cycle contains one or two hetero atoms selected from O, S, and N and in the case of the presence of NH in the heterocyclic ring, the nitrogen atom may be in the form of an amide, carbamate or urea, 0846 aryl (including but not limited to phenyl, substi tuted phenyl, naphthyl, Substituted naphthyl), 0847 alkylaryl (including but not limited to alkylphe nyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubsti tuted naphthyl), 0848 heteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thia Zolyl, diazolyl pyrazolyl, triazolyl all of which may either unsubstituted or substituted), and 0849 alkylheteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isox azolyl, diazolyl pyrazolyl, triazolyl all of which may either unsubstituted or substituted); 0850 or RandR or RandR are joined together in some embodiments to form: 0851 a 3-10 membered cyclic ring (which may either be substituted or unsubstituted), 0852 a 5-6 membered aryl ring (which may either be substituted or unsubstituted), 0853 a 3-10 membered heterocyclic ring (which may either be substituted or unsubstituted) where the hetero cycle contains one or two hetero atoms selected from O, S, and N, or 0854 a 5-6 membered heteroaryl ring (which may or may not be substituted) where the heterocycle contains one or two hetero atoms selected from O, S, and N. US 2015/0265555 A1 Sep. 24, 2015 81
-continued -continued N N N N' NH
N1 N s O lulu2 2N N- 2N 0857. In other embodiments, a bitter receptor ligand is S selected from a compound having a structural Formula X: (X) O
R1 J3. N NN N
N N N N1 N N1 N O u-2N
2 N 2 N R2 wherein tr 'c's - 0858. R. RandR are each independently selected from: 0859 H, 0860 C-C straight chain or branched chain alkyl, 0861 C-C, cycloalkyl, and 0862 C-C alkylcycloalkyl. 0863. In some instances, a compound of Formula X is selected from the following structures: N N N 2 2 O O
NN N HN N
O N O N
O O H / NN N NN N
O J2N N O J-2N N
0864. In other embodiments, a bitter receptor ligand is selected from a compound having a structural Formula XI: (XI)
0856 In some instances, a bitter receptor ligand is selected from the following structures: US 2015/0265555 A1 Sep. 24, 2015 82 wherein 0888. In some instances, a compound of Formula XI is 0865 R. R. R. R. and Rs are independently selected selected from the following structures: from: 0866 H,
0867 OH, 0868 O-alkyl (including but not limited to C-Cs straight chain or branched chain alkyl). 0869 O-cycloalkyl (including but not limited to C-C, cycloalkyl). 0870 O-alkylcycloalkyl (including but not limited to C-C alkylcycloalkyl). 0871 O-acyl (including but not limited to esters, thioesters), 0872 C-C straight chain or branched chain alkyl (in cluding but not limited to hetero substituted alkyl chains with oxygen, silicon, Sulphur and Substituted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), 0873 C-C straight chain or branched chain alkenyl (including but not limited to hetero substituted alkyl chains with oxygen, silicon, Sulphur and Substituted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), 0874 C-C straight chain or branched chain alkynyl (including but not limited to hetero substituted alkyl chains with oxygen, silicon, Sulphur and Substituted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), 0875 C-C, cycloalkyl, 0876 C-C heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N, 0877 C-C alkylcycloalkyl, 0878 C-C alkylheterocycloalkyl, where the hetero cycle contains one or two hetero atoms selected from O, S, and N and in the case of the presence of NH in the heterocyclic ring, the nitrogen atom may be in the form of an amide, carbamate or urea, 0879 aryl (including but not limited to phenyl, substi tuted phenyl, naphthyl, Substituted naphthyl), 0880 alkylaryl (including but not limited to alkylphe nyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubsti tuted naphthyl), 0881 heteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thia Zolyl, diazolyl pyrazolyl, triazolyl all of which may either unsubstituted or substituted), and 0882 alkylheteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isox azolyl, diazolyl pyrazolyl, triazolyl all of which may either unsubstituted or substituted); and 0883 X is selected from: 0884 O, 0885 S, 0886 NH, and 0887 NR, where R is C-C straight chain or branched chain alkyl (including but not limited to hetero substi tuted alkyl chains with oxygen, silicon, Sulphur and substituted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl). US 2015/0265555 A1 Sep. 24, 2015 83
-continued -continued
US 2015/0265555 A1 Sep. 24, 2015 84
0889. In some instances, a bitter receptor ligand is selected 0897 O-acyl (including but not limited to esters, from the following structures: thioesters), 0898 C-C straight chain or branched chain alkyl (in cluding but not limited to hetero substituted alkyl chains with oxygen, silicon, Sulphur and Substituted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), 0899) C-C straight chain or branched chain alkenyl (including but not limited to hetero substituted alkyl HO chains with oxygen, silicon, Sulphur and Substituted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), 0900 C-C straight chain or branched chain alkynyl HO (including but not limited to hetero substituted alkyl chains with oxygen, silicon, Sulphur and Substituted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), (0901 C-C, cycloalkyl, 0902 C-C heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N, 0903 C-C alkylcycloalkyl, 0904 C-C alkylheterocycloalkyl, where the hetero cycle contains one or two hetero atoms selected from O, HO S, and N and in the case of the presence of NH in the heterocyclic ring, the nitrogen atom may be in the form of an amide, carbamate or urea, HO 0905 aryl (including but not limited to phenyl, substi tuted phenyl, naphthyl, Substituted naphthyl), 0906 alkylaryl (including but not limited to alkylphe nyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubsti tuted naphthyl), 0907 heteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thia zolyl, diazolyl pyrazolyl, triazolyl all of which may 0890. In other embodiments, a bitter receptor ligand is either unsubstituted or substituted), and selected from a compound having a structural Formula XII: 0908 alkylheteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isox azolyl, diazolyl pyrazolyl, triazolyl all of which may (XII) either unsubstituted or substituted); (0909 with the proviso that 0910 when one of R and R is substituted the other of R and R must be hydrogen, 0911 or R and R combine to represent a carbonyl (C=O) group, a thiocarbonyl (C=S) group, an imino (C—NH) group or a substituted imino C=NR) group: (0912 and wherein the bond adjacent to R, may be a either a single CC bond or a double CC bond. 0913. In some instances, a compound of Formula XII is selected from the following structures:
wherein 0891 R. R. R. R. R. R. and R, are each indepen dently selected from: 0892 H, 0893 OH, (0894 O-alkyl (including but not limited to C-C, straight chain or branched chain alkyl). 0895 O-cycloalkyl (including but not limited to C-C, cycloalkyl). 0896 O-alkylcycloalkyl (including but not limited to C-Cs alkylcycloalkyl). US 2015/0265555 A1 Sep. 24, 2015 85
-continued -continued
US 2015/0265555 A1 Sep. 24, 2015 86
-continued -continued
0914. In other embodiments, a bitter receptor ligand is selected from a compound having a structural Formula XIII:
(XIII) R1 H R4 N N R5
X r R3In 1 R2 R6
O
H N R7 Y s
wherein 0915 R and R are independently selected from: 0916 H, (0917 C-C straight chain or branched chain alkyl, 0918 C-C, cycloalkyl, and 0919) C-C alkylcycloalkyl: 0920 X and Y are independently is selected from: 0921 O, and 0922 S; 0923. R. R. and Rs are independently selected from: 0924 C-C straight chain or branched chain alkyl, 0925 C-C, cycloalkyl, 0926 C-C alkylcycloalkyl, and 0927 aryl (including but not limited to phenyl, substi
tuted phenyl, naphthyl, substituted naphthyl); 0928 R is selected from: 0929 H, 0930 OH, 0931 O-alkyl (including but not limited to C-Cs straight chain or branched chain alkyl). 0932 O-cycloalkyl (including but not limited to C-C, cycloalkyl), and 0933 O-alkylcycloalkyl (including but not limited to C-C alkylcycloalkyl, 0934 R is selected from: 0935 C7-C straight chain or branched chain alkyl, 0936 C-C straight chain or branched chain alkenyl, and 0937 C7-C straight chain or branched chain alkynyl. US 2015/0265555 A1 Sep. 24, 2015 87
0938. In some instances, a compound of Formula XIII is 0945 combinations of 6-deoxy carbohydrate residues, selected from the following structures: and/or 2,6-dideoxy carbohydrate residues, and/or glu cose residues; (0946 R is selected from: 0947 H, 0948 C-C straight chain or branched chain alkyl (in cluding but not limited to hetero substituted alkyl chains with oxygen, silicon, Sulphur and Substituted alkyl chains with OH, O-alkyl, SH, S-alkyl, NH, NH-alkyl). gro (0949) C-C, cycloalkyl, 0950 C-C heterocycloalkyl, where the heterocycle O contains one or two hetero atoms selected from O, S, and N, H N 0951 C-C alkylcycloalkyl, 0952 C-C alkylheterocycloalkyl, where the hetero cycle contains one or two hetero atoms selected from O, r S, and N 0953 aryl (including but not limited to phenyl, substi tuted phenyl, naphthyl, Substituted naphthyl), 0954 alkylaryl (including but not limited to alkylphe nyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubsti Cr-O tuted naphthyl), 0955 heteroaryl (including but not limited to pyridyl, No furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thia zolyl, diazolyl pyrazolyl, triazolyl all of which may either unsubstituted or substituted), O / ( 0956 alkyl heteroaryl (including but not limited to (CH2)4 / pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isox azolyl, diazolyl pyrazolyl, triazolyl all of which may O either unsubstituted or substituted), 0957 tigloyl, 0958 aroyl (including substituted and unsubstituted 0939. In other embodiments, a bitter receptor ligand is benzoyl), and selected from a compound having a structural Formula XIV: 0959 alkoyl (including any organic ester); and 0960 R is selected from: (XIV) 0961 C-C straight chain or branched chain alkyl (in cluding but not limited to hetero substituted alkyl chains with oxygen, silicon, Sulphur and Substituted alkyl chains with OH, O-alkyl, SH, S-alkyl, NH, NH-alkyl). 0962 C-C, cycloalkyl, 0963 C-C heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N, 0964 C-C alkylcycloalkyl, 0965 C-C alkylheterocycloalkyl, where the hetero cycle contains one or two hetero atoms selected from O, wherein S, and N), 0940 R is selected from: 0966 and wherein the dotted lines indicate the optional 0941 H, presence of either a C4-C5 double bond or a C5-C6 0942 one or more 6-deoxy carbohydrate residues, double bond (i.e., standard steroidal ring nomenclature). 0943 one or more 2,6-dideoxy carbohydrate residues, 0967. In some instances, a compound of Formula XIV is 0944 one or more glucose residues, and selected from the following structures: O
N O
HO OH MeO OH OMe OMe US 2015/0265555 A1 Sep. 24, 2015 88
-continued
HO O
O O O OM e OH O
MeO O O O O OH O O O HO
MeO O O O O OH O O O OMe
HO O O O O OH O O O OMe O
MeO O O O O OH O O O OH MeO US 2015/0265555 A1 Sep. 24, 2015 89
-continued
O
O N O
MeO O O O O O O O O OH OMe O OMe OMe OMe
0968. In some instances, a bitter receptor ligand is a pino- 0977 CO-alkenylaryl (including but not limited to alk lenic acid. In certain instances, the pinolenic acid has the enyl phenyl, alkenyl Substituted phenyl, alkenyl naph following structure: thyl, alkenyl Substituted naphthyl, cinnamoyl, couma royl, caffeoyl, ferruloyl). 0978. In some instances, a compound of Formula XV is selected from the following structures: 1N1\-1 Y-1 Y-1N 1\-1Noo
0969. In other embodiments, a bitter receptor ligand is selected from a compound having a structural Formula XV:
(XV)
OH wherein OH OH 0970) R, R and R are independently selected from:
0971 H, 0972 CO-alkyl (including but not limited to C-Cs straight chain or branched chain alkyl). 0973 CO-cycloalkyl (including but not limited to C-C, cycloalkyl). 0974 CO-alkylcycloalkyl (including but not limited to C-C alkylcycloalkyl). N N 0975 CO-aryl (including but not limited to alkyl phe nyl, alkyl substituted phenyl, alkyl naphthyl, alkyl sub stituted naphthyl), 0976 CO-alkylaryl (including but not limited to alkyl OMe OH phenyl, alkyl Substituted phenyl, alkyl naphthyl, alkyl OH OMe Substituted naphthyl), and US 2015/0265555 A1 Sep. 24, 2015 90
-continued -continued COOH HO COOH
HO OH
OH HO O O O OH 21 O
S
OH OH
OH OH COOH OMe. HO OH OMe
0979. In other instances, a compound of Formula XV is O O O selected from the following structures: 21 \ O OH
OMe COOH OMe HO OH OH COOH O O HO OH O 21 \ O O O OH O 21 \ O OH
OH OMe OH
OH COOH COOH HO OH HO OH HO COOH
O O O O HO OH O OH 21 \ 21 O O OH O
OH OH
OH OH OH US 2015/0265555 A1 Sep. 24, 2015
-continued zolyl, diazolyl pyrazolyl, triazolyl all of which may HO either unsubstituted or substituted), OH 0996 alkyl heteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isox HOOC O OMe azolyl, diazolyl pyrazolyl, triazolyl all of which may either unsubstituted or substituted), HO O \ OH 0997 CO-alkyl (including but not limited to C-C, straight chain or branched chain alkyl). OH 0998 CO-alkenyl (including but not limited to C-C, straight chain or branched chain alkenyl containing OMe. between 1 and 5 double bonds), HO 0999 CO-cycloalkyl (including but not limited to C-C, cycloalkyl). HOOC 1000 CO-alkylcycloalkyl (including but not limited to C-C alkylcycloalkyl). O HO HO 1001 CO-aryl (including but not limited to alkyl phe O nyl, alkyl substituted phenyl, alkyl naphthyl, alkyl sub stituted naphthyl), 1002 CO-alkylaryl (including but not limited to alkyl 0980. In other embodiments, a bitter receptor ligand is phenyl, alkyl substituted phenyl, alkyl naphthyl, alkyl selected from a compound having a structural Formula XVI: substituted naphthyl), and 1003 CO-alkenylaryl (including but not limited to alk enyl phenyl, alkenyl substituted phenyl, alkenyl naph (XVI) thyl, alkenyl substituted naphthyl, cinnamoyl couma royl, caffeoyl, ferruloyl); 1004 and wherein the bond adjacent to the heterocyclic ring may be a single or a double bond. 1005. In other embodiments, a bitter receptor ligand is selected from a compound having a structural Formula XVII:
(XVII) wherein 0981 X is selected from: 0982) O, 0983 S, 0984 NH, and 0985 NR where R is C-C straight chain or branched chain alkyl, C-C, cycloalkyl, Ca-Co alkylcycloalkyl or CO-alkyl (including but not limited to C-Co straight wherein chain or branched chain alkyl); and 1006 X is selected from: 0986 R and R are each independently selected from: 1007 O, 0987) H, 1008 S. 0988 C-C straight chain or branched chain alkyl (in 1009 NH, and cluding but not limited to hetero substituted alkyl chains 1010 NR where R is C-C straight chain or branched with oxygen, silicon, sulphur and substituted alkyl chain alkyl, C-C, cycloalkyl, Ca-Co alkylcycloalkyl or chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl). CO-alkyl (including but not limited to C to Co straight 0989) C-C, cycloalkyl, chain or branched chain alkyl); 0990 C-C heterocycloalkyl, where the heterocycle 1011 Y is selected from: contains one or two hetero atoms selected from O, S, and 1012 CHO, N, 1013 COOH, and 0991 C-C alkylcycloalkyl, 1014 COOZ where Z is C-Co straight chain or 0992 C-C alkylheterocycloalkyl, where the hetero branched chain alkyl, C-C cycloalkyl, Ca-Co alkylcy cycle contains one or two hetero atoms selected from O. cloalkyl or CO-alkyl (including but not limited to C to S, and N, Co straight chain or branched chain alkyl); and 0993) aryl (including but not limited to phenyl, substi 1015 R is selected from: tuted phenyl, naphthyl, substituted naphthyl), 1016 H, 0994) alkylaryl (including but not limited to alkylphe 1017 C-C straight chain or branched chain alkyl (in nyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubsti cluding but not limited to hetero substituted alkyl chains tuted naphthyl), with oxygen, silicon, Sulphur and substituted alkyl 0995 heteroaryl (including but not limited to pyridyl, chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl). furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thia 1018 C-C, cycloalkyl, US 2015/0265555 A1 Sep. 24, 2015 92
1019 C-C heterocycloalkyl, where the heterocycle -continued contains one or two hetero atoms selected from O, S, and N 1020 C-C alkylcycloalkyl, 1021 C-C alkylheterocycloalkyl, where the hetero cycle contains one or two hetero atoms selected from O, S, and N, 1022 aryl (including but not limited to phenyl, substi tuted phenyl, naphthyl, Substituted naphthyl), 1023 alkylaryl (including but not limited to alkylphe nyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubsti tuted naphthyl), 1024 heteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thia Zolyl, diazolyl pyrazolyl, triazolyl all of which may either unsubstituted or substituted), 1025 alkyl heteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isox azolyl, diazolyl pyrazolyl, triazolyl all of which may either unsubstituted or substituted), 1026 CO-alkyl (including but not limited to C to C. straight chain or branched chain alkyl). 1027 CO-alkenyl (including but not limited to C to C. Straight chain or branched chain alkenyl containing between 1 and 5 double bonds), 1028 CO-cycloalkyl (including but not limited to C-C cycloalkyl). 1029 CO-alkylcycloalkyl (including but not limited to C-Cs alkylcycloalkyl). 1030 CO-aryl (including but not limited to alkyl phe nyl, alkyl substituted phenyl, alkyl naphthyl, alkyl sub stituted naphthyl), 1031 CO-alkylaryl (including but not limited to alkyl phenyl, alkyl Substituted phenyl, alkyl naphthyl, alkyl Substituted naphthyl), and 1032 CO-alkenylaryl (including but not limited to alk enyl phenyl, alkenyl Substituted phenyl, alkenyl naph thyl, alkenyl Substituted naphthyl, cinnamoyl, couma royl, caffeoyl, ferruloyl); and 1033 wherein the bond adjacent to the heterocyclic ring may be a single or a double bond. 1034. In some instances, a compound of Formula XVI or XVII is selected from the following structures: US 2015/0265555 A1 Sep. 24, 2015 93
-continued (XVIII)
wherein 1036 X is selected from any suitable organic or inorganic species capable of being an anion, including but not limited to: 1037 F. 1038 Cl, 1039 Br, 1040 Acetate, and 104.1 Sulphate: 1042 or 1043 X is an internal Zwitterion when R is H; 1044 R is selected from: 1045 H, 1046 C-C straight chain or branched chain alkyl (in cluding but not limited to hetero substituted alkyl chains
with oxygen, silicon, Sulphur and substituted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl). 1047 C-C, cycloalkyl, 1048 C-C heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N, 1049 Ca-Co alkylcycloalkyl. 1050 C-C alkylheterocycloalkyl, where the hetero cycle contains one or two hetero atoms selected from O. S, and N, 1051 aryl (including but not limited to phenyl, substi tuted phenyl, naphthyl, substituted naphthyl), 1052 alkylaryl (including but not limited to alkylphe nyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubsti tuted naphthyl), 1053 heteroaryl (including but not limited to pyridyl. furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thia zolyl, diazolyl pyrazolyl, triazolyl all of which may either unsubstituted or substituted), and 1054) alkyl heteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isox azolyl, diazolyl pyrazolyl, triazolyl all of which may either unsubstituted or substituted); and 1055 R is selected from: 1056 C-C straight chain or branched chain alkyl (in cluding but not limited to hetero substituted alkyl chains with oxygen, silicon, Sulphur and substituted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl). 1057 C-C, cycloalkyl, 1058 C-C heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N 1059 C-C alkylcycloalkyl, and 1035. In other embodiments, a bitter receptor ligand is 1060 C-C alkylheterocycloalkyl, where the hetero selected from a compound having a structural Formula cycle contains one or two hetero atoms selected from O, XVIII: S, and N. US 2015/0265555 A1 Sep. 24, 2015 94
1061. In some instances, a compound of Formula XVIII is wherein selected from the following structures: 1063 R. RandR are each independently selected from: 1064 H, 1065 C-C straight chain or branched chain alkyl (in COOH COOH COOH cluding but not limited to hetero substituted alkyl chains with oxygen, silicon, Sulphur and Substituted alkyl N N S. chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), 1066 C-C, cycloalkyl, X l X l X 1067 C-C heterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and COOH COOH COOH N, 1068 C-C alkylcycloalkyl, 1069 C-C alkylheterocycloalkyl, where the hetero N S. N cycle contains one or two hetero atoms selected from O, S, and N, Nt X- l 1070 aryl (including but not limited to phenyl, substi tuted phenyl, naphthyl, Substituted naphthyl), 1071 alkylaryl (including but not limited to alkylphe nyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubsti COOMe COOMe COOMe tuted naphthyl), 1072 heteroaryl (including but not limited to pyridyl, 1N rSa rSa furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thia zolyl, diazolyl pyrazolyl, triazolyl all of which may X l X l X either unsubstituted or substituted), 1073 alkyl heteroaryl (including but not limited to COOMe COOMe COOMe pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isox azolyl, diazolyl pyrazolyl, triazolyl all of which may N N N either unsubstituted or substituted), 1074 CO-alkyl (including but not limited to C to Co straight chain or branched chain alkyl). 1075 CO-alkenyl (including but not limited to C to Co straight chain or branched chain alkenyl), 1076 CO-cycloalkyl (including but not limited to C to COOEt COOEt COOEt C, cycloalkyl). 1077 CO-alkylcycloalkyl (including but not limited to C to Cs alkylcycloalkyl). N N S. 1078 CO-aryl (including but not limited to alkyl phe nyl, alkyl substituted phenyl, alkyl naphthyl, alkyl sub X l X l X stituted naphthyl), COOEt COOEt COOEt. 1079 CO-alkylaryl (including but not limited to alkyl phenyl, alkyl Substituted phenyl, alkyl naphthyl, alkyl substituted naphthyl), N S. N 1080 CO-alkenylaryl (including but not limited to alk Nt X- Nt X enyl phenyl, alkenyl Substituted phenyl, alkenyl naph thyl, alkenyl Substituted naphthyl, cinnamoyl, couma royl, caffeoyl, ferruloyl); and 1081) R. RandR are each independently selected from: 1082 H, 1083 OH, 1062. In other embodiments, a bitter receptor ligand is 1084 O—(C-C) straight chain or branched chain selected from a compound having a structural Formula XIX: alkyl (including but not limited to hetero substituted alkyl chains with oxygen, silicon, Sulphur and Substi (XIX) tuted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, R4 NHalkyl), R3 1085 O—(C-C) cycloalkyl, 1086 O—(C-C) heterocycloalkyl, where the hetero O O cycle contains one or two hetero atoms selected from O, R11 R6, S, and N, 1087 O—(C-C) alkylcycloalkyl, 1088 O—(C-C) alkylheterocycloalkyl, where the O heterocycle contains one or two hetero atoms selected O R3 from O, S, and N, R21 1089 O CO-alkyl (including but not limited to C-Co straight chain or branched chain alkyl). US 2015/0265555 A1 Sep. 24, 2015
1090 O CO-alkenyl (including but not limited to -continued C-Co straight chain or branched chain alkenyl), OMe 1091 O CO-cycloalkyl (including but not limited to OMe C-C cycloalkyl). 1092 O CO-alkylcycloalkyl (including but not lim HO ited to C-C alkylcycloalkyl). C OMe 1093 O CO-aryl (including but not limited to alkyl r phenyl, alkyl Substituted phenyl, alkyl naphthyl, alkyl OX H substituted naphthyl), O H 1094 O CO-alkylaryl (including but not limited to O H alkyl phenyl, alkyl Substituted phenyl, alkyl naphthyl, alkyl substituted naphthyl), and HO 1095 O CO-alkenylaryl (including but not limited to alkenyl phenyl, alkenyl Substituted phenyl, alkenyl naphthyl, alkenyl Substituted naphthyl, cinnamoyl, cou r maroyl, caffeoyl, ferruloyl). 1096. In some instances, a compound of Formula XIX is OH O* OH selected from the following structures:
OH
O H
HO On CO '''OH HO t OO HH OH OH OH OH O
HO O s OCOH OH
O H CO '''OH O H OH OH
OH HO OO HH HO O w v OH OV OH OH CO '''OH O OH OMe OH
O H HO O O OMe CO 'OH HO O OH OMe
O H OH HO O * OC OMe O CO 'OH OH OH O H US 2015/0265555 A1 Sep. 24, 2015 96
-continued 1106 alkylaryl (including but not limited to alkylphe nyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubsti tuted naphthyl), HO 1107 heteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thia zolyl, diazolyl pyrazolyl, triazolyl all of which may either unsubstituted or substituted), 1108 alkyl heteroaryl (including but not limited to pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isox azolyl, diazolyl pyrazolyl, triazolyl all of which may either unsubstituted or substituted), 1109 CO-alkyl (including but not limited to C-Co straight chain or branched chain alkyl). 1110 CO-alkenyl (including but not limited to C-Co straight chain or branched chain alkenyl), 1111 CO-cycloalkyl (including but not limited to C-C cycloalkyl). HO 1112 CO-alkylcycloalkyl (including but not limited to C-C alkylcycloalkyl). 1113 CO-aryl (including but not limited to alkyl phe nyl, alkyl substituted phenyl, alkyl naphthyl, alkyl sub stituted naphthyl), 1114 CO-alkylaryl (including but not limited to alkyl phenyl, alkyl Substituted phenyl, alkyl naphthyl, alkyl Substituted naphthyl), and 1115 CO-alkenylaryl (including but not limited to alk enyl phenyl, alkenyl Substituted phenyl, alkenyl naph thyl, alkenyl Substituted naphthyl, cinnamoyl, couma royl, caffeoyl, ferruloyl); and 1097. In other embodiments, a bitter receptor ligand is 1116 R. Rs and Rare each independently selected from: selected from a compound having a structural Formula XX: 1117 H, 1118 OH, 1119 O—(C-C) straight chain or branched chain
(XX) alkyl (including but not limited to hetero substituted alkyl chains with oxygen, silicon, Sulphur and Substi tuted alkyl chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), 1120 O—(C-C2) cycloalkyl, 1121 O—(C-C) heterocycloalkyl, where the hetero cycle contains one or two hetero atoms selected from O, S, and N, 1122 O—(C-C) alkylcycloalkyl, 1123 O—(C-C) alkylheterocycloalkyl, where the heterocycle contains one or two hetero atoms selected from O, S, and N, wherein 1124 O CO-alkyl (including but not limited to C-Co straight chain or branched chain alkyl). 1098 R. RandR are each independently selected from: 1125 O CO-alkenyl (including but not limited to 1099 H, C-Co straight chain or branched chain alkenyl), 1100 C-C straight chain or branched chain alkyl (in 1126 O CO-cycloalkyl (including but not limited to cluding but not limited to hetero substituted alkyl chains C-C, cycloalkyl). with oxygen, silicon, Sulphur and Substituted alkyl 1127 O CO-alkylcycloalkyl (including but not lim chains with OH, Oalkyl, SH, Salkyl, NH, NHalkyl), ited to C-C alkylcycloalkyl). 1101 C-C, cycloalkyl, 1128 O CO-aryl (including but not limited to alkyl 1102 C-C heterocycloalkyl, where the heterocycle phenyl, alkyl Substituted phenyl, alkyl naphthyl, alkyl contains one or two hetero atoms selected from O, S, and substituted naphthyl), N 1129 O CO-alkylaryl (including but not limited to 1103 C-C alkylcycloalkyl, alkyl phenyl, alkyl Substituted phenyl, alkyl naphthyl, 1104 C-C alkylheterocycloalkyl, where the hetero alkyl substituted naphthyl), and cycle contains one or two hetero atoms selected from O, 1130 O CO-alkenylaryl (including but not limited to S, and N, alkenyl phenyl, alkenyl Substituted phenyl, alkenyl 1105 aryl (including but not limited to phenyl, substi naphthyl, alkenyl Substituted naphthyl, cinnamoyl, cou tuted phenyl, naphthyl, Substituted naphthyl), maroyl, caffeoyl, ferruloyl). US 2015/0265555 A1 Sep. 24, 2015 97
1131. In some instances, a compound of Formula XX is -continued selected from the following structures: OH
HO OH
HO O
OH O OH OH
OH O OH
OH OH 0. OH HO O OH HO OH OH
OH O
OH O OH OH
OH OH HO O O 3.OH O OH OH OH OH OH O
HO OMe OH HO O O OH O OH OH
OH
OH OMe 3. HO O O OMe O OMe HO OH
OH O OH O OH c O OMe
HO O OH O OMe OH OH
OH