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US20220041641A1 - Quaternary ammonium salts as inhibitors of trimethylamine production - Google Patents

Quaternary ammonium salts as inhibitors of trimethylamine production Download PDF

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Publication number
US20220041641A1
US20220041641A1 US17/311,064 US201917311064A US2022041641A1 US 20220041641 A1 US20220041641 A1 US 20220041641A1 US 201917311064 A US201917311064 A US 201917311064A US 2022041641 A1 US2022041641 A1 US 2022041641A1
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compound
mmol
alkyl
methyl
optionally substituted
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US17/311,064
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Inventor
Kathleen NUDEL
Jenny Liu
Timothy Briggs
Dinara Shashanka GUNASEKERA
Ana MARTINEZ-DEL CAMPO
Elijah Bogart
Steven Taylor
John Proudfoot
Cheri Ross
Yohannes Teffera
Koji Yasuda
Devin Forest Reed DOUD
Gabriel Billings
Spencer Cory PECK
Danny LaFrance
Kehinde AJAYI
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Senda Biosciences Inc
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Senda Biosciences Inc
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Priority to US17/311,064 priority Critical patent/US20220041641A1/en
Publication of US20220041641A1 publication Critical patent/US20220041641A1/en
Abandoned legal-status Critical Current

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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
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    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
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    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Definitions

  • novel compounds Disclosed herein are novel compounds, pharmaceutical compositions comprising the same, and methods of using the same.
  • Mammalian microbiota can engage in a bidirectional communication with the mammalian host system.
  • mammalian microbiota may be responsible for producing enzymes that can mediate formation of pathologic metabolites. These metabolites, in sufficient quantities, can compromise the host's health and often lead to debilitating diseases.
  • Trimethylamine lyase from Clostridium sporogenes and from Proteus mirabilis can mediate production of trimethylamine (TMA) from choline.
  • Trimethylamine can be also oxidized in vivo (e.g., by Flavin monooxygenase 3 (FMO3)) to produce a trimethylamine N-oxide (TMAO).
  • FMO3 Flavin monooxygenase 3
  • Trimethylaminuria can be characterized by elevated TMA and/or TMAO levels in a subject, a decreased rate of conversion of TMA to TMAO in a subject, or a high ratio of TMA to TMAO in a subject.
  • Trimethylaminuria often leads to, e.g., cardiovascular disease, reduced or impaired kidney function, kidney disease, chronic kidney disease, end-stage renal disease, or diabetes mellitus.
  • the present disclosure provides novel compounds which may act as inhibitors of enzymatic production of pathogenic, bacterial metabolites, pharmaceutical compositions comprising at least one of such compounds, and methods of using the same, such as, for example, in methods for modulating an autoimmunity marker in a subject, and in methods of treating an autoimmunity disorder in a subject.
  • the disclosure provides compounds for the inhibition of choline-trimethylamine lyase (CutC).
  • the disclosure provides compounds for the inhibition of carnitine monooxygenase (CntA).
  • the disclosure provides compounds for the inhibition of betaine reductase.
  • compounds of the present disclosure consist of a cation and a pharmaceutically acceptable counterion.
  • the cation includes at least one glycoside or acylated sugar, and thus the cation is a conjugate which can be advantageous for targeted delivery to a tissue (e.g., a small intestine) having the highest abundance of CutC from Clostridium sporogenes and/or Proteus mirabilis .
  • CutC may be found and targeted in a host of other bacterial species, including, but not limited to, Proteus hauseri, Klebsiella oxytoca, Escherichia coli, Escherichia fergusonii, Paenibacillus thiaminolyticus, Paenibacillus alvei, Paenibacillus uliginis, Streptococcus dysgalactiae, Streptococcus intermedius, Streptococcus suis, Streptococcus castoreus, Streptococcus merionis, Streptococcus ovis, Collinsella tanakaei, Anaerococcus hydrogenalis, Anaerococcus tetradius, Anaerococcus obesiensis, Anaerococcus vaginalis, Eubacterium sp., Lachnospiraceae bacterium, Hungatella hathewayi, Clostridium phytofermentans, Clostridium sac
  • strains exhibiting a high abundance of CutC include, but are not limited to, Proteus hauseri ZMd44, Proteus mirabilis ATCC29906, Klebsiella oxytoca -, Escherichia coli MS 69-1 , Escherichia fergusonii ECD227, Paenibacillus thiaminolyticus, Paenibacillus alvei TS-15, Paenibacillus uliginis N3/975, Streptococcus dysgalactiae subsp.
  • cation is a structure of formula (I):
  • R 2 is C 2-6 alkyl optionally substituted with one or two hydroxyl, oxo, and —O-(acylated sugar);
  • R 1 and R 2 together with the nitrogen atom to which both are attached, combine to form a 4- or 5-membered heterocyclic ring optionally substituted with ethynyl or —(CH 2 ) n —OR s or an acylated sugar, wherein n is 0 or 1, R s is hydrogen or an acylated sugar;
  • R 3 is C 1-6 alkyl optionally substituted with a halogen or hydroxyl
  • R 4 is C 1-6 alkyl or propargyl.
  • cation is a structure of formula (II):
  • R 1 and R 2 together with the nitrogen atom to which both are attached and optionally one or more additional heteroatoms, combine to form a 4-8 membered mono- or bi-cyclic heterocycle optionally substituted with ethynyl, trifluoromethyl, —CH 2 Ph, —OH, or —(CH 2 )OH;
  • R 3 is methyl or propargyl
  • R 4 is methyl or propargyl
  • cation is a structure of formula (III):
  • R 1 and R 2 together with the nitrogen atom to which both are attached and optionally one or more additional heteroatoms, combine to form a 4-8 membered mono- or bi-cyclic heterocycle optionally substituted with ethynyl, —OH, or —(CH 2 )OH;
  • R 3 is C 1-6 alkyl optionally substituted with a halogen, hydroxyl, or ethynyl;
  • R 4 is C 1-6 alkyl or propargyl
  • the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and at least one of the compounds described above.
  • a method of modulating a trimethylaminuria marker in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the compounds or pharmaceutical compositions disclosed herein.
  • the trimethylaminuria marker is the trimethylamine and/or trimethylamine oxide level in the subject's blood, plasma, serum, or urine.
  • provided herein is a method of treating or preventing a disease associated with elevated levels of trimethylamine (TMA) or trimethylamine N-oxide (TMAO), a decreased rate of conversion of TMA to TMAO, or a high ratio of TMA to TMAO in a subject in need thereof, the method comprising administering a therapeutically effective amount of at least one of the compounds or pharmaceutical compositions disclosed herein to the subject.
  • the method further comprises detecting the presence of one or more genetic variants of the FMO3 gene of the subject in need before the administering step.
  • the disease associated with elevated levels of TMA or TMAO, a decreased rate of conversion of TMA to TMAO, or a high ratio of TMA to TMAO is a cardiovascular disease, reduced or impaired kidney function, kidney disease, chronic kidney disease, end-stage renal disease, or diabetes mellitus.
  • the cardiovascular disease is angina, arrhythmia, atherosclerosis, cardiomyopathy, congestive heart failure, coronary artery disease, carotid artery disease, endocarditis, coronary thrombosis, myocardial infarction, high blood pressure/hypertension, hypercholesterolemia, hyperlipidemia, mitral valve prolapse, peripheral artery disease, or stroke.
  • provided herein is a method of inhibiting a CutC choline lyase-mediated conversion of choline to trimethylamine, the method comprising contacting at least one of the compounds or pharmaceutical compositions disclosed herein with the CutC choline lyase.
  • provided herein is a method of inhibiting a CntA carnitine monooxygenase-mediated conversion of carnitine to trimethylamine, the method comprising contacting at least one of the compounds or pharmaceutical compositions disclosed herein with the CntA carnitine monooxygenase.
  • provided herein is a method of inhibiting a betaine reductase-mediated conversion of betaine or gamma-butyrobetaine to trimethylamine, the method comprising contacting at least one of the compounds or pharmaceutical compositions disclosed herein with the betaine reductase.
  • provided herein is a method of treating a subject in need of treatment for trimethylaminuria comprising contacting bacteria in vivo with a therapeutically effective amount of at least one of the compounds or pharmaceutical compositions disclosed herein to the subject.
  • the bacteria are localized in the colon of the subject.
  • the present disclosure provides a method of modulating a trimethylamine marker in a subject in need thereof, the method consisting of administering to the subject in need thereof a therapeutically effective amount of at least one compound of the present disclosure or a pharmaceutical composition of the present disclosure.
  • the trimethylaminuria marker is the trimethylamine and/or trimethylamine oxide levels in the subject's blood, plasma, serum, or urine.
  • the present disclosure provides a method of treating or preventing a disease associated with trimethylaminuria in a subject in need thereof, the method comprising administering a therapeutically effective amount of at least one pharmaceutically acceptable salt of at least one compound of the present disclosure or a pharmaceutical composition of the present disclosure to the subject.
  • a method of identifying a subject suffering from trimethylaminuria, or predicting a predisposition for developing trimethylaminura in a subject comprising: (i) analyzing a sample from the patient to detect the presence of at least one FMO3 genetic variant in the patient, and (ii) identifying identifying a subject suffering from trimethylaminuria or predicting a predisposition for developing trimethylaminura in a subject.
  • the method further comprises (iii) administering a therapeutically effective amount of at least one of the compounds or pharmaceutical compositions disclosed herein to the subject.
  • the FMO3 genetic variant is identified based on public databases reporting pathogenic variants associated with TMAU. In some embodiments, the FMO3 genetic variant is identified based on predicted loss of function of the FMO3 gene product, such as variants introducing frameshifts or premature stop codons into the coding sequence of FMO3. In some embodiments, the variant is identified based on predicted structural modification to the exonic sequence of FMO3.
  • the FMO3 genetic variant is chosen from g.-2092 to 10145del, g.94G>A+A29A2:A30, g.110T>C, g.11145A>G, g.11148G>T, g.11166G>A, g.11177A>G, g.11185delA, g.11192G>T, g.11239T>C, g.15036A>G, g.15123T>A, g.15137G>T, g.15153C>T, g.15526_15527delTG, g.15531T>A, g.15533T>C, g.15539C>A, g.18177G>A, g.18225G>C, g.21429G>T, g.21460G>T, g.21680G>T, g.21684G>A, g.21702delG, g.
  • acyl represents a chemical substituent of formula —C(O)—R, where R is alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclyl alkyl, heteroaryl, or heteroaryl alkyl.
  • R is alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclyl alkyl, heteroaryl, or heteroaryl alkyl.
  • An optionally substituted acyl is an acyl that is optionally substituted as described herein for each group R.
  • Non-limiting examples of acyl include fatty acid acyls (e.g., short chain fatty acid acyls (e.g., acetyl, propionyl, or butyryl)).
  • acylated sugar refers to a carbohydrate, sugar acid, or sugar alcohol having one or more hydroxyls substituted with an acyl (e.g., a fatty acid acyl).
  • the carbohydrate is a monosaccharide.
  • the carbohydrate is a disaccharide.
  • the fatty acid acyl is a short chain fatty acid acyl (e.g., propionyl or butyryl).
  • An acylated sugar can be a compound or a monovalent group. When an acylated sugar is a monovalent group, the group includes one and only one valency for attaching to another molecular fragment.
  • a monosaccharide include arabinose, xylose, fructose, galactose, glucose, glucosinolate, ribose, tagatose, fucose, and rhamnose.
  • Non-limiting examples of a disaccharide include lactose, sucrose, melibiose, gentiobiose, kojibiose, cellobiose, maltose, trehalose and chitobiose.
  • Non-limiting examples of a sugar acid include xylonic acid, gluconic acid, glucuronic acid, galacturonic acid, tartaric acid, saccharic acid, or mucic acid.
  • Non-limiting examples of sugar alcohols are glycerol, erythritol, theritol, arabitol, xylitol, tibitol, mannitol, sorbitol, galactitol, fucitol, iditol, or inositol.
  • acyloxy represents a chemical substituent of formula —OR, where R is acyl.
  • R is acyl.
  • An optionally substituted acyloxy is an acyloxy that is optionally substituted as described herein for acyl.
  • alcohol oxygen atom refers to a divalent oxygen atom, where at least one valency of the oxygen atom is bonded to an sp 3 -hybridized carbon atom.
  • alkanoyl represents a chemical substituent of formula —C(O)—R, where R is alkyl.
  • R is alkyl.
  • An optionally substituted alkanoyl is an alkanoyl that is optionally substituted as described herein for alkyl.
  • alkoxy represents a chemical substituent of formula —OR, where R is a C 1-6 alkyl group, unless otherwise specified.
  • An optionally substituted alkoxy is an alkoxy group that is optionally substituted as defined herein for alkyl.
  • alkenyl represents acyclic monovalent straight or branched chain hydrocarbon groups containing one, two, or three carbon-carbon double bonds. Alkenyl, when unsubstituted, has from 2 to 12 carbon atoms (e.g., 1 to 8 carbons), unless specified otherwise.
  • Non-limiting examples of the alkenyl groups include ethenyl, prop-1-enyl, prop-2-enyl, 1-methylethenyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylprop-1-enyl, 2-methylprop-1-enyl, and 1-methylprop-2-enyl.
  • Alkenyl groups may be optionally substituted as defined herein for alkyl.
  • alkyl refers to an acyclic, straight or branched, saturated hydrocarbon group, which, when unsubstituted, has from 1 to 12 carbons (e.g., 1 to 6 carbons), unless otherwise specified.
  • Alkyl groups are exemplified by methyl; ethyl; n- and iso-propyl; n-, sec-, iso- and tert-butyl; neopentyl, and the like, and may be optionally substituted, valency permitting, with one, two, three, or, in the case of alkyl groups of two carbons or more, four or more substituents independently selected from the group consisting of: alkoxy; acyloxy; alkylsulfinyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; halo; heterocyclyl; heteroaryl; heterocyclylalkyl; heteroarylalkyl; heterocyclyloxy; heteroaryloxy; hydroxy; nitro; thioalkyl; thioalkenyl; thioaryl; thiol; cyano; oxo ( ⁇ O
  • alkylene refers to a divalent, straight or branched, saturated hydrocarbon, in which two valencies replace two hydrogen atoms. Alkyl, when unsubstituted, has from 2 to 12 carbon atoms (e.g., 2 to 6 carbons), unless specified otherwise.
  • Non-limiting examples of the alkylene group include methylene, ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, propane-2,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, butane-1,1-diyl, and butane-2,2-diyl, butane-2,3-diyl.
  • An optionally substituted alkylene is an alkylene that is optionally substituted as described herein for alkyl.
  • alkylsulfinyl represents a group of formula —S(O)-(alkyl).
  • An optionally substituted alkylsulfinyl is an alkylsulfinyl that is optionally substituted as described herein for alkyl.
  • alkylsulfonyl represents a group of formula —S(O) 2 -(alkyl).
  • An optionally substituted alkylsulfonyl is an alkylsulfonyl that is optionally substituted as described herein for alkyl.
  • alkynyl represents an acyclic, monovalent, straight or branched chain hydrocarbon groups containing one, two, or three carbon-carbon triple bonds. Alkynyl, when unsubstituted, has from 2 to 12 carbon atoms (e.g., 2 to 6 carbons), unless specified otherwise.
  • Non-limiting examples of the alkynyl groups include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, and 1-methylprop-2-ynyl.
  • An optionally substituted alkynyl is an alkynyl that is optionally substituted as defined herein for alkyl.
  • aryl represents a mono-, bicyclic, or multicyclic carbocyclic ring system having one or two aromatic rings.
  • Aryl group may include from 6 to 10 carbon atoms. All atoms within an unsubstituted carbocyclic aryl group are carbon atoms.
  • Non-limiting examples of carbocyclic aryl groups include phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, etc.
  • the aryl group may be unsubstituted or substituted with one, two, three, four, or five substituents independently selected from the group consisting of: alkyl; alkenyl; alkoxy; acyloxy; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; halo; heterocyclyl; heteroaryl; heterocyclylalkyl; heteroarylalkyl; heterocyclyloxy; heteroaryloxy; hydroxy; nitro; thioalkyl; thioalkenyl; thioaryl; thiol; and cyano.
  • Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group.
  • aryl alkyl represents an alkyl group substituted with an aryl group.
  • An optionally substituted aryl alkyl is an aryl alkyl, in which aryl and alkyl portions may be optionally substituted as the individual groups as described herein.
  • aryloxy represents a group —OR, where R is aryl.
  • Aryloxy may be an optionally substituted aryloxy.
  • An optionally substituted aryloxy is aryloxy that is optionally substituted as described herein for aryl.
  • carboxylate linker refers to a group R 1 —(CO)—R 2 , where R 1 is a bond to an alcohol or phenolic oxygen atom, and R 2 is a bond to a nitrogen atom.
  • carboxylate refers to a monosaccharide, disaccharide, or an oligosaccharide or an analog of the following structure:
  • R B is H, optionally substituted C 1-6 alkyl, or —CH 2 —OH.
  • carbohydrate may refer to a compound or to a monovalent or multivalent chemical substituent.
  • carbohydrate refers to a chemical substituent
  • the valence(s) reside on the anomeric carbon atom and/or alcohol oxygen atoms.
  • An optionally substituted carbohydrate is a carbohydrate, in which at least one hydroxyl is substituted with an acyl (e.g., a fatty acid acyl).
  • carbonate linker refers to a group R 1 —C(O)—R 2 where R 1 is a bond to a first alcohol or phenolic oxygen atom, and R 2 is a bond to a second alcohol or phenolic oxygen atom.
  • carbonyl refers to a divalent group —C(O)—.
  • carboxylate represents group —COOH or a salt thereof.
  • cycloalkoxy represents a group —OR, where R is cycloalkyl.
  • R is cycloalkyl.
  • An optionally substituted cycloalkoxy is cycloalkoxy that is optionally substituted as described herein for cycloalkyl.
  • ester bond refers to a covalent bond between an alcohol or phenolic oxygen atom and a carbonyl group that is further bonded to a carbon atom.
  • fatty acid refers to a short-chain fatty acid, a medium chain fatty acid, a long chain fatty acid, a very long chain fatty acid, or an unsaturated analogue thereof, or a phenyl-substituted analogue thereof.
  • Short chain fatty acids contain from 1 to 6 carbon atoms
  • medium chain fatty acids contain from 7 to 13 carbon atoms
  • long-chain fatty acids contain from 14 to 22 carbon atoms.
  • a fatty acid may be saturated or unsaturated.
  • An unsaturated fatty acid includes 1, 2, 3, 4, 5, or 6 carbon-carbon double bonds.
  • the carbon-carbon double bonds in unsaturated fatty acids have Z stereochemistry.
  • the carbon-carbon double bonds in unsaturated fatty acids have E stereochemistry.
  • fatty acid acyl refers to a fatty acid, in which the hydroxyl group is replaced with a valency.
  • a fatty acid acyl is a short chain fatty acid acyl.
  • fatty acid acyloxy refers to group —OR, where R is a fatty acid acyl.
  • glycoside refers to a monovalent group that is a monosaccharide, disaccharide, or sugar acid having a valency on an anomeric carbon.
  • monosaccharides include arabinose, xylose, fructose, galactose, glucose, ribose, tagatose, fucose, and rhamnose.
  • disaccharides include lactose, sucrose, melibiose, gentiobiose, kojibiose, cellobiose, maltose, trehalose and chitobiose.
  • sugar acids include xylonic acid, gluconic acid, glucuronic acid, galacturonic acid, tartaric acid, saccharic acid, or mucic acid.
  • glycosidic bond refers to a covalent bond between an oxygen atom and an anomeric carbon atom in a monosaccharide, disaccharide, or sugar acid having an anomeric carbon atom.
  • halogen represents a halogen selected from bromine, chlorine, iodine, and fluorine.
  • heteroaryl represents a monocyclic 5-, 6-, 7-, or 8-membered ring system, or a fused or bridging bicyclic, tricyclic, or tetracyclic ring system; the ring system contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and at least one of the rings is an aromatic ring.
  • heteroaryl groups include benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indolyl, isoindazolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, qunazolinyl, quinolinyl, thiadiazolyl (e.g., 1,3,4-thiadiazole), thiazolyl, thienyl, triazolyl, tetrazolyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, etc.
  • bicyclic, tricyclic, and tetracyclic heteroaryls include at least one ring having at least one heteroatom as described above and at least one aromatic ring.
  • a ring having at least one heteroatom may be fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring.
  • fused heteroaryls examples include 1,2,3,5,8,8a-hexahydroindolizine; 2,3-dihydrobenzofuran; 2,3-dihydroindole; and 2,3-dihydrobenzothiophene.
  • Heteroaryl may be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of: alkyl; alkenyl; alkoxy; acyloxy; aryloxy; alkylsulfinyl; alkylsulfonyl; amino; arylalkoxy; cycloalkyl; cycloalkoxy; halogen; heterocyclyl; heterocyclyl alkyl; heteroaryl; heteroaryl alkyl; heterocyclyloxy; heteroaryloxy; hydroxyl; nitro; thioalkyl; thioalkenyl; thioaryl; thiol; cyano; ⁇ O; —NR 2 , where each R is independently hydrogen, alkyl, acyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl; —COOR A , where R A is hydrogen, alkyl, aryl, arylal
  • heteroaryloxy refers to a structure —OR, in which R is heteroaryl. Heteroaryloxy can be optionally substituted as defined for heteroaryl.
  • heterocyclyl represents a monocyclic, bicyclic, tricyclic, or tetracyclic non-aromatic ring system having fused or bridging 4-, 5-, 6-, 7-, or 8-membered rings, unless otherwise specified, the ring system containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • Non-aromatic 5-membered heterocyclyl has zero or one double bonds
  • non-aromatic 6- and 7-membered heterocyclyl groups have zero to two double bonds
  • non-aromatic 8-membered heterocyclyl groups have zero to two double bonds and/or zero or one carbon-carbon triple bond.
  • Heterocyclyl groups have a carbon count of 1 to 16 carbon atoms unless otherwise specified. Certain heterocyclyl groups may have a carbon count up to 9 carbon atoms.
  • Non-aromatic heterocyclyl groups include pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, pyridazinyl, oxazolidinyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, thiazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyranyl, dihydropyranyl, dithiazolyl, etc.
  • heterocyclyl also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and/or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., quinuclidine, tropanes, or diaza-bicyclo[2.2.2]octane.
  • heterocyclyl includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, e.g., a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another heterocyclic ring.
  • fused heterocyclyls include 1,2,3,5,8,8a-hexahydroindolizine; 2,3-dihydrobenzofuran; 2,3-dihydroindole; and 2,3-dihydrobenzothiophene.
  • the heterocyclyl group may be unsubstituted or substituted with one, two, three, four or five substituents independently selected from the group consisting of: alkyl; alkenyl; alkoxy; acyloxy; alkylsulfinyl; alkylsulfonyl; aryloxy; amino; arylalkoxy; cycloalkyl; cycloalkoxy; halogen; heterocyclyl; heterocyclyl alkyl; heteroaryl; heteroaryl alkyl; heterocyclyloxy; heteroaryloxy; hydroxyl; nitro; thioalkyl; thioalkenyl; thioaryl; thiol; cyano; ⁇ O; ⁇ S; —NR 2 , where each R is independently hydrogen, alkyl, acyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl; —COOR A , where R A is hydrogen, alkyl
  • heterocyclyl alkyl represents an alkyl group substituted with a heterocyclyl group.
  • the heterocyclyl and alkyl portions of an optionally substituted heterocyclyl alkyl are optionally substituted as the described for heterocyclyl and alkyl, respectively.
  • heterocyclyloxy refers to a structure —OR, in which R is heterocyclyl. Heterocyclyloxy can be optionally substituted as described for heterocyclyl.
  • hydroxyl and “hydroxy,” as used interchangeably herein, represent —OH.
  • a hydroxyl substituted with an acyl is an acyloxy.
  • a protected hydroxyl is a hydroxyl, in which the hydrogen atom is replaced with an O-protecting group.
  • hydroxyalkyl refers to a C 1-6 alkyl group that is substituted with one or more hydroxyls, provided that each carbon atom in the hydroxyalkyl is attached either to no more than one hydroxyl.
  • hydroxyalkyls include hydroxymethyl, 2-hydroxyethyl, and 1-hydroxyethyl.
  • methene represents a double bonded carbon atom (e.g., the structure of methene may be shown as ⁇ CH 2 ).
  • modulating refers to an observable change in the level of a marker in a subject, as measured using techniques and methods known in the art for the measurement of the marker. Modulating the marker level in a subject may result in a change of at least 1% relative to prior to administration (e.g., at least 5%, 10%, 15%, 20%, 25%, 30%, 35%0, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 98% or more relative to prior to administration; e.g., up to 100% relative to prior to administration). In some embodiments, modulating is increasing the level of a marker in a subject.
  • Increasing the marker level in a subject may result in an increase of at least 1% relative to prior to administration (e.g., at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 98% or more relative to prior to administration; e.g., up to 100% relative to prior to administration).
  • modulating is decreasing the level of a marker in a subject.
  • Decreasing the marker level in a subject may result in a decrease of at least 1% relative to prior to administration (e.g., at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 98% or more relative to prior to administration; e.g., up to 100% relative to prior to administration).
  • at least 1% relative to prior to administration e.g., at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 98% or more relative to prior to administration; e.g., up to 100% relative to prior to administration.
  • the increase or decrease may take place and/or be detectable within a range of time following the administration (e.g., within six hours, 24 hours, 3 days, a week or longer), and may take place and/or be detectable after one or more administrations (e.g., after 2, 3, 4, 5, 6, 7, 8, 9, 10 or more administrations, e.g., as part of a dosing regimen for the subject).
  • oxo represents a divalent oxygen atom (e.g., the structure of oxo may be shown as ⁇ O).
  • pharmaceutically acceptable salt represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Principles for preparing pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use , (Eds. P. H. Stahl and C. G. Wermuth), Wiley-VCH, 2008.
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein, by reacting the free base group with a suitable electrophile, by use of an alkylating agent or via exchange resin, or by exchanging in solution.
  • Representative counterions useful for pharmaceutically acceptable salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, bromide, chloride, iodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate,
  • phenolic oxygen atom refers to a divalent oxygen atom within the structure of a compound, where at least one valency of the phenolic oxygen atom is bonded to an sp 2 -hybridized carbon atom within an aromatic ring.
  • physiological conditions refers to the conditions prevalent in vivo.
  • incubation in simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) at physiologically relevant temperatures (e.g., about 36-37° C.) may be used to simulate physiological conditions representative of a stomach or upper intestine, respectively.
  • Colon conditions may be simulated using a slurry of a healthy human fecal matter under anaerobic conditions.
  • prevent refers to minimizing or partially or completely inhibiting the development of the associated disease, disorder, or condition.
  • Non-limiting examples of the disease, disorder, or condition are those described herein.
  • protecting group represents a group intended to protect a hydroxy, an amino, or a carbonyl from participating in one or more undesirable reactions during chemical synthesis.
  • O-protecting group represents a group intended to protect a hydroxy or carbonyl group from participating in one or more undesirable reactions during chemical synthesis.
  • N-protecting group represents a group intended to protect a nitrogen containing (e.g., an amino or hydrazine) group from participating in one or more undesirable reactions during chemical synthesis.
  • O- and N-protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 3 rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference.
  • Exemplary O- and N-protecting groups include alkanoyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, t-butyldimethylsilyl, tri-iso-propylsilyloxymethyl, 4,4′-dimethoxytrityl, isobutyryl, phenoxyace
  • O-protecting groups for protecting carbonyl containing groups include, but are not limited to: acetals, acylals, 1,3-dithianes, 1,3-dioxanes, 1,3-dioxolanes, and 1,3-dithiolanes.
  • O-protecting groups include, but are not limited to: substituted alkyl, aryl, and aryl-alkyl ethers (e.g., trityl; methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl; 2,2,2,-trichloroethoxymethyl; tetrahydropyranyl; tetrahydrofuranyl; ethoxyethyl; 1-[2-(trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; t-butyl ether; p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p-methoxybenzyl, and nitrobenzyl); silyl ethers (e.g., trimethylsilyl; triethylsilyl; triisopropylsilyl; dimethylisopropylsilyl; t-butyld
  • N-protecting groups include, but are not limited to, chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine, and the like; sulfonyl-containing groups such as benzenesulfonyl, p-toluenesulfonyl, and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyl oxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxy
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).
  • subject represents a human or non-human animal (e.g., a mammal) that is suffering from, or is at risk of, disease, disorder, or condition, as determined by a qualified professional (e.g., a doctor or a nurse practitioner) with or without known in the art laboratory test(s) of sample(s) from the subject.
  • a qualified professional e.g., a doctor or a nurse practitioner
  • Non-limiting examples of diseases, disorders, and conditions include those described herein.
  • sugar acid refers to a monosaccharide, in the linear form of which one or both terminal positions are oxidized to a carboxylic acid.
  • sugar acids There are at least four classes of sugar acids: aldonic acid, ulosonic acid, uronic acid, and aldaric acid. Any of the four sugar acid classes may be used in conjugates disclosed herein.
  • Non-limiting examples of sugar acids include xylonic acid, gluconic acid, glucuronic acid, galacturonic acid, tartaric acid, saccharic acid, or mucic acid.
  • sugar acid acyl refers to a monovalent group that is a sugar acid having a carboxylate, in which —OH is replaced with a valency.
  • thioalkenyl represents a group —SR, where R is alkenyl.
  • R is alkenyl.
  • An optionally substituted thioalkenyl is thioalkenyl that is optionally substituted as described herein for alkenyl.
  • thioalkyl represents a group —SR, where R is alkyl.
  • R is alkyl.
  • An optionally substituted thioalkyl is thioalkyl that is optionally substituted as described herein for alkyl.
  • thioaryl represents a group —SR, where R is aryl.
  • An optionally substituted thioaryl is thioaryl that is optionally substituted as described herein for aryl.
  • Treatment and “treating,” as used herein, refer to the medical management of a subject with the intent to improve, ameliorate, stabilize, or cure a disease, disorder, or condition. This term includes active treatment (treatment directed to improve the disease, disorder, or condition); causal treatment (treatment directed to the cause of the associated disease, disorder, or condition); palliative treatment (treatment designed for the relief of symptoms of the disease, disorder, or condition); and supportive treatment (treatment employed to supplement another therapy).
  • the compounds described herein encompass isotopically enriched compounds (e.g., deuterated compounds), tautomers, and all stereoisomers and conformers (e.g. enantiomers, diastereomers, E/Z isomers, atropisomers, etc.), as well as racemates thereof and mixtures of different proportions of enantiomers or diastereomers, or mixtures of any of the foregoing forms as well as salts (e.g., pharmaceutically acceptable salts).
  • isotopically enriched compounds e.g., deuterated compounds
  • tautomers e.g. enantiomers, diastereomers, E/Z isomers, atropisomers, etc.
  • racemates e.g. enantiomers, diastereomers, E/Z isomers, atropisomers, etc.
  • salts e.g., pharmaceutically acceptable salts.
  • the compounds of the disclosure may target the production of pathogenic metabolites by certain bacteria in a subject, thereby reducing the pathogenic metabolite levels in the subject.
  • the compounds of the disclosure may be a conjugate of the disclosure, e.g., those compounds including a glycoside or an acylated sugar.
  • the conjugate may be cleaved in vivo to remove the glycoside or an acylated sugar from the compound and to release the corresponding unconjugated compound of the disclosure.
  • Conjugates of the disclosure may be advantageous in therapeutic applications benefitting from a particular tissue-targeted delivery of an unconjugated compound of the disclosure.
  • Compounds of the disclosure that include at least one glycoside or at least one acylated sugar are conjugates.
  • Compounds having a fatty acid acyl (e.g., a short chain fatty acid acyl) attached through an ester bond are also conjugates.
  • Acylated sugars that may be used in the conjugates disclosed herein include an acyl (e.g., a fatty acid acyl) and a core selected from the group consisting of a carbohydrate (e.g., a monosaccharide or disaccharide), sugar acid, and sugar alcohol.
  • an acylated sugar may be a monovalent group of the following formula:
  • L is a bond to a pharmaceutically active agent, a compound of formula (I), a compound of formula (II), a compound of formula (III), a carbonate linker, or a carbamate linker;
  • group A is a core selected from the group consisting of carbohydrate (e.g., a monosaccharide or dissaccharide), sugar acid, and sugar alcohol;
  • each R is independently an acyl bonded to an oxygen atom in group A;
  • n is an integer from 0 to the total number of available hydroxyl groups in group A (e.g., 1, 2, 3, 4, or 5).
  • L may be attached to a carbon atom in group A (e.g., an anomeric carbon atom or a carbonyl carbon atom).
  • L may be attached to an oxygen atom in group A (e.g., an alcoholic oxygen atom, a phenolic oxygen atom, or a carboxylate oxygen atom).
  • At least one R is a fatty acid acyl.
  • the fatty acid(s) are short chain fatty acid acyls.
  • the short chain fatty acid acyl is a C 3-6 short chain fatty acid acyl (e.g., propionyl or butyryl).
  • the acylated sugar is peracylated, i.e., all of the available hydroxyls in the acylated sugar are substituted with an acyl.
  • a monosaccharide may be, e.g., arabinose, xylose, fructose, galactose, glucose, ribose, tagatose, fucose, or rhamnose.
  • the monosaccharide is L-arabinose, D-xylose, fructose, galactose, D-glucose, D-ribose, D-tagatose, L-fucose, or L-rhamnose (e.g., the monosaccharide is D-xylose).
  • a disaccharide may be, e.g., lactose, sucrose, melibiose, gentiobiose, kojibiose, cellobiose, maltose, trehalose and chitobiose.
  • a sugar acid may be, e.g., aldonic acid, ulosonic acid, uronic acid, or aldaric acid.
  • a sugar acid may be, e.g., xylonic acid, gluconic acid, glucuronic acid, galacturonic acid, tartaric acid, saccharic acid, or mucic acid.
  • a sugar alcohol may be, e.g., glycerol, erythritol, threitol, arabitol, xylitol, tibitol, mannitol, sorbitol, galactitol, fucitol, iditol, or inositol.
  • An acylated sugar may be covalently linked to a pharmaceutically active agent through a carbon-oxygen bond that is cleavable in vivo, a carbonate linker, or a carbamate linker.
  • the carbon-oxygen bond may be, e.g., a glycosidic bond or ester bond.
  • Acylated sugars having a monosaccharide, disaccharide, or a sugar acid as a core may be covalently linked to a pharmaceutically active agent through a carbon-oxygen bond that is cleavable in vivo (e.g., a glycosidic bond or ester bond), a carbonate linker, or a carbamate linker.
  • one or both carboxylates may be present as O-protected versions (e.g., as alkyl esters (e.g., methyl or ethyl esters)).
  • Acylated sugars having a sugar alcohol as a core may be covalently linked to a pharmaceutically active agent through a carbon-oxygen bond that is cleavable in vivo (e.g., an ester bond), a carbonate linker, or a carbamate linker.
  • Non-limiting examples of acylated sugars are:
  • R is H, —CH 3 , or —CH 2 OR FA ;
  • each R FA is independently H or a fatty acid acyl (e.g., a short chain fatty acid acyl);
  • each R A is independently H or fatty acid acyl
  • R B is H, —CH 3 , —CH 2 —OR A , —OCH 3 , —COOCH 3 , or —COOH.
  • the disclosure provides a compound of a cation and a pharmaceutically acceptable counterion, where the cation is chosen from the following cations:
  • the disclosure provides a compound of a cation and a pharmaceutically acceptable counterion, where the cation is chosen from the following cations:
  • cation is chosen from the following cations:
  • the disclosure provides a compound consisting of a cation and a pharmaceutically acceptable counterion, where the cation is a structure of formula (I):
  • R 2 is C 2-6 alkyl optionally substituted with one or two hydroxyl, oxo, and —O-(acylated sugar);
  • R 1 and R 2 together with the nitrogen atom to which both are attached, combine to form a 4- or 5-membered heterocyclic ring optionally substituted with ethynyl or —(CH 2 ) n —OR s or an acylated sugar, wherein n is 0 or 1, R s is hydrogen or an acylated sugar;
  • R 3 is C 1-6 alkyl optionally substituted with a halogen or hydroxyl
  • R 4 is C 1-6 alkyl or propargyl.
  • the cation comprises at least one acylated sugar.
  • the acylated sugar is chosen from groups of formula (A), groups of formula (B), and groups of formula (C):
  • each R A is independently H or fatty acid acyl
  • R B is H, —C 1-6 alkyl, —C 1-6 alkylene-OR A , —OC 1-6 alkyl, —COOC 1-6 alkyl, or —COOH.
  • acylated sugar is a group of formula (A).
  • each R A is independently H or fatty acid acyl
  • R B is H, —CH 3 , —CH 2 —OR A , —OCH 3 , —COOCH 3 , or —COOH.
  • acylated sugar is a group of formula (B):
  • each R A is independently H or fatty acid acyl
  • R B is H, —CH 3 , —CH 2 —OR A , —OCH 3 , —COOCH 3 , or —COOH.
  • acylated sugar is a group of formula (C):
  • each R A is independently H or fatty acid acyl
  • R B is H, —CH 3 , —CH 2 —OR A , —OCH 3 , —COOCH 3 , or —COOH.
  • each R A is independently chosen from fatty acid acyls. In some embodiments, each R A is independently chosen from short chain fatty acid acyls.
  • the acylated sugar is chosen from groups of formula (A).
  • At least one R A is H. In some embodiments, at least one R A is —COCH 3 . In some embodiments, at least one R A is —COCH 2 CH 3 . In some embodiments, at least one R A is —COCH 2 CH 2 CH 3 .
  • At least three R A are H. In some embodiments, at least three R A are —COCH 3 . In some embodiments, at least three R A are —COCH 2 CH 3 . In some embodiments at least three R A are —COCH 2 CH 2 CH 3 .
  • R B is H. In some embodiments, R B is —CH 3 . In some embodiments, R B is —CH 2 OH. In some embodiments, R B is —CH 2 —OCOCH 3 . In some embodiments, R B is —CH 2 —OCOCH 2 CH 3 . In some embodiments, R B is —COOH. In some embodiments, R B is —COOCH 3 .
  • R B is H, —CH 3 , —CH 2 —OR A , —OCH 3 , —COOCH 3 , or —COOH.
  • R B is H, —C 1-6 alkyl, or —C 1-6 alkylene-OR A wherein R A is H or fatty acid acyl.
  • R B is H, —CH 3 , or —CH 2 —OR A , wherein R A is H or fatty acid acyl.
  • R B is —OC 1-6 alkyl, —COOC 1-6 alkyl, or —COOH.
  • R B is —OCH 3 , —COOCH 3 , or —COOH.
  • the acylated sugar is a group of the following formula:
  • the acylated sugar is a group of the following formula:
  • R 1 is C 2-6 alkyl substituted with —O-(acylated sugar), wherein said C 2-6 alkyl is further optionally substituted with oxo. In some embodiments, R 1 is C 2-6 alkyl substituted with oxo and —O-(acylated sugar). In some embodiments, R 1 is C 3-4 cycloalkyl substituted with hydroxyl, ethynyl, or —O-(acylated sugar). In some embodiments, R 1 is C 3-4 cycloalkyl C 1-2 alkyl. In some embodiments, R 2 is methyl.
  • R 2 is C 2-6 alkyl, wherein the C 2-6 alkyl is substituted with one or two substituents independently selected from the group consisting of hydroxyl, oxo, and —O-(acylated sugar).
  • R 1 and R 2 together with the nitrogen atom to which both are attached, combine to form a 4- or 5-membered heterocyclic ring optionally substituted with ethynyl or —(CH 2 ) n —OR A , wherein n is 0 or 1, and R A is hydrogen or an acylated sugar.
  • R S is hydrogen.
  • R 3 is C 1-6 alkyl substituted with a halogen or hydroxyl.
  • R 4 is propargyl.
  • R 4 is C 1-6 alkyl.
  • R 1 is C 2-6 alkyl substituted with —O-(acylated sugar) and is optionally further substituted with oxo;
  • R 2 is methyl;
  • R 3 is C 1-6 alkyl; and
  • R 4 is propargyl.
  • R 1 is C 2-6 alkyl substituted with isosorbide and is optionally further substituted with oxo and/or methene;
  • R 2 is methyl;
  • R 3 is C 1-6 alkyl; and R 4 is propargyl.
  • R 1 is C 2-6 alkyl substituted with —O-(acylated sugar) and is optionally further substituted with oxo.
  • R 1 is C 2-6 alkyl substituted with —O-(acylated sugar) and further substituted with oxo.
  • R 1 is chosen from C 2 alkyl substituted with —O-(acylated sugar) and optionally further substituted with oxo and C 4 alkyl substituted with —O-(acylated sugar) and optionally further substituted with oxo.
  • R 1 is chosen from C 2 alkyl substituted with —O-(acylated sugar) and optionally further substituted with oxo. In some embodiments, R 1 is chosen from C 2 alkyl substituted with —O-(acylated sugar) and further substituted with oxo. In some embodiments, R 1 is chosen from C 4 alkyl substituted with —O-(acylated sugar) and optionally further substituted with oxo. In some embodiments, R 1 is chosen from C 4 alkyl substituted with —O-(acylated sugar) and further substituted with oxo.
  • R 1 is C 2-6 alkyl substituted with isosorbide and is optionally further substituted with oxo and/or methene.
  • isosorbide is chosen from groups of formula (C):
  • R 1 is C 2 alkyl substituted with isosorbide. In some embodiments, R 1 is C 2-6 alkyl substituted with isosorbide and further substituted with oxo and/or methene. In some embodiments, R 1 is C 2-6 alkyl substituted with isosorbide and further substituted with oxo. In some embodiments, R 1 is C 2 alkyl substituted with isosorbide and further substituted with oxo. In some embodiments, R 1 is C 2-6 alkyl substituted with isosorbide and further substituted with methene. In some embodiments, R 1 is C 2-6 alkyl substituted with isosorbide and further substituted with oxo and methene. In some embodiments, R 1 is C 2-6 alkyl substituted with isosorbide and further substituted with oxo and methene. In some embodiments, R 1 is C 2-6 alkyl substituted with isosorbide and further substituted with oxo and methene. In some embodiments,
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 is C 3-4 cycloalkyl C 1-2 alkyl. In some embodiments, R 1 is C 3-4 cycloalkyl C 1 alkyl. In some embodiments, R 1 is cyclopropylmethyl. In some embodiments, R 1 is cyclobutylmethyl.
  • R 2 is C 2-6 alkyl optionally substituted with one or two hydroxyl, oxo, and —O-(acylated sugar). In some embodiments, R 2 is methyl.
  • R 1 and R 2 together with the nitrogen atom to which both are attached, combine to form a 4- or 5-membered heterocyclic ring optionally substituted with ethynyl or —(CH 2 ) n —OR s or an acylated sugar, wherein n is 0 or 1, R s is hydrogen or an acylated sugar.
  • R 3 is C 1-6 alkyl optionally substituted with a halogen or hydroxyl. In some embodiments, R 3 is C 1-6 alkyl. In some embodiments, R 3 is C 1-6 alkyl optionally substituted with a halogen or hydroxyl. In some embodiments, R 3 is C 1-6 alkyl optionally substituted with a halogen and/or hydroxyl. In some embodiments, R 3 is C 1-6 alkyl optionally substituted with a halogen or hydroxyl. In some embodiments, R 3 is C 1-6 alkyl substituted with a halogen. In some embodiments, R 3 is C 1-6 alkyl substituted with a hydroxyl.
  • R 3 is C 1 alkyl optionally substituted with a halogen. In some embodiments, R 3 is C 1 alkyl substituted with a halogen.
  • R 4 is C 1-6 alkyl or propargyl. In some embodiments, R 4 is C 1 alkyl or propargyl. In some embodiments, R 4 is propargyl.
  • R 1 is C 2-6 alkyl substituted with —O-(acylated sugar) and is optionally further substituted with oxo;
  • R 2 is methyl;
  • R 3 is C 1-6 alkyl; and
  • R 4 is propargyl.
  • R 1 is C 2-6 alkyl substituted with isosorbide and is optionally further substituted with oxo and/or methene;
  • R 2 is methyl;
  • R 3 is C 1-6 alkyl; and
  • R 4 is propargyl.
  • R 1 is chosen from C 2 alkyl substituted with —O-(acylated sugar) and optionally further substituted with oxo and C 4 alkyl substituted with —O-(acylated sugar) and optionally further substituted with oxo; wherein the acylated sugar is chosen from groups of formula (A), groups of formula (B), and groups of formula (C):
  • R 2 is methyl
  • R 3 is methyl
  • R 4 is propargyl
  • R 1 is chosen from C 2 alkyl substituted with isosorbide and optionally further substituted with oxo and C 3 alkyl substituted with isosorbide and optionally further substituted with oxo and methene;
  • isosorbide is chosen from groups of formula (C):
  • R 2 is methyl
  • R 3 is methyl
  • R 4 is propargyl
  • R 1 is C 3-4 cycloalkyl C 1-2 alkyl
  • R 2 is C 2-6 alkyl optionally substituted with one or two hydroxyl, oxo, and —O-(acylated sugar); or R 1 and R 2 , together with the nitrogen atom to which both are attached, combine to form a 4- or 5-membered heterocyclic ring optionally substituted with ethynyl or —(CH 2 ) n —OR s or an acylated sugar, wherein n is 0 or 1, R s is hydrogen or an acylated sugar; R 3 is C 1-6 alkyl optionally substituted with a halogen or hydroxyl; and R 4 is C 1-6 alkyl or propargyl.
  • R 1 is C 3-4 cycloalkyl C 1 alkyl.
  • R 2 is C 2 alkyl optionally substituted with one or two hydroxyl groups.
  • R 1 and R 2 together with the nitrogen atom to which both are attached, combine to form a 5-membered heterocyclic ring optionally substituted with ethynyl, —OH, or —CH 2 OH.
  • R 3 is C 1 alkyl optionally substituted with a halogen.
  • R 4 is C 1 alkyl or propargyl.
  • a method of treating a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the invention, a pharmaceutical composition of the invention, or the compound of formula (I-a) or (I-b), where the compound of formula (I-a) is:
  • R 1 is H or C 1-3 alkyl optionally substituted with hydroxyl
  • R 2 is H or C 1-3 alkyl optionally substituted with hydroxyl
  • R 3 is absent or alkyl
  • Z q is absent or a pharmaceutically acceptable counterion present in the stoichiometric ratio appropriate for the compound of formula (I-a) to have no net charge
  • n 2, 3, or 4;
  • X 1 is C, S, or P
  • R 1 is propargyl or C 1-6 alkyl
  • R 2 is absent, hydroxyl, or oxo
  • Z q is a pharmaceutically acceptable counterion present in the stoichiometric ratio appropriate for the compound of formula (I-b) to have no net charge.
  • cation is a structure of formula (II):
  • R 1 and R 2 together with the nitrogen atom to which both are attached and optionally one or more additional heteroatoms, combine to form a 4-8 membered mono- or bi-cyclic heterocycle optionally substituted with ethynyl, trifluoromethyl, —CH 2 Ph, —OH, or —(CH 2 )OH;
  • R 3 is methyl or propargyl
  • R 4 is methyl or propargyl
  • cation is a structure of formula (III):
  • R 1 and R 2 together with the nitrogen atom to which both are attached and optionally one or more additional heteroatoms, combine to form a 4-8 membered mono- or bi-cyclic heterocycle optionally substituted with ethynyl, —OH, or —(CH 2 )OH;
  • R 3 is C 1-6 alkyl optionally substituted with a halogen, hydroxyl, or ethynyl;
  • R 4 is C 1-6 alkyl or propargyl
  • R 2 , R 3 , and R 4 are methyl.
  • a method of inhibiting a CutC choline lyase-mediated conversion of choline to trimethylamine includes contacting the compound described above with the CutC choline lyase.
  • a method of modulating a trimethylamine marker in a subject in need thereof includes administering to the subject in need thereof a therapeutically effective amount of the compound described above (e.g., as a pharmaceutical composition).
  • the trimethylaminuria marker can be, e.g., trimethylamine and/or trimethylamine oxide levels in the subject's blood, plasma, serum, or urine.
  • the amount of the trimethylaminuria marker can be reduced in accordance with the methods of the disclosure.
  • Trimethylaminuria and the associated cardiovascular disorders can be treated using the compounds described above. Accordingly, a method of treating a subject in need thereof includes administering to the subject in need thereof a therapeutically effective amount of the compound described above. For example, a method of treating or preventing a disease associated with trimethylaminuria in a subject in need thereof includes administering a therapeutically effective amount of the compound described above (e.g., as a pharmaceutical composition).
  • the disease associated with trimethylaminuria may be, e.g., a cardiovascular disease, reduced or impaired kidney function, kidney disease, chronic kidney disease, end-stage renal disease, or diabetes mellitus.
  • the cardiovascular disease may be, e.g., angina, arrhythmia, atherosclerosis, cardiomyopathy, congestive heart failure, coronary artery disease, carotid artery disease, endocarditis, coronary thrombosis, myocardial infarction, high blood pressure/hypertension, hypercholesterolemia, hyperlipidemia, mitral valve prolapse, peripheral artery disease, or stroke.
  • a method of modulating a trimethylaminuria marker in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the compounds or pharmaceutical compositions disclosed herein.
  • the trimethylaminuria marker is the trimethylamine and/or trimethylamine oxide level in the subject's blood, plasma, serum, or urine.
  • provided herein is a method of treating or preventing a disease associated with elevated levels of trimethylamine (TMA) or trimethylamine N-oxide (TMAO), a decreased rate of conversion of TMA to TMAO, or a high ratio of TMA to TMAO in a subject in need thereof, the method comprising administering a therapeutically effective amount of at least one of the compounds or pharmaceutical compositions disclosed herein to the subject.
  • the method further comprises detecting the presence of one or more genetic variants of the FMO3 gene of the subject in need before the administering step.
  • the disease associated with elevated levels of TMA or TMAO, a decreased rate of conversion of TMA to TMAO, or a high ratio of TMA to TMAO is a cardiovascular disease, reduced or impaired kidney function, kidney disease, chronic kidney disease, end-stage renal disease, or diabetes mellitus.
  • the cardiovascular disease is angina, arrhythmia, atherosclerosis, cardiomyopathy, congestive heart failure, coronary artery disease, carotid artery disease, endocarditis, coronary thrombosis, myocardial infarction, high blood pressure/hypertension, hypercholesterolemia, hyperlipidemia, mitral valve prolapse, peripheral artery disease, or stroke.
  • provided herein is a method of inhibiting a CutC choline lyase-mediated conversion of choline to trimethylamine, the method comprising contacting at least one of the compounds or pharmaceutical compositions disclosed herein with the CutC choline lyase.
  • provided herein is a method of inhibiting a CntA carnitine monooxygenase-mediated conversion of carnitine to trimethylamine, the method comprising contacting at least one of the compounds or pharmaceutical compositions disclosed herein with the CntA carnitine monooxygenase.
  • provided herein is a method of inhibiting a betaine reductase-mediated conversion of betaine or gamma-butyrobetaine to trimethylamine, the method comprising contacting at least one of the compounds or pharmaceutical compositions disclosed herein with the betaine reductase.
  • provided herein is a method of treating a subject in need of treatment for trimethylaminuria comprising contacting bacteria in vivo with a therapeutically effective amount of at least one of the compounds or pharmaceutical compositions disclosed herein to the subject.
  • the bacteria are localized in the colon of the subject.
  • the present disclosure provides a method of modulating a trimethylamine marker in a subject in need thereof, the method consisting of administering to the subject in need thereof a therapeutically effective amount of at least one compound of the present disclosure or a pharmaceutical composition of the present disclosure.
  • the trimethylaminuria marker is the trimethylamine and/or trimethylamine oxide levels in the subject's blood, plasma, serum, or urine.
  • the present disclosure provides a method of treating or preventing a disease associated with trimethylaminuria in a subject in need thereof, the method comprising administering a therapeutically effective amount of at least one pharmaceutically acceptable salt of at least one compound of the present disclosure or a pharmaceutical composition of the present disclosure to the subject.
  • compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.
  • Pharmaceutical compositions typically include a compound as described herein and a physiologically acceptable excipient (e.g., a pharmaceutically acceptable excipient).
  • the compound described herein can also be used in the form of the free acid/base, in the form of salts, zwitterions, or as solvates. All forms are within the scope of the disclosure.
  • the compounds, salts, zwitterions, solvates, or pharmaceutical compositions thereof may be administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the compounds described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration, and the pharmaceutical compositions formulated accordingly.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.
  • compositions for use in accordance with the present disclosure thus can be formulated in a conventional manner using one or more physiologically acceptable carriers having excipients and auxiliaries that facilitate processing of compounds disclosed herein into preparations which can be used pharmaceutically.
  • compositions which can contain one or more physiologically acceptable carriers.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semisolid, or liquid material (e.g., normal saline), which acts as a vehicle, carrier or medium for the active ingredient.
  • the compositions can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, and soft and hard gelatin capsules.
  • the type of diluent can vary depending upon the intended route of administration.
  • the resulting compositions can include additional agents, e.g., preservatives.
  • excipient or carrier is selected on the basis of the mode and route of administration.
  • Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), a well-known reference text in this field, and in the USP/NF (United States Pharmacopeia and the National Formulary).
  • excipients examples include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include lubricating agents, e.g., talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents, e.g., methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • lubricating agents e.g., talc, magnesium stearate, and mineral oil
  • wetting agents emulsifying and suspending agents
  • preserving agents e.g., methyl- and propylhydroxy-benzoates
  • sweetening agents and flavoring agents.
  • Other exemplary excipients
  • compositions can be manufactured in a conventional manner, e.g., by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
  • Methods well known in the art for making formulations are found, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York. Proper formulation is dependent upon the route of administration chosen.
  • the formulation and preparation of such compositions is well-known to those skilled in the art of pharmaceutical formulation.
  • the compounds can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.
  • the dosage of the compound used in the methods described herein, or pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions thereof can vary depending on many factors, e.g., the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the subject to be treated.
  • One of skill in the art can determine the appropriate dosage based on the above factors.
  • the compounds used in the methods described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response.
  • a suitable daily dose of a compound disclosed herein will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • a compound disclosed herein may be administered to the subject in a single dose or in multiple doses. When multiple doses are administered, the doses may be separated from one another by, for example, 1-24 hours, 1-7 days, or 1-4 weeks.
  • the compound may be administered according to a schedule, or the compound may be administered without a predetermined schedule. It is to be understood that, for any particular subject, specific dosage regimes should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • the compounds may be provided in a dosage form.
  • the unit dosage form may be an oral unit dosage form (e.g., a tablet, capsule, suspension, liquid solution, powder, crystals, lozenge, sachet, cachet, elixir, syrup, and the like) or a food product serving (e.g., the active agents may be included as food additives or dietary ingredients).
  • the dosage form is designed for administration of at least one compound disclosed herein, where the total amount of an administered compound is from 0.1 g to 10 g (e.g., 0.5 g to 9 g, 0.5 g to 8 g, 0.5 g to 7 g, 0.5 g to 6 g, 0.5 g to 5 g, 0.5 g to 1 g, 0.5 g to 1.5 g, 0.5 g to 2 g, 0.5 g to 2.5 g, 1 g to 1.5 g, 1 g to 2 g, 1 g to 2.5 g, 1.5 g to 2 g, 1.5 g to 2.5 g, or 2 g to 2.5 g).
  • 0.1 g to 10 g e.g., 0.5 g to 9 g, 0.5 g to 8 g, 0.5 g to 7 g, 0.5 g to 6 g, 0.5 g to 5 g, 0.5 g to 1 g, 0.5 g to 1.5 g, 0.5 g to
  • the compound is consumed at a rate of 0.1 g to 10 g per day (e.g., 0.5 g to 9 g, 0.5 g to 8 g, 0.5 g to 7 g, 0.5 g to 6 g, 0.5 g to 5 g, 0.5 g to 1 g per day, 0.5 g to 1.5 g per day, 0.5 g to 2 g per day, 0.5 g to 2.5 g per day, 1 g to 1.5 g per day, 1 g to 2 g per day, 1 g to 2.5 g per day, 1.5 g to 2 g per day, 1.5 g to 2.5 g per day, or 2 g to 2.5 g per day) or more.
  • 0.1 g to 10 g per day e.g., 0.5 g to 9 g, 0.5 g to 8 g, 0.5 g to 7 g, 0.5 g to 6 g, 0.5 g to 5 g, 0.5 g to 1 g per day, 0.5
  • an effective amount of the compound disclosed herein may be, for example, a total daily dosage of, e.g., between 0.5 g and 5 g (e.g., 0.5 to 2.5 g) of any of the compound described herein.
  • the dosage amount can be calculated using the body weight of the subject.
  • daily dosages exceed 5 g/day the dosage of the compound may be divided across two or three daily administration events.
  • the time period during which multiple doses of a compound disclosed herein are administered to a subject can vary.
  • doses of the compounds are administered to a subject over a time period that is 1-7 days; 1-12 weeks; or 1-3 months.
  • the compounds are administered to the subject over a time period that is, for example, 4-11 months or 1-30 years.
  • the compounds disclosed herein are administered to a subject at the onset of symptoms.
  • the amount of the compound that is administered may vary during the time period of administration. When a compound is administered daily, administration may occur, for example, 1, 2, 3, or 4 times per day.
  • a compound described herein may be administered to a subject with a pharmaceutically acceptable diluent, carrier, or excipient, in unit dosage form.
  • a pharmaceutically acceptable diluent, carrier, or excipient in unit dosage form.
  • Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer the compound to subjects suffering from a disorder. Administration may begin before the subject is symptomatic.
  • Exemplary routes of administration of the compounds disclosed herein or pharmaceutical compositions thereof, used in the present disclosure include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration.
  • the compounds desirably are administered with a physiologically acceptable carrier (e.g., a pharmaceutically acceptable carrier).
  • Pharmaceutical formulations of the compounds described herein formulated for treatment of the disorders described herein are also part of the present disclosure.
  • the compounds disclosed herein are administered to a subject orally.
  • the compounds disclosed herein are administered to a subject topically.
  • oral dosage forms can be, for example, in the form of tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals, which contain the active ingredient(s) in a mixture with physiologically acceptable excipients (e.g., pharmaceutically acceptable excipients).
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiad
  • Formulations for oral administration may also be presented as chewable tablets, as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
  • Controlled release compositions for oral use may be constructed to release the active drug by controlling the dissolution and/or the diffusion of the active drug substance. Any of a number of strategies can be pursued in order to obtain controlled release and the targeted plasma concentration versus time profile.
  • controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes.
  • compositions include biodegradable, pH, and/or temperature-sensitive polymer coatings.
  • Dissolution or diffusion-controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix.
  • a controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols.
  • the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.
  • liquid forms in which the compounds and compositions of the present disclosure can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils, e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils, e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Dosages for buccal or sublingual administration typically are 0.1 to 500 mg per single dose as required.
  • the physician determines the actual dosing regimen which is most suitable for an individual subject, and the dosage varies with the age, weight, and response of the particular subject.
  • the above dosages are exemplary of the average case, but individual instances exist where higher or lower dosages are merited, and such are within the scope of this disclosure.
  • compositions may take the form of tablets, lozenges, etc. formulated in a conventional manner.
  • Liquid drug formulations suitable for use with nebulizers and liquid spray devices and electrohydrodynamic (EHD) aerosol devices will typically include a compound disclosed herein with a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is a liquid, e.g., alcohol, water, polyethylene glycol, or a perfluorocarbon.
  • another material may be added to alter the aerosol properties of the solution or suspension of compounds disclosed herein. Desirably, this material is liquid, e.g., an alcohol, glycol, polyglycol, or a fatty acid.
  • compositions for nasal administration also may conveniently be formulated as aerosols, drops, gels, and powders.
  • the formulations may be provided in a single or multidose form.
  • dosing may be achieved by the subject administering an appropriate, predetermined volume of the solution or suspension.
  • this may be achieved, for example, by means of a metering atomizing spray pump.
  • the compounds may further be formulated for aerosol administration, particularly to the respiratory tract by inhalation and including intranasal administration.
  • the compounds for nasal or inhalation administration will generally have a small particle size for example on the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • the active ingredient is provided in a pressurized pack with a suitable propellant, e.g., a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide, or other suitable gas.
  • a suitable propellant e.g., a chlorofluorocarbon (CFC)
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant, e.g., lecithin.
  • a surfactant e.g., lecithin.
  • the dose of drug may be controlled by a metered valve.
  • the active ingredients may be provided in a form of a dry powder, e.g., a powder mix of the compound in a suitable powder base, e.g., lactose, starch, and starch derivatives, e.g., hydroxypropylmethyl cellulose, and polyvinylpyrrolidine (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.
  • Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device.
  • the sealed container may be a unitary dispensing device, e.g., a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use.
  • the dosage form comprises an aerosol dispenser, it will contain a propellant, which can be a compressed gas, e.g., compressed air or an organic propellant, e.g., fluorochlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomizer.
  • compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the compounds disclosed herein may be dissolved or suspended in a parenterally acceptable liquid vehicle.
  • acceptable vehicles and solvents water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution and isotonic sodium chloride solution.
  • the aqueous formulation may also contain one or more preservatives, for example, methyl, ethyl or n-propyl p-hydroxybenzoate. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), herein incorporated by reference.
  • USP-NF United States Pharmacopeia-National Formulary
  • the parenteral formulation can be any of the five general types of preparations identified by the USP-NF as suitable for parenteral administration:
  • Exemplary formulations for parenteral administration include solutions of the compounds prepared in water suitably mixed with a surfactant, e.g., hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.
  • Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols, e.g., polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes.
  • Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds or biologically active agents within the compounds.
  • Other potentially useful parenteral delivery systems for compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
  • the parenteral formulation can be formulated for prompt release or for sustained/extended release of the compound.
  • exemplary formulations for parenteral release of the compound include: aqueous solutions, powders for reconstitution, cosolvent solutions, oil/water emulsions, suspensions, oil-based solutions, liposomes, microspheres, and polymeric gels.
  • R 2 is C 2-6 alkyl optionally substituted with one or two hydroxyl, oxo, and —O-(acylated sugar);
  • R 1 and R 2 together with the nitrogen atom to which both are attached, combine to form a 4- or 5-membered heterocyclic ring optionally substituted with ethynyl or —(CH 2 ) n —OR s or an acylated sugar, wherein n is 0 or 1, R s is hydrogen or an acylated sugar;
  • R 3 is C 1-6 alkyl optionally substituted with a halogen or hydroxyl
  • R 4 is C 1-6 alkyl or propargyl.
  • R 1 is C 2-6 alkyl substituted with —O-(acylated sugar) and is optionally further substituted with oxo.
  • R 2 is methyl.
  • R 3 is C 1-6 alkyl.
  • R 4 is propargyl. 9. The compound of embodiment 4, wherein
  • R 1 is C 2-6 alkyl substituted with —O-(acylated sugar) and is optionally further substituted with oxo;
  • R 2 is methyl
  • R 3 is C 1-6 alkyl
  • R 4 is propargyl
  • R 1 is C 2-6 alkyl substituted with isosorbide and is optionally further substituted with oxo and/or methene;
  • R 2 is methyl
  • R 3 is C 1-6 alkyl
  • R 4 is propargyl
  • R 1 is chosen from C 2 alkyl substituted with —O-(acylated sugar) and optionally further substituted with oxo and C 4 alkyl substituted with —O-(acylated sugar) and optionally further substituted with oxo;
  • acylated sugar is chosen from groups of formula (A), groups of formula (B), and groups of formula (C):
  • R 2 is methyl
  • R 3 is methyl
  • R 4 is propargyl
  • R 1 is chosen from C 2 alkyl substituted with isosorbide and optionally further substituted with oxo and C 3 alkyl substituted with isosorbide and optionally further substituted with oxo and methene;
  • isosorbide is chosen from groups of formula (C):
  • R 2 is methyl
  • R 3 is methyl
  • R 4 is propargyl
  • R 1 is C 3-4 cycloalkyl C 1-2 alkyl
  • R 2 is C 2-6 alkyl optionally substituted with one or two hydroxyl, oxo, and —O-(acylated sugar);
  • R 1 and R 2 together with the nitrogen atom to which both are attached, combine to form a 4- or 5-membered heterocyclic ring optionally substituted with ethynyl or —(CH 2 ) n —OR s or an acylated sugar, wherein n is 0 or 1, R s is hydrogen or an acylated sugar;
  • R 3 is C 1-6 alkyl optionally substituted with a halogen or hydroxyl
  • R 4 is C 1-6 alkyl or propargyl.
  • R 1 is C 3-4 cycloalkyl C 1 alkyl.
  • R 2 is C 2 alkyl optionally substituted with one or two hydroxyl groups.
  • R 1 and R 2 together with the nitrogen atom to which both are attached, combine to form a 5-membered heterocyclic ring optionally substituted with ethynyl, —OH, or —CH 2 OH.
  • R 3 is C 1 alkyl optionally substituted with a halogen.
  • R 4 is C 1 alkyl or propargyl. 19.
  • R 1 and R 2 together with the nitrogen atom to which both are attached and optionally one or more additional heteroatoms, combine to form a 4-8 membered mono- or bi-cyclic heterocycle optionally substituted with ethynyl, trifluoromethyl, —CH 2 Ph, —OH, or —(CH 2 )OH;
  • R 3 is methyl or propargyl
  • R 4 is methyl or propargyl
  • R 1 and R 2 together with the nitrogen atom to which both are attached and optionally one or more additional heteroatoms, combine to form a 4-8 membered mono- or bi-cyclic heterocycle optionally substituted with ethynyl, —OH, or —(CH 2 )OH;
  • R 3 is C 1-6 alkyl optionally substituted with a halogen, hydroxyl, or ethynyl;
  • R 4 is C 1-6 alkyl or propargyl
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of any one of embodiments 1 to 20.
  • 22. A method of modulating a trimethylaminuria marker in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of any one of embodiments 1 to 20 or the pharmaceutical composition of embodiment 21.
  • 23. The method of embodiment 22, wherein the trimethylaminuria marker is the trimethylamine and/or trimethylamine oxide levels in the subject's blood, plasma, serum, or urine. 24.
  • a method of treating or preventing a disease associated with elevated levels of trimethylamine (TMA) or trimethylamine N-oxide (TMAO), a decreased rate of conversion of TMA to TMAO, or a high ratio of TMA to TMAO in a subject in need thereof comprising administering a therapeutically effective amount of the compound of any one of embodiments 1 to 20 or the pharmaceutical composition of embodiment 21 to the subject. 25. The method of embodiment 24, further comprising detecting the presence of one or more genetic variants of the FMO3 gene of the subject in need before the administering step. 26.
  • TMA trimethylamine
  • TMAO trimethylamine N-oxide
  • a decreased rate of conversion of TMA to TMAO, or a high ratio of TMA to TMAO is a cardiovascular disease, reduced or impaired kidney function, kidney disease, chronic kidney disease, end-stage renal disease, or diabetes mellitus.
  • a method of inhibiting a CntA carnitine monooxygenase-mediated conversion of carnitine to trimethylamine comprising contacting the compound of any one of embodiments 1 to 20 with the CntA carnitine monooxygenase.
  • a method of treating a subject in need of treatment for trimethylaminuria comprising contacting bacteria in vivo with a therapeutically effective amount of the compound of any one of embodiments 1 to 20 or the pharmaceutical composition of embodiment 21 to the subject.
  • the title compounds may exist as a trifluoroacetate salt after prep-HPLC but one of ordinary skill in the art would understand that the salt may be changed by conventional methods of salt formation.
  • This compound may be synthesized according to the experimental procedure described for Compound 1.
  • This compound may be synthesized according to the experimental procedure described for Compound 1.
  • This compound may be synthesized according to the experimental procedure described for Compound 1.
  • This compound may be synthesized according to the experimental procedure described for Compound 1.
  • This compound may be synthesized according to the experimental procedure described for Compound 1.
  • This compound may be synthesized according to the experimental procedure described for Compound 7.
  • This compound may be synthesized according to the experimental procedure described for Compound 7.
  • This compound may be synthesized according to the experimental procedure described for Compound 7.
  • This compound may be synthesized according to the experimental procedure described for Compound 13.
  • This compound may be synthesized according to the experimental procedure described for Compound 13.
  • This compound may be synthesized according to the experimental procedure described for Compound 13.
  • This compound may be synthesized according to the experimental procedure described for Compound 13.
  • This compound may be synthesized according to the experimental procedure described for Compound 13.
  • This compound may be synthesized according to the experimental procedure described for Compound 19.
  • This compound may be synthesized according to the experimental procedure described for Compound 19.
  • This compound may be synthesized according to the experimental procedure described for Compound 19.
  • This compound may be synthesized according to the experimental procedure described for Compound 19.
  • This compound may be synthesized according to the experimental procedure described for Compound 19.
  • This compound may be synthesized according to the experimental procedure described for Compound 26.
  • This compound may be synthesized according to the experimental procedure described for Compound 30.
  • the reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC [water (0.1% TFA)-ACN].
  • the title compound (0.006 g, 10.5 ⁇ mol, 2.5% yield, mixture of anomers) was obtained as colorless oil.
  • This compound may be synthesized according to the experimental procedure described for Compound 33.
  • This compound may be synthesized according to the experimental procedure described for Compound 36.
  • This compound may be synthesized according to the experimental procedure described for Compound 38.
  • This compound may be synthesized according to the experimental procedure described for Compound 38.
  • This compound may be synthesized according to the experimental procedure described for Compound 38.
  • This compound may be synthesized according to the experimental procedure described for Compound 45.
  • This compound may be synthesized according to the experimental procedure described for Compound 45.
  • This compound may be synthesized according to the experimental procedure described for Compound 1.
  • Compound 70 N-(2-(((3S,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-2-oxoethyl)-N,N-dimethylprop-2-yn-1-aminium trifluoroacetate
  • reaction mixture was quenched by addition of H 2 O (40 mL) at 0° C., and then diluted with EtOAc (40 mL) and extracted with EtOAc (40 mL*3). The combined organic layers were dried over Na 2 SO 4 , filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • reaction mixture was quenched by addition of H 2 O (30 mL) at 15° C., and then diluted with EtOAc (30 mL) and extracted with EtOAc (30 mL*4). The combined organic layers were dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to give a residue.
  • This compound may be synthesized according to the experimental procedure described for Compound 344.
  • This compound may be synthesized according to the experimental procedure described for Compound 344.
  • Tetrahydrofuran (5 mL) was added to 60% NaH (0.2 g, 5.0 mmol, 1.3 eq) in mineral oil under nitrogen, followed by addition of TBAI (71 mg, 0.22 mmol, 0.05 eq), then cooled to 0° C.
  • Compound 1,2:5,6-Di-O-isopropylidene- ⁇ -D-glucofuranose (Sigma Aldrich, CAS: 582-52-5, 1 g, 3.8 mmol, 1 eq) in THF (3 mL) was added dropwise, followed by dropwise addition of benzyl bromide (0.55 mL, 4.6 mmol, 1.2 eq).
  • Residue was purified by normal phase flash chromatography (0-10% methanol in DCM) to give (2S,3S,4R,5S,6S)-2-(acetoxymethyl)-6-(2-(dimethylamino)ethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate, Iodide (1.6 g, 37%) as a yellow oil that crystallized upon standing.
  • Residue was purified by normal phase flash chromatography (0-10% methanol in DCM) to give (2S,3S,4R,5S,6S)-2-(acetoxymethyl)-6-(2-(dimethylamino)ethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate, Iodide (1.0 g, 42%) as a yellow oil that crystallized upon standing.
  • This compound may be synthesized according to the experimental procedure described for Compound 7.
  • This compound may be synthesized according to the experimental procedure described for Compound 325.

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IT202300012522A1 (it) 2023-06-22 2024-12-22 Alfasigma Spa Fluorometil-carnitina per uso come inibitore di colina trimetilammina (tma) liasi.
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