WO2017123823A1 - Alkyl-, acyl-, urea-, and aza-uracil sulfide:quinone oxidoreductase inhibitors - Google Patents

Alkyl-, acyl-, urea-, and aza-uracil sulfide:quinone oxidoreductase inhibitors Download PDF

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WO2017123823A1
WO2017123823A1 PCT/US2017/013273 US2017013273W WO2017123823A1 WO 2017123823 A1 WO2017123823 A1 WO 2017123823A1 US 2017013273 W US2017013273 W US 2017013273W WO 2017123823 A1 WO2017123823 A1 WO 2017123823A1
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alkyl
compound
salt
phenyl
hydrogen
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Andrew W. Hinman
Weng Chang
Kevin Mccusker
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Bioelectron Technology Corporation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil

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Abstract

This application discloses compounds and pharmaceutical compositions and methods of using the same for inhibition of sulfide:quinone oxidoreductase (SQOR).

Description

ALKYL, ACYL, UREA, AND AZA-URACIL SULFIDE : QUINONE
OXIDOREDUCTASE INHIBITORS
FIELD
[0001] This application discloses compounds and compositions and methods of using the same for inhibition of sulfide:quinone oxidoreductase (SQOR).
BACKGROUND
[0002] Mitochondrial metabolism of H2S is coupled to the synthesis of ATP. The first step of this pathway is catalyzed by sulfide:quinone oxidoreductase (SQOR or SQR), an inner mitochondrial membrane-bound flavoenzyme that is ubiquitously expressed in animals and also found in some lower eukaryotes. SQOR catalyzes a 2-electron oxidation of H2S to sulfane sulfur (S°) using coenzyme Q as electron acceptor. The enzyme also appears to require an acceptor for the sulfane sulfur. Sulfite has been proposed as the physiological acceptor of the sulfane sulfur and further proposed that the SQOR reaction is the predominant source of the thiosulfate (a known intermediate in the oxidation of H2S by intact animals and the major product formed in glutathi one-depleted cells or mitochondria) produced during H2S oxidation by mammalian tissues. Jackson, M.R., et al. "Human Sulfide:Quinone Oxidoreductase Catalyzes the First Step in Hydrogen Sulfide Metabolism and Produces a Sulfane Sulfur Metabolite", Biochemistry. Publication Date (Web): 01 Aug 2012.
SUMMARY
[0003] Provided herein are compounds, compositions (including pharmaceutical compositions) comprising the compounds, and methods of using the same for inhibition of sulfide:quinone oxidoreductase (SQOR).
[0004] In one aspect, provided herein is a compound of Formula la:
Figure imgf000002_0001
Formula la
wherein Ria is hydrogen or methyl; Y1 is -C(0)-(C4-Cio n-alkyl); Wi is C(R3); and one of R2a and R3a is halo and the other is hydrogen or methyl; wherein when Ria is H and one of R2a and R3a is hydrogen then the other is selected from the group consisting of Br, CI, and I; or a salt thereof; or
Ria is hydrogen; Y1 is -C(0)-(C3-C15 alkyl) or -C(0)-(phenyl); Wi is nitrogen; and R2a is methyl or halo; or a salt thereof; or
a compound selected from
Figure imgf000003_0001
or a salt thereof.
[0005] In another aspect, provided herein is a pharmaceutical composition comprising a compound, as described herein (including, but not limited to, a compound according to any one of Formulas I, la, II, III, IV, and V, or any embodiments thereof, as described herein (including any of the specific compounds recited herein), and a pharmaceutically acceptable carrier. In another aspect, provided herein is a pharmaceutical composition comprising an active agent and a pharmaceutically acceptable carrier, wherein the active agent consists of, or consists essentially of, a compound as described herein(including, but not limited to, a compound according to any one of Formulas I, la, II, III, IV, and V, or any embodiments thereof), as described herein (including any of the specific compounds recited herein ). Any one or more of the compounds described herein, including a compound according to any one of Formulas I, la, II, III, IV, and V, or any embodiments thereof as described herein (including any of the specific compounds recited herein) , can be formulated into a unit dose formulation.
[0006] In another aspect, provided herein is a method of inhibiting SQOR activity in an individual or a tissue sample, including: administering to the individual or tissue sample an effective amount of a compound of Formula I:
Figure imgf000004_0001
Formula I
wherein
Ri is Ci-Cio alkyl optionally substituted with phenyl; or Ri is hydrogen;
R2 is selected from the group consisting of hydrogen, halo, and methyl;
R3 is selected from the group consisting of hydrogen, halo, and methyl;
W is C(R3) or nitrogen; and
Y is selected from the group consisting of C1-C10 alkyl optionally substituted with phenyl, with the proviso that Y contains 3-12 carbons total; -C(O)-(C4-Ci0 n-alkyl); -C(0)NH- (C3-C10 n-alkyl); -C(0)NH-(Ci-C2 n-alkyl-phenyl); -C(0)-( C3-Ci5 alkyl); and -C(O)- (phenyl); or
a salt thereof;
or administering a compound of any one of Formulas Ia-V, or any embodiments thereof, as described herein (including any of the specific compounds described herein)); or administering a pharmaceutical composition as described herein(including any of the compositions described in the foregoing paragraph).
[0007] In another aspect, provided herein is the use of a compound as described herein, including, but not limited to, any of the foregoing embodiments, for inhibiting SQOR. In another aspect, provided herein is the use of a compound as described herein, including, but not limited to, any of the foregoing embodiments, in the manufacture of a medicament for use in inhibiting SQOR.
DETAILED DESCRIPTION
[0008] Provided herein are compounds useful in inhibiting SQOR. SQOR converts hydrogen sulfide to thiosulfate; excess hydrogen sulfide in a cell induces decreased respiration and/or hibernation. Accordingly, these compounds are useful in increasing endogenous hydrogen sulfide. The compounds may be useful in decreasing respiration rate and/or inducing hibernation in an individual, tissue, or cell. Decreased cellular respiration may be useful, for example, in some or any embodiments, trauma settings in order to decrease cellular damage from respiration until the patient can be stabilized. In some or any embodiments, decreased cellular respiration may be useful to stabilize a donor organ prior to transplantation. In some or any embodiments, decreased cellular respiration may be useful for protection from hypoxic and ischemic injury.
Definitions
[0009] The abbreviations used herein have their conventional meaning within the chemical and biological arts, unless otherwise specified.
[0010] It is to be understood that the description of compounds, compositions, formulations, and methods of treatment described herein include "comprising", "consisting of, and "consisting essentially of embodiments. In some embodiments, for all compositions described herein, and all methods using a composition described herein, the compositions can either comprise the listed components or steps, or can "consist essentially of the listed components or steps. When a composition is described as "consisting essentially of the listed components, the composition contains the components listed, and may contain other components which do not substantially affect the condition being treated, but do not contain any other components which substantially affect the condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the condition being treated, the composition does not contain a sufficient concentration or amount of the extra components to substantially affect the condition being treated. When a method is described as "consisting essentially of the listed steps, the method contains the steps listed, and may contain other steps that do not substantially affect the condition being treated, but the method does not contain any other steps which substantially affect the condition being treated other than those steps expressly listed. As a non-limiting specific example, when a composition is described as 'consisting essentially of a component, the composition may additionally contain any amount of pharmaceutically acceptable carriers, vehicles, or diluents and other such components which do not substantially affect the condition being treated.
[0011] Reference to "about" a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X". [0012] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with temperatures, doses, amounts, or weight percent of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by those of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. Specifically, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent within 15%, within 10%, within 5%, within 4%, within 3%), within 2%, within 1%, or within 0.5% of the specified dose, amount, or weight percent.
[0013] As used herein, the terms "a" or "an," refer to one or more, unless context clearly dictates otherwise.
[0014] As used herein, the terms "subject," "individual," or "patient" refer to an individual organism, in some embodiments a vertebrate, in other embodiments a mammal, in yet other embodiments a human.
[0015] As used herein, the terms "SQR" and "SQOR" are used interchangeably herein and refer to the enzyme sulfide:quinone oxidoreductase.
[0016] While the compounds described herein can occur and can be used as the neutral (non- salt) compound, the description is intended to embrace all salts of the compounds described herein, as well as methods of using such salts of the compounds. In some embodiments, the salts of the compounds include pharmaceutically acceptable salts. Pharmaceutically acceptable salts are those salts which can be administered as drugs or pharmaceuticals to humans and/or animals and which, upon administration, retain at least some of the biological activity of the free compound (neutral compound or non-salt compound). The desired salt of a basic compound may be prepared by methods known to those of skill in the art by treating the compound with an acid. In some embodiments, inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. In some embodiments, organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid. Salts of basic compounds with amino acids, such as aspartate salts and glutamate salts, can also be prepared. The desired salt of an acidic compound can be prepared by methods known to those of skill in the art by treating the compound with a base. In some embodiments, inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts. In some embodiments, organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, Ν,Ν-dibenzylethylenediamine, and triethylamine salts. Salts of acidic compounds with amino acids, such as lysine salts, can also be prepared.
[0017] Included herein, if chemically possible, are all stereoisomers of the compounds, including diastereomers and enantiomers. Also included are mixtures of possible stereoisomers in any ratio, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly indicated in a structure, the structure is intended to embrace all possible stereoisomers of the compound depicted. If stereochemistry is explicitly indicated for one portion or portions of a molecule, but not for another portion or portions of a molecule, the structure is intended to embrace all possible stereoisomers for the portion or portions where stereochemistry is not explicitly indicated.
[0018] The description of compounds herein also includes all isotopologues, in some embodiments, partially deuterated or perdeuterated analogs of all compounds herein.
[0019] As used herein, the term "alkyl" is intended to embrace a saturated linear, branched, or cyclic hydrocarbon, or any combination thereof. The point of attachment of the alkyl group to the remainder of the molecule can be at any chemically possible location on the alkyl group. In some embodiments, non-limiting examples of "Ci-C6 alkyl" include methyl, ethyl, ^-propyl, isopropyl, cyclopropyl, «-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopropyl-methyl, methyl-cyclopropyl, pentyl, cyclopentyl, hexyl, and cyclohexyl. In some embodiments, alkyl is a saturated linear or branched hydrocarbon. In some embodiments, alkyl comprises a cyclic hydrocarbon.
[0020] As used herein, the term "alkyl-phenyl" is intended to embrace any alkyl, as defined herein, having at least one phenyl substituent (in some embodiments, one or two phenyl substituents); where the alkyl is attached to the remainder of the compound and the phenyl(s) are attached to any chemically-possible location on the carbon atom of the alkyl moiety. In some embodiments, the alkyl of the alkyl-phenyl is Ci-C6 n-alkyl-phenyl or Ci-C2 n-alkyl- phenyl. In some embodiments, the alkyl of the alkyl-phenyl is Ci-C2 n-alkyl-phenyl. In some embodiments, the alkyl-phenyl is benzyl, phenethyl, 3-phenylpropyl, a-methylbenzyl, a- ethylbenzyl, or a-propylbenzyl, and the like.
[0021] As used herein, the terms "solvent", "inert organic solvent" or "inert solvent" refer to a solvent inert under the conditions of the reaction being described in conjunction therewith. Solvents employed in synthesis of the compounds disclosed herein include, in some embodiments, methanol ("MeOH"), acetone, water, acetonitrile, 1,4-dioxane, dimethylformamide ("DMF"), benzene, toluene, xylene, tetrahydrofuran ("THF"), chloroform, methylene chloride (or dichloromethane, ("DCM")), diethyl ether, pyridine, and the like, as well as mixtures thereof. Unless specified to the contrary, the solvents used in the reactions disclosed herein are inert organic solvents.
[0022] As used herein, the term "q.s." refers to adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).
[0023] As used herein, the terms "pharmaceutical formulation" and "pharmaceutical composition" are used interchangeably herein.
[0024] In one embodiment, provided is a method of inhibiting SQOR activity in an individual or a tissue sample, comprising: administering an effective amount of a compound of Formula I which is according to Formula II or a pharmaceutical composition thereof as described herein:
Figure imgf000008_0001
Formula II
wherein: Ri is Ci-Cio alkyl optionally substituted with phenyl, with the proviso that Ri contains 3-12 carbons total; Y is Ci-Cio alkyl optionally substituted with phenyl, with the proviso that Y contains 3-12 carbons total; R3 is selected from the group consisting of hydrogen, methyl, and halo; and R2 is hydrogen or fluoro; or a salt thereof. In some embodiments, Ri is C5-n-alkyl, C6-n-alkyl, C7-n-alkyl, C8-n-alkyl, -(CH2)3-CH(CH3)2, - CH2CH2-cyclohexyl, or -CH2CH2-phenyl. In some embodiments, Y is C5-n-alkyl, C6-n-alkyl, Cv-n-alkyl, C8-n-alkyl, -(CH2)3-CH(CH3)2, -CH2CH2-cyclohexyl, or -CH2CH2-phenyl. In some embodiments, Ri and Y are independently selected from the group consisting of C4-C7 alkyl. In some embodiments, Ri and Y are independently selected from the group consisting of C5-C6 alkyl. In some embodiments, including any of the foregoing embodiments, Ri is the same as Y. In some embodiments, including any of the foregoing embodiments, R3 is hydrogen. In some embodiments, including any of the foregoing embodiments, R3 is methyl. In some embodiments, including any of the foregoing embodiments, R3 is halo. In some embodiments, including any of the foregoing embodiments, R3 is chloro. In some
embodiments, including any of the foregoing embodiments, R2 is fluoro. In some
embodiments, including any of the foregoing embodiments, R2 is hydrogen. In some embodiments, the compound is:
Figure imgf000009_0001
a salt thereof. In some embodiments, the compound is:
Figure imgf000009_0002
or a salt thereof. In some embodiments, the compound is: or a salt thereof. In some embodiments, the compound is:
; or a salt thereof. In some embodiments, the compound is: ; or a salt thereof. In some embodiments, the compound is:
; or a salt thereof. In some embodiments, the compound is:
r a salt thereof. In some embodiments, the compound is:
Figure imgf000010_0002
; or a salt thereof. In some embodiments, the compound is:
Figure imgf000011_0001
or a salt thereof. In some embodiments, including any of the foregoing embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, including any of the foregoing embodiments, the compound has a formula according to Formula II. In some embodiments, Ri is Cs-n-alkyl. In some embodiments, Ri is C6-n-alkyl. In some embodiments, Ri is C7-n-alkyl. In some embodiments, Ri is C8-n-alkyl. In some embodiments, Ri is -(CH2)3-CH(CH3)2. In some embodiments, Ri is -CH2CH2-cyclohexyl. In some embodiments, Ri is -CH2CH2-phenyl. In some embodiments, Y is C5-n-alkyl. In some embodiments, Y is C6-n-alkyl. In some embodiments, Y is C7-n-alkyl. In some embodiments, Y is C8-n-alkyl. In some embodiments, Y is -(CH2)3-CH(CH3)2. In some embodiments, Y is - CH2CH2-cyclohexyl. In some embodiments, Y is -CH2CH2-phenyl. In some embodiments, including any of the foregoing embodiments, R3 is bromo. In some embodiments, including any of the foregoing embodiments, R3 is fluoro. In some embodiments, including any of the foregoing embodiments, R3 is iodo.
[0025] In another embodiment, provided is a method of inhibiting SQOR activity in an individual or a tissue sample, comprising: administering an effective amount of a compound of Formula I which is according to Formula III, or a pharmaceutical composition thereof as described herein, to the individual or tissue sample:
Figure imgf000011_0002
Formula III
wherein
one of R3 and R2 is halo and the other is hydrogen or methyl; and
Y is selected from the group consisting of -C(O)-(C4-Ci0 n-alkyl); -C(O)NH-(C3-Ci0 n-alkyl); -C(0) H-(Ci-C2 n-alkyl-phenyl); -C(0)-( C3-Ci5 alkyl); and -C(0)-(phenyl); or a salt thereof. In some embodiments, including any of the foregoing embodiments, Y is -C(0)-(C4- C8 n-alkyl). In some embodiments, including any of the foregoing embodiments, Y is -C(O)- (C6-C7 n-alkyl). In some embodiments, including any of the foregoing embodiments, Y is - C(0)-(C6 n-alkyl). In some embodiments, including any of the foregoing embodiments, Y is -C(0)-(C7 n-alkyl). In some embodiments, including any of the foregoing embodiments, R3 is hydrogen. In some embodiments, including any of the foregoing embodiments, R3 is methyl. In some embodiments, including any of the foregoing embodiments, R3 is halo. In some embodiments, including any of the foregoing embodiments, R3 is chloro. In some embodiments, including any of the foregoing embodiments, R3 is iodo. In some embodiments, including any of the foregoing embodiments, R2 is halo. In some embodiments, including any of the foregoing embodiments, R2 is bromo. In some embodiments, including any of the foregoing embodiments, R2 is chloro. In some embodiments, including any of the foregoing embodiments, R2 is fluoro. In some embodiments, including any of the foregoing embodiments, R2 is hydrogen. In some embodiments, the compound is:
Figure imgf000012_0001
; or a salt thereof. In some embodiments, the compound is:
or a salt thereof. In some embodiments, the compound is:
Figure imgf000012_0002
or a salt thereof. In some embodiments, the compound is: or a salt thereof. In some embodiments, the compound is:
or a salt thereof. In some embodiments, the compound is:
or a salt thereof. In some embodiments, the compound is:
a salt thereof. In some embodiments, the compound is:
Figure imgf000013_0001
Me ; or a salt thereof. In some embodiments, including any of the foregoing embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, including any of the foregoing embodiments, the compound has a formula according to Formula III. In some embodiments, including any of the foregoing embodiments, Y is - C(0) H-(C4-C8 n-alkyl). In some embodiments, including any of the foregoing embodiments, Y is -C(0) H-(C6-C7 n-alkyl). In some embodiments, including any of the foregoing embodiments, Y is
-C(0) H-(C6 n-alkyl). In some embodiments, including any of the foregoing embodiments, Y is -C(0) H-(C7 n-alkyl). In some embodiments, including any of the foregoing embodiments, Y is -C(0) H-(Ci-C2 n-alkyl-phenyl). In some embodiments, including any of the foregoing embodiments, Y is -C(0)-( C3-C15 alkyl). In some embodiments, including any of the foregoing embodiments, Y is -C(0)-(phenyl). In some embodiments, including any of the foregoing embodiments, R3 is bromo. In some embodiments, including any of the foregoing embodiments, R3 is fluoro. In some embodiments, including any of the foregoing embodiments, R2 is iodo.
[0026] In another embodiment, provided is a method of inhibiting SQOR activity in an individual or a tissue sample, comprising: administering an effective amount of a compound of Formula I which is according to Formula IV, or a pharmaceutical composition thereof as described herein, to the individual or tissue sample:
Figure imgf000014_0001
Formula IV
wherein
R2 is halo; and
Y is selected from the group consisting of -C(O) H-(C3-Ci0 n-alkyl) and -C(0) H-(Ci-C2 n- alkyl-phenyl); or a salt thereof. In some embodiments, Y is -C(0) H-(C3-Cio n-alkyl). In some embodiments, Y is -C(0) H-(C3 n-alkyl). In some embodiments, Y is -C(0) H-(C6 n-alkyl). In some embodiments, Y is -C(0) H-(C8 n-alkyl). In some embodiments, Y is - C(0) H-(Ci-C2 n-alkyl-phenyl). In some embodiments, Y is -C(0) H-(Ci alkyl-phenyl). In some embodiments, Y is -C(0) H-(C2 n-alkyl-phenyl). In some embodiments, including any of the foregoing embodiments, R2 is fluoro. In some embodiments, including any of the foregoing embodiments, R2 is chloro. In some embodiments, the compound is:
Figure imgf000014_0002
thereof. In some embodiments, the compound is:
Figure imgf000014_0003
; or a salt thereof. In some embodiments, the compoun ; or a salt thereof. In some
embodiments, the compound is:
Figure imgf000015_0001
or a salt thereof. In some
embodiments, the compound is:
Figure imgf000015_0002
or a salt thereof. In some embodiments,
the compound a salt thereof. In some embodiments, the
compound is:
Figure imgf000015_0003
; or a salt thereof. In some embodiments, including any of the foregoing embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, including any of the foregoing embodiments, the compound has a formula according to Formula IV. In some embodiments, including any of the foregoing embodiments, R2 is bromo. In some embodiments, including any of the foregoing embodiments, R2 is iodo.
[0027] In one embodiment, provided is a method of inhibiting SQOR activity in an individual or a tissue sample, comprising: administering an effective amount of a compound of Formula I according to Formula V as described herein, or a pharmaceutical composition thereof as described herein, to the individual or tissue sample:
Figure imgf000016_0001
Formula V
wherein
R2 is methyl or halo; and
Y is selected from the group consisting of -C(0)-(C3-Ci5 alkyl), and -C(0)-(phenyl); or a salt thereof. In some embodiments, Y is -C(0)-(isopropyl), -C(0)-(C5-n-alkyl), -C(0)-(C6- n-alkyl), -C(0)-(C7-n-alkyl), -C(0)-(C8-n-alkyl), -C(0)-(C9-n-alkyl), -C(O)-(Ci0-n-alkyl), - C(0)-(Cn-n-alkyl), -C(0)-(Ci2-n-alkyl), -C(0)-(Ci3-n-alkyl), -C(0)-(cyclohexyl), -C(O)- (CH2-cyclohexyl), -C(0)-(CH2CH2-cyclopentyl), or -C(0)-(phenyl). In some embodiments,
Y is -C(0)-(isopropyl), -C(0)-(C5-n-alkyl), -C(0)-(C6-n-alkyl), -C(0)-(C7-n-alkyl), -C(0)-(C8-n- alkyl), -C(0)-(C9-n-alkyl), -C(O)-(Ci0-n-alkyl), -C(0)-(Cn-n-alkyl), -C(0)-(Ci2-n-alkyl), or -C(0)-(Ci3-n-alkyl). In some embodiments, Y is -C(0)-(cyclohexyl), -C(0)-(CH2- cyclohexyl), or -C(0)-(CH2CH2-cyclopentyl). In some embodiments, Y is -C(0)-(phenyl). In some embodiments, including any of the foregoing embodiments, R2 is methyl. In some embodiments, including any of the foregoing embodiments, R2 is halo (e.g. fluoro, chloro, bromo, or iodo). In some embodiments, including any of the foregoing embodiments, R2 is
bromo. In some embodiments, the compound is:
Figure imgf000016_0002
Figure imgf000016_0003
Figure imgf000017_0001
thereof. In some embodiments, the compound is: · or a salt thereof. In some embodiments, the compound is:
Figure imgf000017_0002
Me · or a salt thereof. In some embodiments, the compoun r a salt thereof. In some embodiments, the compound is: a salt thereof. In some embodiments, the compound is:
Figure imgf000017_0003
Me · r a salt thereof. In some embodiments, the compound is:
Figure imgf000017_0004
or a salt thereof. In some embodiments, or a salt thereof. In some
embodiments, the compound is
Figure imgf000018_0001
; or a salt thereof. In some embodiments, the
Figure imgf000018_0002
or a salt thereof. In some embodiments, the compound is:
; or a salt thereof. In some embodiments, including any of the foregoing embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, including any of the foregoing embodiments, the compound has a formula according to Formula V. In some embodiments, Y is -C(0)-(C3-Ci5 alkyl). In some embodiments, Y is -C(0)-(isopropyl). In some embodiments, Y is -C(0)-(C5-n-alkyl). In some embodiments, Y is -C(0)-(C6-n-alkyl). In some embodiments, Y is -C(0)-(C7-n-alkyl). In some embodiments, Y is -C(0)-(C8-n- alkyl). In some embodiments, Y is -C(0)-(Cci-n-alkyl). In some embodiments, Y is -C(O)- (Cio-n-alkyl). In some embodiments, Y is -C(0)-(Cn-n-alkyl). In some embodiments, Y is - C(0)-(Ci2-n-alkyl). In some embodiments, Y is -C(0)-(Ci3-n-alkyl). In some embodiments, Y is -C(0)-(cyclohexyl). In some embodiments, Y is -C(0)-(CH2-cyclohexyl). In some embodiments, Y is -C(0)-(CH2CH2-cyclopentyl). In some embodiments, including any of the foregoing embodiments, R2 is fluoro. In some embodiments, including any of the foregoing embodiments, R2 is chloro. In some embodiments, including any of the foregoing embodiments, R2 is iodo.
[0028] In another embodiment, provided is a compound of Formula la:
Figure imgf000019_0001
Ria is hydrogen or methyl; Yi is -C(O)-(C4-Ci0 n-alkyl); W1 is C(R3); and one of R2a and R3a is halo and the other is hydrogen or methyl; wherein when Ria is H and one of R2a and R3a is hydrogen then the other is selected from the group consisting of Br, CI, and I; or a salt thereof; or Ria is hydrogen; Y1 is -C(0)-(C3-C15 alkyl) or -C(0)-(phenyl); Wi is nitrogen; and R2a is methyl or halo; or a salt thereof; or a compound selected from
Figure imgf000019_0002
or a slat thereof. In some or any embodiments, the Compound of Formula la is where Ria is hydrogen or methyl; Y1 is -C(O)-(C4-C10 n-alkyl); Wi is C(R3); and one of R2a and R3a is halo and the other is hydrogen or methyl; wherein when Ria is H and one of R2a and R3a is hydrogen then the other is selected from the group consisting of Br, CI, and I; or a salt thereof. In some or any embodiments, the Compound of Formula la is where Ria is hydrogen; Yi is -C(0)-(C3-Ci5 alkyl) or -C(0)-(phenyl); Wi is nitrogen; and R2a is methyl or halo; or a salt thereof. In some or any embodiments, Ria is hydrogen. In some or any embodiments, Ria is methyl. In some or any embodiments, Ria is hydrogen; Yi is -C(0)-(C3-C15 alkyl) or -C(0)-(phenyl); W1 is nitrogen; and R2a is methyl or Br. In some or any embodiments, the Compound of Formula la is where Ria is hydrogen; Y1 is -C(0)-(C3-C15 alkyl); Wi is nitrogen; and R2a is methyl or halo; or a salt thereof. In some or any embodiments, the Compound of Formula la is where Ria is hydrogen; Yi is -C(0)-(phenyl); W1 is nitrogen; and R2a is methyl or halo; or a salt thereof. In some or any embodiments, the compound is selected from:
Figure imgf000020_0001
the compound is
Figure imgf000021_0001
In some embodiments, the compound is
Figure imgf000021_0002
In some embodiments, the compound is In some embodiments, the compound is
Figure imgf000021_0003
In some embodiments, the compound
Figure imgf000021_0004
[0029] In some embodiments, the compound is:
Figure imgf000021_0005
mpound is:
pound is:
Figure imgf000022_0001
; or a salt thereof. In some embodiments, the compound is:
salt thereof. In some embodiments, the compound is: or a salt thereof. In some embodiments, the compound is:
Figure imgf000022_0002
or a salt thereof. In some embodiments, the compound is: r a salt thereof. In some embodiments, the compound is:
or a salt thereof. In some embodiments, the compound is: r a salt thereof. In some embodiments, the compound is: r a salt thereof. In some embodiments, the compound is
Figure imgf000023_0001
or a salt thereof.
[0030] In some embodiments, the compound
Figure imgf000023_0002
Figure imgf000024_0001
or a salt thereof. In thereof. In some embodiments, the compound i some embodiments, the compound is:
Figure imgf000025_0001
or a salt thereof.
[0031] In some embodiments, the compound
Figure imgf000025_0002
Figure imgf000025_0003
e
Figure imgf000025_0004
mbodiments, the compound is: ; or a salt thereof. In some embodiments,
O
O^NT — — 'Me
the compound is: H ; or a salt thereof. In some embodiments, the
compound is:
Figure imgf000025_0005
; or a salt thereof. In some embodiments, the
Figure imgf000026_0001
salt thereof. In some embodiments, the compoun ; or a salt thereof. In some embodiments, the compound is:
Figure imgf000027_0001
Me · or a salt thereof. In some embodiments, the compoun r a salt thereof. In some embodiments, the compound is: a salt thereof. In some embodiments, the compound is:
Figure imgf000027_0002
Me · r a salt thereof. In some embodiments, the compound is: Me · or a salt thereof. In some embodiments, the com
Figure imgf000027_0003
pound is: ; or a salt thereof. In some embodiments, the compound is:
Figure imgf000028_0001
; or a salt thereof. In some embodiments, the
compound is:
Figure imgf000028_0002
; or a salt thereof. In some embodiments, the compound is:
Figure imgf000028_0003
; or a salt thereof.
[0033] In another embodiment is a pharmaceutical composition comprising a compound as described herein (including but not limited to a compound described in any of the preceding paragraphs) and a pharmaceutically acceptable carrier. In another aspect is a pharmaceutical composition comprising an active agent and a pharmaceutically acceptable carrier, wherein the active agent consists of, or consists essentially of, a compound as described herein (including but not limited to a compound described in any of the preceding paragraphs). Any one or more of the compounds described herein, including all of the foregoing compounds, can be formulated into a unit dose formulation.
[0034] In another embodiment is the use of a compound as described herein, including but not limited to any of the foregoing embodiments, for inhibiting SQOR. In another aspect is the use of a compound as described herein, including but not limited to any of the foregoing embodiments, in the manufacture of a medicament for use in inhibiting SQOR.
Pharmaceutical compositions
[0035] The compounds described herein can be formulated as pharmaceutical compositions by formulation with additives such as pharmaceutically acceptable excipients, pharmaceutically acceptable carriers, and pharmaceutically acceptable vehicles. The terms "pharmaceutically acceptable excipients," "pharmaceutically acceptable carriers," and "pharmaceutically acceptable vehicles" are used interchangeably herein. Suitable pharmaceutically acceptable excipients, carriers and vehicles include processing agents and drug delivery modifiers and enhancers, such as, in some embodiments, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl- -cyclodextrin, polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more thereof. Other suitable pharmaceutically acceptable excipients are described in "Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991), and "Remington: The Science and Practice of Pharmacy," Lippincott Williams & Wilkins, Philadelphia, 20th edition (2003) and 21st edition (2005), incorporated herein by reference.
[0036] A pharmaceutical composition can comprise a unit dose formulation. The unit dose may be sufficient as a single dose to have the desired effect, or alternatively, the unit dose may be a dose administered periodically.
[0037] Pharmaceutical compositions containing the compounds disclosed herein may be in any form suitable for the intended method of administration, including, in some embodiments, a solution, a suspension, or an emulsion. Liquid carriers are typically used in preparing solutions, suspensions, and emulsions. Liquid carriers contemplated for use in the practice include in some embodiments, water, saline, pharmaceutically acceptable organic solvent(s), pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more thereof. The liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like. Suitable organic solvents include, in some embodiments, monohydric alcohols, such as ethanol, and polyhydric alcohols, such as glycols. Suitable oils include, in some embodiments, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like. For parenteral administration, the carrier can also be an oily ester such as ethyl oleate, isopropyl myristate, and the like. Compositions disclosed herein may also be in the form of microparticles, microcapsules, liposomal encapsulates, and the like, as well as combinations of any two or more thereof.
[0038] Time-release or controlled release delivery systems may be used, such as a diffusion controlled matrix system or an erodible system, as described for example in: Lee, "Diffusion- Controlled Matrix Systems", pp. 155-198 and Ron and Langer, "Erodible Systems", pp. 199- 224, in "Treatise on Controlled Drug Delivery", A. Kydonieus Ed., Marcel Dekker, Inc., New York 1992. The matrix may be, in some embodiments, a biodegradable material that can degrade spontaneously in situ and in vivo, in some embodiments, by hydrolysis or enzymatic cleavage, e.g., by proteases. The delivery system may be, in some embodiments, a naturally occurring or synthetic polymer or copolymer, in some embodiments, in the form of a hydrogel. Exemplary polymers with cleavable linkages include polyesters, polyorthoesters, polyanhydrides, polysaccharides, poly(phosphoesters), polyamides, polyurethanes, poly(imidocarbonates) and poly(phosphazenes).
[0039] The compounds disclosed herein may be administered enterally, orally, parenterally, sublingually, by inhalation (e.g., as mists or sprays), rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. In some embodiments, suitable modes of administration include oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intraarterial, intramuscular, intraperitoneal, intranasal (e.g. via nasal mucosa), subdural, rectal, gastrointestinal, and the like, and directly to a specific or affected organ or tissue. For delivery to the central nervous system, spinal and epidural administration, or administration to cerebral ventricles, can be used. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intra- sternal injection, or infusion techniques. The compounds are mixed with pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for the desired route of administration. Oral administration is a preferred route of administration, and formulations suitable for oral administration are preferred formulations. The compounds described for use herein can be administered in solid form, in liquid form, in aerosol form, or in the form of tablets, pills, powder mixtures, capsules, granules, injectables, creams, solutions, suppositories, enemas, colonic irrigations, emulsions, dispersions, food premixes, and in other suitable forms. The compounds can also be administered in liposome formulations. The compounds can also be administered as prodrugs, where the prodrug undergoes transformation in the treated subject to a form which is therapeutically or prophylactically effective. Additional methods of administration are known in the art.
[0040] In some embodiments, especially those embodiments where a formulation is used for injection or other parenteral administration including the routes listed herein, but also including embodiments used for oral, gastric, gastrointestinal, or enteric administration, the formulations and preparations used in the methods disclosed herein are sterile. Sterile pharmaceutical compositions are compounded or manufactured according to pharmaceutical- grade sterilization standards (United States Pharmacopeia Chapters 797, 1072, and 1211; California Business & Professions Code 4127.7; 16 California Code of Regulations 1751, 21 Code of Federal Regulations 211) known to those of skill in the art.
[0041] Injectable preparations, in some embodiments, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, in some embodiments, as a solution in propylene glycol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
[0042] Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
[0043] Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.
[0044] The compounds disclosed herein can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound disclosed herein, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p. 33 et seq (1976). [0045] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host to which the active ingredient is administered and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, body area, body mass index (BMI), general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the type, progression, and severity of the particular disease undergoing therapy. The pharmaceutical unit dosage chosen is usually fabricated and administered to provide a defined final concentration of drug in the blood, tissues, organs, or other targeted region of the body. The effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.
[0046] In some embodiments, dosages which can be used are an effective amount within the dosage range of about 0.1 mg/kg to about 300 mg/kg body weight, or within about 1.0 mg/kg to about 100 mg/kg body weight, or within about 1.0 mg/kg to about 50 mg/kg body weight, or within about 1.0 mg/kg to about 30 mg/kg body weight, or within about 1.0 mg/kg to about 10 mg/kg body weight, or within about 10 mg/kg to about 100 mg/kg body weight, or within about 50 mg/kg to about 150 mg/kg body weight, or within about 100 mg/kg to about 200 mg/kg body weight, or within about 150 mg/kg to about 250 mg/kg body weight, or within about 200 mg/kg to about 300 mg/kg body weight, or within about 250 mg/kg to about 300 mg/kg body weight. Compounds disclosed herein may be administered in a single daily dose, or the total daily dosage may be administered in divided dosage of two, three or four times daily.
[0047] While the compounds disclosed herein can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more other agents. When additional active agents are used in combination with the compounds disclosed herein, the additional active agents may generally be employed in therapeutic amounts as indicated in the Physicians' Desk Reference (PDR) 53rd Edition (1999), or such therapeutically or prophylactically useful amounts as would be known to one of ordinary skill in the art.
[0048] The compounds disclosed herein and the other therapeutically active agents can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions disclosed herein may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient. When administered in combination with other therapeutic agents, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
EXAMPLES
Preparation of Compounds
[0049] The compounds disclosed herein can be prepared from readily available starting materials; non-limiting exemplary methods are described in the Examples. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
Synthetic Reaction Parameters
[0050] The compounds herein are synthesized by an appropriate combination of generally well-known synthetic methods. Techniques useful in synthesizing the compounds herein are both readily apparent and accessible to those of skill in the relevant art in light of the teachings described herein. While the Examples illustrate certain of the diverse methods available for use in assembling the compounds herein, they are not intended to define the scope of reactions or reaction sequences that are useful in preparing the compounds herein. Synthetic methods for other compounds disclosed herein will be apparent to one skilled in the art in view of the illustrative examples.
Exemplary Synthetic Schemes for the Preparation of Compounds Disclosed Herein
Synthetic Example 1
[0051] Compounds disclosed herein including of Formula II may generally be prepared according to the followin procedure:
Figure imgf000033_0001
To a solution of uracil (1.0 eq) in DMF (0.1 M) is added 1-Iodoalkanes (2.2 eq) and K2C03 (2.2 eq). The mixture is stirred at rt for 16 h. The crude is diluted with EtAOc, and the organic layer is washed with water, brine, and dried with Na2S04; then is filtered and cone, in vacuo. The residue is purified by column to afford the title compound.
[0052] The following compounds were made according to the above procedure:
Figure imgf000034_0001
1H MR (400 MHz, Chloroform -J) δ 7.18 (d, J= 5.2 Hz, 1H), 3.99 - 3.92 (m, 3H), 3.75 - 3.68 (m, 3H), 1.75 - 1.59 (m, 4H), 1.41 - 1.27 (m, 8H), 0.94 - 0.88 (m, 6H);
Figure imgf000034_0002
1H MR (400 MHz, Chloroform-i ) δ 7.18 (d, J= 5.2 Hz, OH), 3.98
- 3.91 (m, 2H), 3.75 - 3.66 (m, 2H), 1.66-1.54 (m, 4H), 1.39 - 1.24 (m, 12H), 0.94 - 0.83 (m, 6H);
Figure imgf000034_0003
1H MR (400 MHz, Chloroform-i ) δ 7.17 (d, J = 5.2 Hz, 1H), 3.99 - 3.91 (m, 2H), 3.75 - 3.68 (m, 2H), 1.76 - 1.56 (m, 4H), 1.1-14 (m, 16H), 0.92 - 0.82
Figure imgf000034_0004
3.98 - 3.92 (m, 2H), 3.74 - 3.68 (m, 2H), 1.65 (dt, J= 22.3, 7.2 Hz, 4H), 1.29 (m, 20H), 0.92
- 0.83 (m, 6H);
Figure imgf000034_0005
δ 3.97 - 3.91 (m, 2H), 3.81 - 3.76 (m, 2H), 2.28 (s, 3H), 1.32-1.25 (m, 24H), 0.91 - 0.84 (m, 6H);
Figure imgf000035_0001
1H MR (400 MHz, Chloroform-i ) δ 7.18 (d, J= 5.2 Hz, 1H), 3.97
3.90 (m, 2H), 3.73 3.65 (m, 2H), 1.74 - 1.52 (m, 4H), 1.26 - 1.15 (m, 6H), 0.89 (m, Hz, 12H);
Figure imgf000035_0002
1H MR (400 MHz, Chloroform-i ) δ 3.96-3.92 (m, 2H), 3.85 - 3.
(m, 2H), 2.28 (d, J 3.6 Hz, 3H), 1.71 - 1.54 (m, 6H), 1.34 (m, 6H), 0.90 (m, 6H);
Figure imgf000035_0003
1H MR (400 MHz, Chloroform-i ) δ 7.16 (d, J= 5.2 Hz, 1H), 4.01 - 3.94 (m, 2H), 3.77 - 3.70 (m, 2H), 1.79-1.59 (m, 10H), 1.59 - 1.46 (m, 7H), 1.39 - 1.07 (m, 9H), 1.06 - 0.89 (m, 4H);
Figure imgf000035_0004
1H MR (400 MHz, CDC13): δ 7.32-7.29 (m, 7H), 7.28-7.25 (m, 1H), 7.13 (d, J= 6.8 Hz, 2H), 6.82 (d, J= 5.2 Hz, 1H), 4.20 (t, J= 7.6 Hz, 2H), 3.93 (t, J= 7.2 Hz, 2H), 2.96-2.93 (m, 4H); and
Figure imgf000035_0005
1H MR (400 MHz, Chloroform-i ) δ 5.88 (s, 1H), 4.07 - 3.98 (m,
2H), 3.95 - 3.85 (m, 2H), 1.76 - 1.55 (m, 6H), 1.42 - 1.26 (m, 8H), 0.94-.87 (m, 6H). Synthetic Example 2
[0053] Compounds disclosed herein including of Formula III may also be generally prepared according to the following procedure:
Figure imgf000036_0001
To a solution of uracil (1.0 eq) in DCM is added acyl chloride (1.5 eq) and TEA (2.0 eq). The crude is cone, in vacuo and the residue is purified by column.
[0054] The following compounds were made according to the above procedure:
Figure imgf000036_0002
1H NMR (400 MHz, Chloroform-i ) δ 8.54 (d, J = 0.4 Hz, 1H 1.77 - 1.67 (m, 2H), 1.40 - 1.23 (m, 10H), 0.94 - 0.85 (m, 3H);
Figure imgf000036_0003
2H), 2.35 (d, J = 0.5 Hz, 3H), 1.74 (m, 2H), 1.34 - 1.23 (m, 8H), 0.91 - 0.85 (t, J = 0.5, 3H);
Figure imgf000036_0004
δ 7.39 (d, J = 0.4 Hz
1H), 2.84 (t, J = 7.3 Hz, 2H), 1.80 - 1.71 (m, 2H), 1.30 (m, 8H), 0.92 - 0.86 (m, 3H);
Figure imgf000036_0005
1H MR (400 MHz, Chloroform-i ) δ 5.85 (s, 1H), 2.82 (t, J = 7.3 Hz, 2H), 1.74 (p, J = 7.4 Hz, 2H), 1.40 - 1.20 (m, 8H), 0.93 - 0.84 (m, 3H);
Figure imgf000037_0001
i H m/iR 400 MHz chloroform-ii δ 6.24 (s, 1H), 2.81 (t, J 7.3 Hz, 2H), 1.73 (p, J= 7.4 Hz, 2H), 1.37-14 (m, 8H), 0.94 - 0.83 (m, 3H);
Figure imgf000037_0002
1H MR (400 MHz, CDC13): δ 8.26 (d, J = 6.8 Hz, 1H), 3.38 (s,
7.6 Hz, 2H), 1.73-1.71 (m, 2H), 1.36-1.27 (m, 8H), 0.88 (t, J = 6.0 Hz,
Figure imgf000037_0003
MUz CDci3): δ 8.30-8.28 (m, 1H), 8.20 (br. s, 1H), 3.11 (t, J = 8.0 Hz, 2H), 1.74-1.66 (m, 2H), 1.39-1.23 (m, 8H), 0.88 (t, J = 4.8 Hz, 3H).
Synthetic Example 3
[0055] Compounds disclosed herein including of Formula IV may also be generally prepared according to the following procedure:
Figure imgf000037_0004
To a solution of uracil (1.0 eq) in pyridine is added isocyanate (1.8 eq) and DMAP (1.1 eq). The
mixture is stirred at rt for 16 h, and then is concentrated in vacuum below 35C. The residue is purified by pre-TLC (PE/EA, 5: 1) to give the crude product, and the crude is further purified by
pre-HPLC to provide product.
[0056] The following compounds were made using an analogous procedure:
Figure imgf000038_0001
1H NMR (400 MHz, CDC13): δ 9.00 (br. s, 1H), 8.50-8.47 (m, 1H), 3.39-
3.33 (m, 2H), 1.67-1.59 (m, 2H), 0.99-0.95 (m, 3H);
Figure imgf000038_0002
1H NMR (400 MHz, CDC13): δ 8.96 (br. s, 1H), 8.49-8.46 (m,
1H 3.42-3.36 (m, 1H), 1.62-1.56 (m, 1H), 1.37-1.26 (m, 6H), 0.89 (t, J= 6.4 Hz, 3H);
Figure imgf000038_0003
1H NMR (400 MHz, CDC13): δ 8.95 (br. s, 1H), 8.49-8.46 (m, 1H), 3.41-3.35 (m, 2H), 1.62-1.58 (m, 2H), 1.32-1.22 (m, 10H), 0.88 (t, J= 6.8 Hz, 3H);
Figure imgf000038_0004
1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 9.54 (t, J = 5.9 Hz, 1H), 8.38 (d, J = 7.5 Hz, 1H), 7.36 - 7.17 (m, 5H), 4.48 (d, J = 5.9 Hz, 2H), 2.53 (s, 1H), 1.22 (s, 2H);
Figure imgf000038_0005
1H NMR (400 MHz, CDC13): δ 12.60 (br s, 1H), 9.19 (br s, 1H), 8.36
(d, J = 7.6 Hz, 1H), 7.31-7.19 (m, 5H), 3.53-3.49 (m, 2H), 2.81 (t, J = 7.6 Hz, 2H); and
Figure imgf000038_0006
NMR (400 MHz, CDC13): δ 8.98 (br s, 1H), 8.63 (s, 1H), 3.40-3.36 (m, 2H), 1.61-1.56 (m, 2H), 1.31-1.27 (m, 10H), 0.86 (t, J = 6.8 Hz, 3H).
Synthetic Example 3
[0057] Compounds disclosed herein including of Formula V may also be generally prepared according to the following
procedure:
Figure imgf000039_0001
To a solution of uracil (1.0 eq) in DCM is added acyl chloride (1.5 eq) and TEA (2.0 eq). The crude is cone, in vacuo and the residue is purified by column.
[0058] The following compounds were made according to the above procedure:
Figure imgf000039_0002
1H NMR (400 MHz, Chloroform-i ) δ 2.95 (t, J = 7.4 Hz, 2H), 2.34 (s, 3H), 1.72 (p, J = 1.5 Hz, 2H), 1.43 - 1.31 (m, 6H), 0.92 - 0.85 (m, 3H);
Figure imgf000039_0003
δ 2.98 - 2.91 (m, 2H), 1.78 - 1.69
(m, 2H), 1.40 1.32 (m, 4H), 0.96 - 0.87 (m, 3H);
Figure imgf000039_0004
1H NMR (400 MHz, Chloroform-i ) δ 3.97 - 3.86 (m, 2H), 1.65 (q, J= 7.8 Hz, 2H), 1.42 - 1.19 (m, 8H), 0.96 - 0.81 (m, 3H);
Figure imgf000039_0005
i H 400 MHZj chloroforms ) 5 2.95 (t, J
2H), 1.72 (q, J = 7.4 Hz, 2H), 1.42 - 1.16 (m, 12H), 0.92 - 0.84 (m, 3H);
Figure imgf000040_0001
Me iH (400 chloroform-ii δ 2.95 (t, J = 7.4
Hz, 2H), 2.35 (t, J = 7.5 Hz, 2H), 1.78 - 1.69 (m, 4H), 1.30 - 1.26 (m, 12H), 0.92 - 0.84 (m, 3H);
Figure imgf000040_0002
7.4 Hz, 2H), 1.73 (p, J= 7.4 Hz, 2H), 1.30-1.20 (m, 20H), 0.91 - 0.84 (m, 3H);
Figure imgf000040_0003
1H NMR (400 MHz, Chloroform-d) δ 3.58 (q, J
6.9 Hz, 6H);
Figure imgf000040_0004
1H NMR (400 MHz, Chloroform-i ) δ 7.84 (dd, J
7.5 Hz, OH), 7.53 (t, J = 7.8 Hz, 2H);
Figure imgf000040_0005
1H NMR (400 MHz, Chloroform-i ) δ 3.37 - 3.23 (m, 1H), 1.89 (dd, J 41.4, 13.0 Hz, 2H), 1.72 (d, J= 12.5 Hz, 4H), 1.45 - 1.08 (m, 4H);
Figure imgf000041_0001
1H NMR (400 MHz, Chloroform-i ) δ 2.83 (d, J
6H), 1.20-1.10 (m, 5H); and
Figure imgf000041_0002
1H NMR (400 MHz, Chloroform-i ) δ 3.01 - 2.92 (m, 2H), 1.88 - 1.69 (m, 5H), 1.68 - 1.35 (m, 5H), 1.12 (t, J= 11.0 Hz, 2H).
Biological Example 1. SQOR Inhibition
Figure imgf000041_0003
Reagents
[0059] SQR: 18.06 μΜ (25 mM Tris pH 7.5, 25% (v/v) glycerol, 150 mM NaCl, 2 mM βΜΕ) stored at -80 °C. A working stock with a concentration of 1 μΜ is prepared by mixing 2 μΐ^ of this stock with 34.1 μΐ^ of enzyme diluent immediately before use.
Enzyme diluent: 50 mM Tris pH 7.5, 10% glycerol, 300 mM NaCl, 1 mM EDTA.
lOx Assay buffer solution: 1M Tris, pH 7.5, 5 mM EDTA.
Detergent: 10% (v/v) Triton X-100 reduced (Sigma: X100RS, CAS: 92046-34-9).
Inhibitor Stocks: in DMSO. For experiments varying the concentration of inhibitor, a dilution series from a concentrated DMSO stock (usually 1-10 mM) in DMSO is prepared just prior to assays.
CoQi Stock: 10 mM in DMSO.
Na2S Stock: 80 mM (19.21 mg/mL of the nonahydrate) in water. The 8 mM stock used is made from this concentrated stock. This solution is prepared fresh daily.
Na2SC>3 Stock: 80 mM (10.08 mg/mL) in water. This solution is prepared fresh daily. ATG (aurothioglucose) Stock: 1 mM (>100x) in water. This stock is prepared from 10 or 100 mM stock (in water) stored at -20 C. ATG hydrate solid from Sigma: A0606.
Assay Conditions
[0060] Final assay conditions are as follows:
100 mM Tris pH 7.5;
0.5 mM EDTA;
0.1% (v/v) Triton X-100 reduced;
5 nM SQR;
25 μΜ coQi, resulting in 0.25% residual DMSO;
200 μΜ Na2S;
2 mM Na2S03; and
0-100 μΜ Inhibitor, resulting in less than 2% total residual DMSO. Assay Monitoring
[0061] The monitoring for this assay is absorbance based, specifically UV. The assay readout is the amount of CoQ remaining in the oxidized form. This is determined by monitoring the absorbance of the oxidized quinone at 278 nm.
Data Analysis
[0062] Absorbance data is analyzed as follows:
Absorbance vs. time data is extracted from the plate-reader software or other data source. A least-squares fit of the linear portion of the data is used to determine the slope representing the reduction of coQi at 278 nm. This is accomplished using Microsoft Excel, SigmaPlot, GraphPad Prism, or other appropriate software. These slopes are conveniently represented in units of mAU/s.
[0063] The activity of SQR in the presence of the inhibitor is compared to that in the absence of any inhibitor (DMSO control).
% activity remaining is calculated as follows:
% residual activity = 100 χ
Figure imgf000042_0001
% inhibition is calculated as follows:
Figure imgf000042_0002
As reference, 10 μΜ ATG (aurothioglucose) inhibits SQR by 95-100%. [0064] For potency determination, the % activity is plotted against the logio of the concentration of inhibitor added. This plot can be fitted (commonly in GraphPad Prism) using the following expression:
(Top-Bottom)
Y = Bottom + (1=+lo(0oB,cSo)-:.)*>»)
Where Y is the activity, either as % or fraction; Top is plateau value of the activity in the absence of inhibitor; Bottom is the plateau value of the activity reached in the limit of saturating inhibitor; IC50 is the concentration of inhibitor at which enzymatic activity is 50% of that in the absence of inhibitor (note that activity in this case is the delta between top- and bottom, which may not be 100%); x is the log of inhibitor concentration; and h is the Hill coefficient, reflecting cooperativity in the binding of inhibitor: a value of -1 indicates no cooperativity. If there is no possibility of cooperativity, h is defined as -1.
[0065] Below is a plot of SQR activity vs log [ATG]— ATG was titrated from 0-100 uM with a threefold dilution series— with the corresponding fitted parameters. The IC50 is 930 nM, with a 95% CI of 644-1330 nM.
, sat S/S03
Figure imgf000043_0001
log10 [ATG]
Figure imgf000043_0002
[0066] The following compounds were tested according to the above procedure in Biological Example 1. Results are presented in Embodiments A-D.
Embodiment A. Inhibition of SQOR with compounds disclosed herein
Figure imgf000043_0003
Figure imgf000044_0001
Figure imgf000045_0001
* indicates 10-50%, ** indicates >50%; ++ indicates <20 uM
Embodiment B. Inhibition of SQOR with compounds disclosed herein
Figure imgf000046_0001
* indicates 10-50%, + indicates 20-100 uM; ++ indicates <20 uM Embodiment C. Inhibition of SQOR with compounds disclosed herein
Figure imgf000047_0001
* indicates 10-50%, ** indicates >50%, + indicates 20-100 uM; ++ indicates <20 uM
Embodiment D. Inhibition of SQOR with compounds disclosed herein
Figure imgf000048_0001
Figure imgf000049_0001
+++ indicates <20 uM
[0067] The disclosures of all publications, patents, patent applications and published patent applications referred to herein by an identifying citation are hereby incorporated herein by reference in their entirety.
[0068] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

What is claimed is:
1. A method for inhibiting SQOR activity in an individual or a tissue sample, comprising:
administering an effective amount of a compound of Formula I:
Figure imgf000050_0001
Formula I
wherein
Ri is Ci-Cio alkyl optionally substituted with phenyl; or Ri is hydrogen;
R2 is selected from the group consisting of hydrogen, halo, and methyl;
R3 is selected from the group consisting of hydrogen, halo, and methyl;
W is C(R3) or nitrogen; and
Y is selected from the group consisting of C1-C10 alkyl optionally substituted with phenyl, with the proviso that Y contains 3-12 carbons total; -C(O)-(C4-Ci0 n-alkyl); -C(0)NH- (C3-C10 n-alkyl); -C(0) H-(Ci-C2 n-alkyl-phenyl); -C(0)-( C3-Ci5 alkyl); and -C(O)- (phenyl); or
a salt thereof; or
administering a pharmaceutical composition comprising the compound or salt thereof and further comprising a pharmaceutically acceptable vehicle;
to the individual or tissue sample.
2. The method of claim 1, wherein the compound is according to Formula II:
Figure imgf000050_0002
Formula II
wherein
Ri is C1-C10 alkyl optionally substituted with phenyl, with the proviso that R1 contains 3-12 carbons total;
R2 is selected from the group consisting of hydrogen and fluoro; R3 is selected from the group consisting of hydrogen, halo, and methyl; and
Y is Ci-Cio alkyl optionally substituted with phenyl, with the proviso that R1 contains 3-12 carbons total; or
a salt thereof.
3. The method of claim 2, wherein Ri is C5-n-alkyl, C6-n-alkyl, C7-n-alkyl, C8-n- alkyl, -(CH2)3-CH(CH3)2, -CH2CH2-cyclohexyl, or -CH2CH2-phenyl.
4. The method of claim 2 or 3, wherein Y is C5-n-alkyl, C6-n-alkyl, C7-n-alkyl, C8-n- alkyl, -(CH2)3-CH(CH3)2, -CH2CH2-cyclohexyl, or -CH2CH2-phenyl.
5. The method of claim 2, wherein Ri and Y are independently selected from the group consisting of C4-C7 alkyl.
6. The method of claim 2, wherein Ri and Y are independently selected from the group consisting of C5-C6 alkyl.
7. The method of any one of claims 2-6, wherein Ri is the same as Y.
8. The method of any one of claims 2-7, wherein R3 is hydrogen.
9. The method of any one of claims 2-7, wherein R3 is methyl.
10. The method of any one of claims 2-7, wherein R3 is halo.
11. The method of any one of claims 2-7, wherein R3 is chloro.
12. The method of any one of claims 2-11, wherein R2 is fluoro.
13. The method of any one of claims 2-11, wherein R2 is hydrogen.
14. The method of claim 1, wherein the compound is according to Formula III:
Figure imgf000051_0001
Formula III
wherein
one of R2 and R3 is halo and the other is hydrogen or methyl; and
Y is -C(0)-(C4-Cio n-alkyl); or
a salt thereof.
15. The method of claim 14, wherein Y is -C(0)-(C -C8 n-alkyl).
16. The method of claim 14, wherein Y is -C(0)-(C6-C7 n-alkyl).
17. The method of claim 14, wherein Y is -C(0)-(C6 n-alkyl).
18. The method of claim 14, wherein Y is -C(0)-(C7 n-alkyl).
19. The method of any one of claims 14-18, wherein R3 is hydrogen.
20. The method of any one of claims 14-18, wherein R3 is methyl.
21. The method of any one of claims 14-18, wherein R3 is halo.
22. The method of any one of claims 14-18, wherein R3 is chloro.
23. The method of any one of claims 14-18, wherein R3 is iodo.
24. The method of any one of claims 14-23, wherein R2 is halo.
25. The method of any one of claims 14-23, wherein R2 is bromo.
26. The method of any one of claims 14-23, wherein R2 is chloro.
27. The method of any one of claims 14-23, wherein R2 is fluoro.
28. The method of any one of claims 14-23, wherein R2 is hydrogen.
29. The method of claim 1, wherein the compound is according to Formula IV:
Figure imgf000052_0001
Formula IV
wherein
R2 is halo; and
Y is selected from the group consisting of -C(O) H-(C3-Ci0 n-alkyl) and -C(0) H-(Ci-C2 n- alkyl-phenyl); or
a salt thereof.
30. The method of claim 29, wherein Y is -C(O) H-(C3-Ci0 n-alkyl).
31. The method of claim 29 or 30, wherein Y is -C(0) H-(C3 n-alkyl).
32. The method of claim 29 or 30, wherein Y is -C(0) H-(C6 n-alkyl).
33. The method of claim 29 or 30, wherein Y is -C(0) H-(C8 n-alkyl).
34. The method of claim 29, wherein Y is -C(0) H-(d-C2 n-alkyl-phenyl).
35. The method of claim 29 or 34, wherein Y is -C(0) H-(Ci alkyl -phenyl).
36. The method of claim 29 or 34, wherein Y is -C(0) H-(C2 n-alkyl-phenyl).
37. The method of any one of claims 29-36, wherein R2 is fluoro.
38. The method of any one of claims 29-36, wherein R2 is chloro.
39. The method of claim 1, wherein the compound is according to Formula V:
Figure imgf000053_0001
Formula V
wherein
R2 is methyl or halo; and
Y is selected from the group consisting of -C(0)-(C3-Ci5 alkyl), and -C(0)-(phenyl); or a salt thereof.
40. The method of claim 39, wherein Y is -C(0)-(isopropyl), -C(0)-(C5-n-alkyl), -C(O)- (C6-n-alkyl), -C(0)-(C7-n-alkyl), -C(0)-(C8-n-alkyl), -C(0)-(C9-n-alkyl), -C(O)-(Ci0-n- alkyl), -C(0)-(Cn-n-alkyl), -C(0)-(Ci2-n-alkyl), -C(0)-(Ci3-n-alkyl), -C(0)-(cyclohexyl), - C(0)-(CH2-cyclohexyl), -C(0)-(CH2CH2-cyclopentyl), or -C(0)-(phenyl).
41. The method of claim 39 or 40, wherein Y is -C(0)-(isopropyl), -C(0)-(C5-n-alkyl), -C(0)-(C6-n-alkyl), -C(0)-(C7-n-alkyl), -C(0)-(C8-n-alkyl), -C(0)-(C9-n-alkyl), -C(0)-(Cio- n-alkyl), -C(0)-(Cn-n-alkyl), -C(0)-(Ci2-n-alkyl), or -C(0)-(Ci3-n-alkyl).
42. The method of claim 39, wherein Y is -C(0)-(cyclohexyl), -C(0)-(CH2-cyclohexyl), or
-C(0)-(CH2CH2-cyclopentyl).
43. The method of claim 39, wherein Y is -C(0)-(phenyl).
44. The method of any one of claims 39-43, wherein R2 is methyl.
45. The method of any one of claims 39-43, wherein R2 is halo.
46. The method of any one of claims 39-43, wherein R2 is bromo.
47. The method of claim 1 wherein Ri is hydrogen or methyl; Y is -C(0)-(C4-Cio n- alkyl); W is C(R3); and one of R3 and R2 is halo and the other is hydrogen or methyl; wherein when Ri is H and one of R2 and R3 is hydrogen then the other is selected from the group consisting of Br, CI, and I; or a salt thereof; or Ri is hydrogen; Y is -C(0)-(C3-Ci5 alkyl) or - C(0)-(phenyl); W is nitrogen; and R2 is methyl or halo; or a salt thereof; or
48. The method of claim 1 wherein the compound is selected from
Figure imgf000053_0002
Figure imgf000054_0001
Figure imgf000055_0001
49. A compound of Formula la:
Figure imgf000055_0002
Formula la
wherein
Ria is hydrogen or methyl; Yi is -C(O)-(C4-Ci0 n-alkyl); W1 is C(R3); and one of R2a and R3a is halo and the other is hydrogen or methyl; wherein when Ria is H and one of R2a and R3a is hydrogen then the other is selected from the group consisting of Br, CI, and I; or a salt thereof; or
Ria is hydrogen; Yi is -C(0)-(C3-C15 alkyl) or -C(0)-(phenyl); W1 is nitrogen; and R2a is methyl or halo; or a salt thereof; or
a compound selected from
Figure imgf000056_0001
or a salt thereof.
50. A pharmaceutical composition comprising the compound of claim 49, and further comprising a pharmaceutically acceptable vehicle.
51. The method of any one of claims 1-48 where the salt is a pharmaceutically acceptable salt.
52. The compound of claim 49 or the composition of claim 50 where the salt is a pharmaceutically acceptable salt.
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10202325B2 (en) 2011-07-19 2019-02-12 Bioelectron Technology Corporation Methods for selective oxidation of alpha tocotrienol in the presence of non-alpha tocotrienols
US10251847B2 (en) 2014-12-16 2019-04-09 Bioelectron Technology Corporation Polymorphic and amorphous forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide
US10703701B2 (en) 2015-12-17 2020-07-07 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders
US10738014B2 (en) 2016-11-15 2020-08-11 Ptc Therapeutics, Inc. 2-substituted amino-naphth (1,2-d) imidazol-5-one compounds or pharmaceutically acceptable salts thereof
US10745371B2 (en) 2015-12-16 2020-08-18 Ptc Therapeutics, Inc. Methods for enriching alpha-tocotrienol from mixed tocol compositions
US10968166B2 (en) 2007-11-06 2021-04-06 Ptc Therapeutics, Inc. 4-(P-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases
US11174212B2 (en) 2018-10-17 2021-11-16 Ptc Therapeutics, Inc. 2,3,5-trimelthyl-6-nonylcyclohexa-2,5-diene-1,4-dione for suppressing and treating alpha-synucleinopathies, tauopathies, and other disorders
US11312697B2 (en) 2008-10-28 2022-04-26 Ptc Therapeutics, Inc. Process for the production of alpha-tocotrienol and derivatives
US11786486B2 (en) 2021-07-08 2023-10-17 Ptc Therapeutics, Inc. Pharmaceutical compositions comprising 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4071519A (en) * 1975-11-05 1978-01-31 Mitsui Toatsu Chemicals, Incorporated 1-Carbamoyl-5-fluorouracil derivatives
US4088646A (en) * 1975-01-22 1978-05-09 Asahi Kasei Kogyo Kabushiki Kaisha 5-Fluorouracil derivatives
WO2000011952A1 (en) * 1998-08-31 2000-03-09 Pro-Neuron, Inc. Compositions and methods for treatment of mitochondrial diseases
WO2002083651A2 (en) * 2001-04-11 2002-10-24 Queen's University At Kingston Pyrimidine compounds as anti-ictogenic and/or anti-epileptogenic agents
WO2013178576A1 (en) * 2012-05-28 2013-12-05 Fondazione Istituto Italiano Di Tecnologia Acid ceramidase inhibitors and their use as medicaments

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4088646A (en) * 1975-01-22 1978-05-09 Asahi Kasei Kogyo Kabushiki Kaisha 5-Fluorouracil derivatives
US4071519A (en) * 1975-11-05 1978-01-31 Mitsui Toatsu Chemicals, Incorporated 1-Carbamoyl-5-fluorouracil derivatives
WO2000011952A1 (en) * 1998-08-31 2000-03-09 Pro-Neuron, Inc. Compositions and methods for treatment of mitochondrial diseases
WO2002083651A2 (en) * 2001-04-11 2002-10-24 Queen's University At Kingston Pyrimidine compounds as anti-ictogenic and/or anti-epileptogenic agents
WO2013178576A1 (en) * 2012-05-28 2013-12-05 Fondazione Istituto Italiano Di Tecnologia Acid ceramidase inhibitors and their use as medicaments

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"Methods in Cell Biology", vol. XIV, 1976, ACADEMIC PRESS, NEW YORK, N.W., pages: 33
"Physicians' Desk Reference (PDR", 1999
"Remington: The Science and Practice of Pharmacy", 2003, LIPPINCOTT WILLIAMS & WILKINS, PHILADELPHIA
"Remington's Pharmaceutical Sciences", 1991, MACK PUB. CO., NEW JERSEY
BANAVARA L MYLARI ET AL: "Anticoccidial derivatives of 6-azauracil. 1. Enhancement of activity by benzylation of nitrogen-1. Observations on the design of nucleotide analogs in chemotherapy", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 20, no. 4, 1 April 1977 (1977-04-01), pages 475 - 483, XP008143741, ISSN: 0022-2623, DOI: 10.1021/JM00214A003 *
JACKSON, M.R. ET AL.: "Human Sulfide:Quinone Oxidoreductase Catalyzes the First Step in Hydrogen Sulfide Metabolism and Produces a Sulfane Sulfur Metabolite", BIOCHEMISTRY, 1 August 2012 (2012-08-01)
JERZY BELTOWSKI ET AL: "Modulation of H 2 S Metabolism by Statins: A New Aspect of Cardiovascular Pharmacology", ANTIOXIDANTS AND REDOX SIGNALING, vol. 17, no. 1, 1 July 2012 (2012-07-01), US, pages 81 - 94, XP055354741, ISSN: 1523-0864, DOI: 10.1089/ars.2011.4358 *
LEE, DIFFUSION-CONTROLLED MATRIX SYSTEMS, pages 155 - 198
RON; LANGER: "Treatise on Controlled Drug Delivery", 1992, MARCEL DEKKER, INC., NEW YORK, article "Erodible Systems", pages: 199 - 224

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US11312697B2 (en) 2008-10-28 2022-04-26 Ptc Therapeutics, Inc. Process for the production of alpha-tocotrienol and derivatives
US10202325B2 (en) 2011-07-19 2019-02-12 Bioelectron Technology Corporation Methods for selective oxidation of alpha tocotrienol in the presence of non-alpha tocotrienols
US11304914B2 (en) 2014-12-16 2022-04-19 Ptc Therapeutics, Inc. Polymorphic and amorphous forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide
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US11938101B2 (en) 2014-12-16 2024-03-26 Ptc Therapeutics, Inc. Polymorphic forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide
US10745371B2 (en) 2015-12-16 2020-08-18 Ptc Therapeutics, Inc. Methods for enriching alpha-tocotrienol from mixed tocol compositions
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US11390588B2 (en) 2016-11-15 2022-07-19 Ptc Therapeutics, Inc. 2-substituted amino-naphth (1,2-d) imidazol-5-one compounds of pharmaceutically acceptable salts thereof
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