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WO2025024564A1 - Petites molécules empêchant l'accumulation induite par statine de hmg coa réductase - Google Patents

Petites molécules empêchant l'accumulation induite par statine de hmg coa réductase Download PDF

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WO2025024564A1
WO2025024564A1 PCT/US2024/039362 US2024039362W WO2025024564A1 WO 2025024564 A1 WO2025024564 A1 WO 2025024564A1 US 2024039362 W US2024039362 W US 2024039362W WO 2025024564 A1 WO2025024564 A1 WO 2025024564A1
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compound
formula
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amine
group
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Russell Debose-Boyd
Tian QIN
Dong-Jae JUN
Yangyang YANG
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University of Texas System
University of Texas at Austin
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University of Texas System
University of Texas at Austin
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • Th is invention was made with government support undergrant no. GM141088 awarded by the National Institutes of Health (NIH). The government has certain rights in the invention.
  • compositions and methods for treating or reducing the risk of acquiring a cardiovascular or cholesterol related disorder are provided herein.
  • Cholesterol related disorders include any one or more of the following: hypercholesterolemia, hyperlipidemia, heart disease, metabolic syndrome, diabetes, coronary heart disease, stroke, cardiovascular diseases, Alzheimer's disease and generally dyslipidemias, which can be manifested, for example, by an elevated total serum cholesterol, elevated LDL, elevated triglycerides, elevated VLDL, and/or low HDL.
  • HMG CoA reductase is the rate-limiting enzyme in the mevalonate pathwaythat produces cholesterol and nonsterol isoprenoids including geranylgeranyl pyrophosphate (GGpp).
  • Feedback control of HMGCR involves its sterol -induced binding to ER membrane proteins called Insigs, which is obligatory for ubiquitination and ER-associated degradation (ERAD) of HMGCR.
  • Insigs geranylgeranyl pyrophosphate
  • ESD ER-associated degradation
  • Sterols also cause HMGCR to bind UbiA prenyltransferase domain-containing protein-1 (UBIAD1 ), which uses GGpp to synthesize a subtype of vitamin K2.
  • UBIAD1 UbiA prenyltransferase domain-containing protein-1
  • UBIAD1 binding protects HMGCR from ERAD, allowing cells to continuously synthesize nonsterol isoprenoids when sterols are abundant.
  • GGpp triggers release of UBIAD1 from HMGCR, enhancing ERAD and stimulating translocation of UBIAD1 from ER to Golgi.
  • statins More than 20 million American take statins daily to lower plasma low density lipoprotein (LDL)-cholesterol and reduce incidence of atherosclerotic cardiovascular disease (ACVD) and heart attacks.
  • Statins competitively inhibit HMGCR and reduce cholesterol synthesis in liver, stimulating expression of hepatic LDL-receptors that remove LDL from circulation.
  • statins reduce plasma LDL by up to 50%, further reduction is limited because the drugs block ERAD of HMGCR, causing its marked accumulation in livers of animals and humans. This accumulation partially overcomes inhibitory effects of statins, allowingcontinued synthesis of cholesterol th at limits LDL lowering. Because of this limitation, statins only reduce heart attacks by 30%. There is a need thereof for better treatments for cholesterol related disorders.
  • a compound of Formula (I) is provided Formula (I) wherein Ri and R2 are independently of each other hydrogen, halogen, alkyl, alkyl amine, alkyl sulfonamide, aryl, substituted aryl, heterocyclic aryl amine, substituted heterocyclic aryl amine, cyclic aliphatic amine, heterocyclic aliphatic amine, substituted heterocyclic aliphatic amine, alkyne; or together with the carbon atom to form a cycloalkyl, a cycloalkenyl, or a heterocyclylalkyl ring;
  • R3 is an aryl or substituted aryl
  • Y is an oxygen, nitrogen, or sulfur; or a pharmaceutically acceptable salt thereof.
  • the substituted aryl is a phenyl group with a substituted carbon atom on a para position as in Formula (II) Formula (II).
  • X in Formula (II) is a halogen or a cycloalkane carbonitrile with formula -CnH(2n-2)CN, wherein n is 3 or more.
  • the halogen is fluorine, chlorine, or iodine.
  • the compound of Formula (I) comprises a biotin group.
  • the biotin group is linked to the compound via the alkyne group.
  • the compound is photoactivatable.
  • Ri is hydrogen and R2 is selected from the group consisting of branched or unbranched alkyl, alkyl amine, alkyl sulfonamide, alkyne, aryl, substituted aryl, heterocyclic aryl amine, substituted heterocyclic aryl amine, heterocyclic aliphatic amine, and substituted heterocyclic aliphatic amine.
  • R2 is selected from the group consisting of propane, isopentane, neopentane, toluene, 3-methylpyridine, 4-methylpyridine, 1-fluoro-4-methylbenzene, toluene, te/t- butyl 3-methylazetidine-1 -carboxylate, 1 -(methylsu If ony I )pi peri dine, ethanesulfonamide, and /V,/V-dimethylpropan-1 -amine.
  • Ri and R2 combine to form a heterocycle with both amine and ether groups as in Formula (III) Formula (III) wherein X is a halogen or a cycloalkane carbonitrile with formula -CnH(2n-2)CN, wherein n is 3 or more.
  • Ri and R2 are diethylenimide oxide.
  • the compound is:
  • the compound of Formula (I) is an allosteric activator of a protein encoding gene.
  • the compound of Formula (I) is an allosteric activator of the protein encoding gene UBIAD1 .
  • the compound increases affinity of UBIAD1 for GGpp.
  • a method of treating or reducing the risk of acquiring a cardiovascular or cholesterol related disorder to a subject in need thereof includes administering a therapeutically effective amount of a compound as described above orApatinib to the subject.
  • the subject has a high blood plasma cholesterol value relative to a predetermined blood plasma cholesterol value and/or has a genetic predisposition to high blood plasma cholesterol.
  • the subject has a high blood plasma cholesterol value relative to a predetermined blood plasma cholesterol value and the predetermined blood plasma cholesterol value is less than or equal to 200 mg/dL.
  • the subject has a genetic predisposition to high blood plasma cholesterol and the genetic predisposition is a mutation in UBIAD1 , LDLR, APOB, SREBP, SCAP, and/or PCSK9 genes.
  • the cholesterol is a low-density lipoprotein (LDL)-cholesterol.
  • LDL low-density lipoprotein
  • the cardiovascular or cholesterol related disorder is Schnyder corneal dystrophy (SCD), corneal dystrophy, peripheral artery disease, hypercholesterolemia, hyperlipidemia/ dyslipidemia, sitosterolemia, atherosclerosis, arteriosclerosis, or xanthoma.
  • SCD Schnyder corneal dystrophy
  • corneal dystrophy peripheral artery disease
  • hypercholesterolemia hyperlipidemia/ dyslipidemia
  • sitosterolemia atherosclerosis
  • arteriosclerosis arteriosclerosis
  • xanthoma xanthoma
  • the compound reduces plasma cholesterol value by enabling ubiquitination and ER-associated degradation of HMG CoA reductase.
  • FIG. 1 represents an exemplary experiment illustrating a chemical reaction equation for the general synthesis of compounds in accordance with certain embodiments of the present disclosure.
  • FIG. 2 represents exemplary starting materials pyridine derivatives.
  • FIG. 3 represents an immunoblot of cells lacking endogenous UBIAD1 transfected with an expression plasmid encoding HMG CoA reductase in certain embodiments of the present disclosure.
  • FIG. 4 represents a SDS-PAGE and immunoblot analysisof proteins in certain embodiments of the present disclosure.
  • “About” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “slightly above” or “slightly below” the endpoint without affecting the desired result.
  • the term “about” in association with a numerical value means that the numerical value can vary plus orminus by 5% or less of the numerical value.
  • any feature or combination of features setforth herein can be excluded or omitted.
  • any feature or combination of features setforth herein can be excluded or omitted.
  • “Pharmaceutical composition” means a mixture of substances suitable for administering to an individual that includes a pharmaceutical agent.
  • a pharmaceutical composition comprises one or more of the compounds as disclosed herein compounded with suitable pharmaceutical excipients.
  • the language “pharmaceutical composition” includes preparations suitable for administration to mammals, e.g., humans. When the compounds described herein are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 % to 99.5% (preferably, 1 % to 90%) of active ingredient in combination with a pharmaceutically acceptable excipient.
  • phrases “pharmaceutically acceptable” refers to molecular entities and compositions that are physiologically tolerable and do not typically produce a toxic, allergic, or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. or European Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • the language “effective amount” of the compound as used herein is defined as the amountof the molecules of the present disclosure that are necessary to result in the desired physiological change in the cell or tissue to which it is administered.
  • the term "therapeutically effective amount” as used herein is defined as the amount of the molecu les or compositions of the present disclosu re that ach ieves a desired effect with respect to treating or preventing a cardiovascular or cholesterol related disorder that is linked to UBIAD1 .
  • an amount of molecules that provides a physiological change is considered an "effective amount” ora “therapeutically effective amount.”
  • a therapeutically effective amount of the compound described herein is the amount sufficient to treat Schnyder corneal dystrophy.
  • an effective amount of the compound described herein is the amount sufficient to lower the blood plasma cholesterol.
  • the effective amount can vary depending on such factors as the size and weight of the subject, the type of illness, or the particular compound described herein. For example, the choice of the compound described herein can affectwhat constitutes a “therapeutically effective amount.”
  • One of ordinary skill in the art would be able to study the factors contained herein and make the determination regarding the therapeutically effective amount of the compounds described herein without undue experimentation.
  • the term “patient”, “subject”, including “test subject” refers to any organism to which the compound or compounds described herein are administered in accordance with the present disclosure e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, humans, insects, worms, etc.). In an aspect, the subject is a human. Both pediatric and adult subjects are included.
  • the subject can be at least 6 months old (e.g., 6 months or older, 12 months or older, 18 months or older, 2 years or older, 4 years or older, 6 years or older, 10 years or older, 13 years or older, 16 years or older, 18 years or older, 21 years or older, 25 years or older, 30 years or older, 35 years or older, 40 years or older, 45 years or older, 50 years or older, 60 years or older, 65 years or older, 70 years or older, 75 years or older, 80 years or older, 85 years or older, 90 years or older, or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16 ,18, 20, 21 , 24, 25, 27, 28, 30, 33, 35, 37, 39, 40, 42, 44, 45, 48, 50, 52, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, 100, 101 , 102, 103, 104, or more years old).
  • a subject can be at least 6 months old (e.g.,
  • treating refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or ameliorating one or more symptoms of such condition or disorder.
  • treatment refers to any type of intervention, or the administration of a compound as disclosed herein, to a subject with the objective of reversing, alleviating, ameliorating, inhibiting, slowingdown orpreventingtheonset, progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with a disease.
  • the disease is a cardiovascular or cholesterol related disorder as provided herein.
  • alkyl as used herein means a straight or branched hydrocarbon radical having from 1 to 10 carbon atoms and includes, for example, methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, neopentyl, and the like.
  • alkenyl as used means straight and branched hydrocarbon radicals having from 2 to 8 carbon atoms and at least one double bond and includes, but is not limited to, ethenyl, 3-buten-1 -yl, 2-ethenylbutyl, 3-hexen-1 -yl, and the like.
  • alkenyl includes cycloalkenyl, and heteroalkenyl in which 1 to 3 heteroatoms selected from O, S, N, or substituted nitrogen may replace carbon atoms.
  • alkynyl as used means straightand branched hydrocarbon radicals having from 2 to 8 carbon atoms and at least one triple bond and includes, but is not limited to, ethynyl, 3-butyn-1 -yl, propynyl, 2-butyn-1 -yl, 3-pentyn-1 -yl, and the like.
  • cycloalkyl as used means a monocyclic or polycyclic hydrocarbyl group having from 3 to 8 carbon atoms, for instance, cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl.
  • groups can be substituted with groups such as hydroxy, keto, amino, alkyl, and dialkylamino, and the like. Also included are rings in which 1 to 3 heteroatoms replace carbons.
  • heterocyclyl means a cycloalkyl group also bearing at least one heteroatom selected from 0, S, N, or substituted nitrogen.
  • heteroatoms include, butare not limited to, oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, and morpholine.
  • alkoxy means a straight or branched chain alkyl groups having 1 -10 carbon atoms and linked through oxygen. Examples of such groups include, butare not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, n eopen toxy, hexoxy, 2- hexoxy, 3-hexoxy, and 3-methylpentoxy.
  • alkoxy refers to polyethers such as — 0— (CH2)2— 0— CH3, and the like.
  • alkyl, alkenyl, alkoxy, and alkynyl groups described herein are optionally substituted, prefer-ably by 1 to 3 groups selected from NR4R5, phenyl, substituted phenyl, th io C 1 -C6 alkyl, C1 -C6alkoxy, hydroxy, carboxy, C1 -C6 alkoxycarbonyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur.
  • “Substituted nitrogen” means nitrogen bearing C1 -C6 alkyl or (CH2)pPh where p is 1 , 2, or 3. Perhalo and polyhalo substitution is also included.
  • substituted alkyl groups include, but are not limited to, 2- aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2- dimethylaminopropyl, ethoxycarbonyl methyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropyl propyl, pentafluoroethyl, 3-morpholinopropyl, piper-azinylmethyl, and 2-(4- methylpiperazinyl)ethyl.
  • substituted alkynyl groups include, but are not limited to, 2- methoxyethynyl, 2-ethylsulfanylethynyl, 4-(1 -piperazinyl)-3-(butynyl), 3-phenyl-5- hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, andthe like.
  • Typical substituted alkoxy groups include aminomethoxy, trifluoromethoxy, 2- diethylaminoethoxy, 2-eth oxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like.
  • substituted alkyl, alkenyl, and alkynyl groups include, but are not limited to, dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1- yl, 5-ethylmethylamino-3-pentyn-1 -yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyl, 3- imidazolidin-1 -ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl, 3- chlorophenylmethyl, and the like.
  • anion as used herein means a negatively charged counterion such as chloride, bromide, trifluoroacetate, and triethylammonium.
  • acyl as used herein means an alkyl or aryl (Ar) group having from 1 -10 carbon atoms bonded through a carbonyl group, i.e., R — C(O) — .
  • acyl includes, but is not limited to, a C1 -C6 alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by an amine, amide, carboxylic, or heterocyclic group.
  • Typical acyl groups include acetyl, benzoyl, and the like.
  • aryl refers to an aromatic monocyclic hydrocarbon ring system or a polycyclic ring system where at least one of the rings in the ring system is an aromatic hydro-carbon ring and any other aromatic rings in the ring system include only hydrocarbons.
  • a monocyclic aryl group can have from 6 to 14 carbon atoms and a polycyclic aryl group can have from 8 to 14 carbon atoms.
  • the aryl group can be covalently attached to the defined chemical structure at any carbon atom(s) that result in a stable structure.
  • an aryl group can have only aromatic carbocyclic rings, e.g., phenyl, 1 -naphthyl, 2- naphthyl, anthracenyl, phenanthrenyl groups, and the like.
  • an aryl group can be a polycyclic ring system in which at least one aromatic carbocyclic ring is fused (i.e., having a bond in common with) to one or more cycloalkyl or cycloheteroalkyl rings.
  • aryl groups include, among others, benzo derivatives of cyclopentane (i.e., an indanyl group, which is a 5,6-bicyclic cycloal kyl/aromatic ring system), cyclohexane (i.e., a tetrahydronaphthyl group, which is a 6,6-bicyclic cycloalkyl/aromatic ring system), imidazoline (i.e., a benzimidazolinyl group, which is a 5,6-bicyclic cycloheteroalkyl/aromatic ring system), and pyran (i.e., a chromenyl group, which is a 6,6-bicyclic cycloheteroal kyl/aromatic ring system).
  • aryl groups include benzodioxanyl, benzodioxolyl, chromanyl, indolinyl groups, and
  • halogen or “halo” as used herein means fluorine, bromine, chlorine, and iodine.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • a haloalkyl group can have 1 to 10 carbon atoms (e.g., from 1 to 8 carbon at-oms).
  • Examples of haloalkyl groups include CFs, C2F5, CHF2, CH2F, CCI3, CHCI2, CH2CI, C2CI5, and the like.
  • Perhaloalkyl groups i.e., alkyl groups wherein all of the hydrogen atoms are replaced with halogen atoms (e.g., CFsand C2F5), are included within the definition of “haloalkyl.”
  • a Ci- 10 haloalkyl group can have the formula — CiH2i+1 -jXj, wherein X is F, Cl, Br, or I, i is an integer in the range of 1 to 10, and j is an integer in the range of 0 to 21 , provided thatj is less than or equal to 2i+1 .
  • heteroaryl refers to an aromatic monocyclic ring system containing at least one ring heteroatom selected from 0, N, and S or a polycyclic ring system where at least one of the rings in the ring system is aromatic and contains at least one ring heteroatom.
  • a heteroaryl group as a whole, can have from 5 to 14 ring atoms and contain 1 -5 ring heteroatoms.
  • heteroaryl groups can include monocyclic heteroaryl rings fused to one or more aromatic carbocyclic rings, non-aromatic carbocyclic rings, or non-aromatic cycloheteroalkyl rings.
  • the heteroaryl group can be covalently attached to the defined chemical structure at any heteroatom or carbon atom that results in a stable structure.
  • heteroaryl rings do not contain 0 — 0, S — S, or S — 0 bonds.
  • one or more N or S atoms in a heteroaryl group can be oxidized (e.g., pyridine N-oxide, thiophene S-oxide, thiophene S,S-dioxide).
  • heteroaryl rings examples include pyrrolyl, furyl, thienyl, pyridyl, pyrimidyl, pyri-dazinyl , pyrazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, quinolyl, 2-methylquinolyl, isoquinolyl, quinoxalyl, quinazolyl, benzotriazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzoxadiazolyl, benzoxazolyl, cinnolinyl, 1 H- indazolyl, 2H-ind
  • heteroaryl groups include 4,5,6,7-tetrahydroindolyl, tetrahydroqu in o-linyl, benzoth ienopyridinyl, benzofuropyridinyl groups, and the like.
  • lower alkenyl refers to alkenyl groups which contains 2 to 6 carbon atoms.
  • An alkenyl group is a hydrocarbyl group containing at least one carbon-carbon double bond. As defined herein, it may be unsubstituted or substituted with the substituents described herein.
  • the carbon-carbon double bonds may be between any two carbon atoms of the alkenyl group. It is preferred that it contains 1 or 2 carbon -carbon double bonds and more preferably one carbon -carbon double bond.
  • the alkenyl group may be straight chained or branched.
  • Examples include but are not limited to ethenyl, 1 -propenyl, 2-propenyl, 1 -butenyl, 2-butenyl, 2-methyl-1 - propenyl, 1 ,3-butadienyl, and the like.
  • lower alkynyl refers to an alkynyl group containing 2-6 carbon atoms.
  • An alkynyl group is a hydrocarbyl group containing at least one carbon-carbon triple bond.
  • the carbon-carbon triple bond may be between any two carbon atom of the alkynyl group.
  • the alkynyl group contains 1 or
  • alkynyl group may be straight chained or branched. Exam-pies include but are not limited to ethynyl, 1 -propynyl, 2-propynyl, 1 -butynyl, 2-butynyl and the like.
  • carrieroxy refers to an alkoxycarbonyl group, where the attachment to the main chain is through the carbonyl group, e.g., — C(O) — .
  • Examples include but are not limited to methoxy carbonyl, ethoxy carbonyl, and the like.
  • cycloalkyl refersto a non -aromatic carbocyclic group including cyclized alkyl, alkenyl, and alkynyl groups.
  • a cycloalkyl group can be monocyclic(e.g., cyclohexyl)orpolycyclic(e.g., containingfused, bridged, and/orspiro ring systems), wherein the carbon atoms are located inside or outside of the ring system.
  • a cycloalkyl group, as a whole, can have from 3 to 14 ring atoms (e.g., from
  • cyclo-alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, adamantyl, and spiro[4.5]decanyl groups, as well as theirhomologs, isomers, and the like.
  • heteroatom refers to an atom of any element other than carbon or hydrogen and includes, for example, nitrogen, oxygen, sulfur, phosphorus, and selenium.
  • cycloheteroalkyl refers to a non -aromatic cycloalkyl group that contains at least one (e.g., one, two, three, four, or five) ring heteroatom selected from 0, N, and S, and optionally contains one or more (e.g., one, two, or three) double or triple bonds.
  • a cyclo-heteroalkyl group as a whole, can have from 3 to 14 ring atoms and contains from 1 to 5 ring heteroatoms (e.g., from 3-6 ring atoms for a monocyclic cycloheteroalkyl group and from 7 to 14 ring atoms for a polycyclic cycloheteroalkyl group).
  • the cycloheteroalkyl group can be covalently attached to the defined chemical structure at any heteroatom(s) or carbon atom(s) that results in a stable structure.
  • N or S atoms in a cycloheteroalkyl ring may be oxidized (e.g., morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S,S-dioxide).
  • Cyclohet-eroalkyl groups can also contain one or more oxo groups, such as phthalimidyl, piperidonyl, oxazolidinonyl, 2,4(1 H,3H)-dioxo-pyrimidinyl, pyridin-2(1 H)- onyl, and the like.
  • cyclo-heteroalkyl groups include, among others, morpholinyl, thiomorpholinyl, pyranyl, imidazolidinyl, imidazolinyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrol idinyl, pyrrolinyl , tetrahydrofuranyl, tet-rahydrothienyl, piperidinyl, piperazinyl, azetidine, and the like.
  • the compounds described herein may contain chiral centers and therefore may exist in different enantiomeric and diastereomeric forms.
  • One aspect described herein encompasses all optical isomers or stereoisomers of the compounds described herein both as racemic mixtures and as individual enantiomers or diastereoisomers, or mixtures thereof, and to all pharmaceutical compositions or methods of treatment described herein that contain or employ them, respectively.
  • Individual isomers can be obtained by known methods, such as optical resolution, optically selective reaction, or chiral chromatographic separation in the preparation of the final product or its intermediate.
  • the compounds described herein can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • the solvated forms, including hydrated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope described herein.
  • Compounds described herein also includes isotopically labelled compounds, which are identical to those described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass numberusually found in nature.
  • isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • isotopically labelled compounds described herein and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • Compounds described herein also includes compounds conjugated with probes including but not restricted to photocrosslinkers, dyes, biotin etc.
  • analog refers to a small organic compound, a nucleotide, a protein, or a polypeptide that possesses similar or identical activity or function(s) as the compound, nucleotide, protein or polypeptide or compound having the desired activity and therapeutic effect (e.g., inhibition of tumor growth), but need not necessarily comprise a sequence or structure that is similar or identical to the sequence or structure of the preferred embodiment.
  • derivative refers to either a compound, a protein or polypeptide that comprises an amino acid sequence of a parent protein or polypeptide that has been altered by the introduction of amino acid residue substitutions, deletions or additions, or a nucleic acid or nucleotide that has been modified by either introduction of nucleotide substitutions or deletions, additions or mutations.
  • the derivative nucleic acid, nucleotide, protein, or polypeptide possesses a similar or identical function as the parent polypeptide.
  • Results of the present disclosure is based in part on the surprising discovery that Apatinib, a tyrosine kinase inhibitor th at inhibits vascular endothelial growth factor receptor-2 (VEGFR2), restores the Golgi localization of SCD-associated N102S variant of UBIAD1.
  • Apatinib also accelerates ERAD of HMGCR in the presence of wild type UBIAD1.
  • Apatinib also enhances GGpp-induced ER-to-Golgi transport of the protein.
  • SCD Schnyder corneal dystrophy
  • Novel lead compounds and analogs and derivatives thereof provided herein were synthesized and tested in in vitro assays and found to be effective in restoring the Golgi localization of SCD-associated N102S variant of UBIAD1 .
  • the active derivatives are modified on the pyridine ring that mediates the kinase inhibitory activity of Apatinib.
  • the compounds include a photoactivatable Apatinib derivative harboring an alkyne group for biotin conjugation. This molecule stimulates ER-to-Golgi trafficking of wild type and N102S UBIAD1. Moreover, the molecule photoaffinity labels UBIAD1 in a manner that is blocked by the Apatinib parent compound and SAR derivatives the stimulate Golgi transport of Apatinib.
  • the disclosure provides compounds comprising Formula (I) or a pharmaceutically acceptable salt thereof:
  • Ri and R2 are independently of each other hydrogen, halogen, alkyl, alkyl amine, alkyl sulfonamide, aryl, substituted aryl, heterocyclic aryl amine, substituted heterocyclic aryl amine, cyclic aliphatic amine, heterocyclic aliphatic amine, substituted heterocyclic aliphatic amine, alkyne; or together with the carbon atom to form a cycloalkyl, a cycloalkenyl, or a heterocyclylalkyl ring;
  • R3 is an aryl or substituted aryl
  • Y is an oxygen, nitrogen, or sulfur.
  • the disclosure provides compounds comprising Formula (II) wherein the substituted aryl is a phenyl group with a substituted carbon atom on a para position as in Formula (II) or a pharmaceutically acceptable salt thereof:
  • Ri and R2 are independently of each other hydrogen, halogen, alkyl, alkyl amine, alkyl sulfonamide, aryl, substituted aryl, heterocyclic aryl amine, substituted heterocyclic aryl amine, cyclic aliphatic amine, heterocyclic aliphatic amine, substituted heterocyclic aliphatic amine, alkyne; or together with the carbon atom to form a cycloalkyl, a cycloalkenyl, or a heterocyclylalkyl ring;
  • R3 is an aryl or substituted aryl
  • X is a halogen or a cycloalkane carbonitrile with formula -CnH(2n-2)CN, wherein n is 3 or more;
  • Y is an oxygen, nitrogen, or sulfur.
  • the disclosure provides compounds comprising Formula (III) wherein R1 and R2 combine to form a heterocycle with both amine and ether groups and X is a halogen or a cycloalkane carbonitrile with formula -CnH(2n-2)CN, wherein n is 3 or more or a pharmaceutically acceptable salt thereof: Formula (III).
  • the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN, R1 is hydrogen, and R2 is methylbenzyl as shown below: (Compound 1 ).
  • the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN, R1 is hydrogen, and R2 is neopentane as shown below: (Compound 2).
  • the disclosure provides compounds comprising Formula (I) or a pharmaceutically acceptable salt thereof wherein Ri is hydrogen, R2 is methylpyridine, and R3 is cyclohexane as shown below: (Compound 3).
  • the disclosure provides compounds comprising Formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is hydrogen, R2 is 4-methylpyridine, and R3 is toluene as shown below: (Compound 4).
  • the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN, R1 is hydrogen, and R2 is 3-methylpyradine as shown below: (Compound s).
  • the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formu la -CsHsCN, Ri is hydrogen, and R2 is 1 -fluoro-4-methylbenzene as shown below: (Compound s).
  • the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbonitrile with formula -CsHsCN, R1 is hydrogen, and R2 is propane as shown below: (Compound 7).
  • the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbonitrile with formula -CsHsCN, Ri is methyl, and R2 is methyl benzyl as shown below: (Compound 8).
  • the disclosure provides compounds comprising Formula (III) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN and the heterocycle is morpholine as shown below: (Compound 9).
  • the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN, R1 is hydrogen, and R2 is 1 - (methylsulfonyl)piperidine as shown below: (Compound 10).
  • the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN, R1 is hydrogen, and R2 is isopentane as shown below: (Compound 11 ).
  • the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbonitrile with formula -CsHsCN, Ri is hydrogen, and R2 is ethanesulfonamide, wherein the heterocycle is morpholine as shown below: (Compound 12).
  • the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN, R1 is hydrogen, and R2 is neopentyl as shown below: (Compound 13).
  • the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formu la -CsHsCN, Ri is hydrogen, and R2 is tert-butyl 3-ethylazetidine- 1 -carboxylate as shown below: (Compound 14).
  • the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN, R1 is hydrogen, and R2 is N,N-dimethylpropan-1- amine as shown below: (Compound 15).
  • the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN, R1 and R2 are hydrogen as shown below:
  • the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is fluorine, Ri is hydrogen, and R2 is 4-methyl pyridine as shown below: (Compound 17)
  • the disclosure provides the compound of Table 1 , listed as compounds 1-17:
  • the compounds provided herein may be used for treatment or a wide range of a cardiovascular or cholesterol related disorders.
  • a method of treating a cardiovascular or cholesterol related disorder by administering to a subject in need thereof, one or more of the compounds disclosed herein.
  • a therapeutically effective amount of the one or more compounds disclosed herein is administered.
  • the cardiovascular or cholesterol related disorder may be Schnyder corneal dystrophy (SCD), corneal dystrophy, peripheral artery disease, hypercholesterolemia, hyperlipidemia/ dyslipidemia, sitosterolemia, atherosclerosis, arteriosclerosis, or xanthoma.
  • SCD Schnyder corneal dystrophy
  • corneal dystrophy peripheral artery disease
  • hypercholesterolemia hyperlipidemia/ dyslipidemia
  • sitosterolemia hyperlipidemia/ dyslipidemia
  • atherosclerosis atherosclerosis
  • arteriosclerosis arteriosclerosis
  • xanthoma xanthoma
  • the subject has a high blood plasma cholesterol value relative to a predetermined blood plasma cholesterol value and/or has a genetic predisposition to high blood plasma cholesterol. In some aspects, the subject has a high blood plasma cholesterol value relative to a predetermined blood plasma cholesterol value and the predetermined blood plasma cholesterol value is less than or equal to 200 mg/dL.
  • the subject has a genetic predisposition to high blood plasma cholesterol and the genetic predisposition is a mutation in UBIAD1 , LDLR, APOB, SREBP, SCAP, and/or PCSK9 genes.
  • a method of activating the allosteric activator of UBIAD1 that enhances its affinity for GGpp in a subject is augmented, which leads to accelerated ERAD of HMGCR that prevents its statin- induced overaccumulation.
  • the compounds may be used to treat patients with the eye disease Schnyder Corneal Dystrophy, which is caused by mutations in UBIAD1 and results in the opacification of the cornea owing to the accumulation of cholesterol in the tissue.
  • the one or more compounds used in a method of treating a cardiovascular or cholesterol related disorder comprises Apatinib.
  • the one or more compounds used in a method of treating a cardiovascular or cholesterol related disorder comprises one or more of compounds 1 -17.
  • the one or more compounds comprises one or more of compounds 5-17.
  • the one or more compounds comprises compound 1.
  • the one or more compounds comprises compound 2.
  • the one or more compounds comprises compound 3.
  • the one or more compounds comprises compound 4.
  • the one or more compounds comprises compound s.
  • the one or more compounds comprises compound 6.
  • the one or more compounds comprises compound 7.
  • the one or more compounds comprises compound s.
  • the one or more compounds comprises compound 9.
  • the one or more compounds comprises compound 10.
  • the one or more compounds comprises compound 11.
  • the one or more compounds comprises compound 12. In some aspects, the one or more compounds comprises compound 13. In some aspects, the one or more compounds comprises compound 14. In some aspects, the one or more compounds comprises compound 15. In some aspects, the one or more compounds comprises compound 16. In some aspects, the one or more compounds comprises compound 17.
  • the one or more compounds may be pharmaceutically active or are prodrugs.
  • the one or more compounds maybe a pharmaceutically acceptable salt.
  • the one or more compounds may be Apatinib.
  • the one or more compounds may be one or more of the compounds listed in Table 1 as 1 -17.
  • the one or more compounds may be administered to the subject in a therapeutically effective amount.
  • the subject may be an animal or human.
  • the one or more compounds may be administered as a pharmaceutical compositions.
  • the subject treated is typically a human subject, although it is to be understood the methods described herein are effective with respect to other animals, such as mammals and vertebrate species.
  • the term “subject” includes individuals that have been diagnosed with a cardiovascular or cholesterol related disorder because of missense mutations in UBIAD1 .
  • the current disclosure also encompasses use of disclosed compounds of treatment of Schnyder corneal dystrophy (SCD).
  • the current disclosure encompasses use of the disclosed compositions for restoration of Golgi localization of SCD-associated N102S variant of UBIAD1 , in a subject in need thereof.
  • the present disclosure provides pharmaceutical compositions.
  • the pharmaceutical compositions of the instant disclosure include at least one compound according to the instant disclosure for use to treat, prevent, or ameliorate a cardiovascular or cholesterol related disorder in a subject in need thereof.
  • the compound can be, for example as described in Section 1.
  • the pharmaceutical compositions can be administered to treat a disease or disorder, such as, but not limited to, those described in Section 2.
  • a pharmaceutical composition that comprises one or more of the compounds disclosed herein and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical compositions disclosed herein are used in the methods of treating a cardiovascular or cholesterol related disorder as disclosed herein.
  • the pharmaceutical compositions disclosed herein may comprise a therapeutically effective amount of one or more of the compounds disclosed herein.
  • the compounds disclosed herein may be administered to a subject in need thereof in a therapeutically effective amount.
  • compositions can includeatleast one compound disclosed herein and at least one pharmaceutically acceptable carrier.
  • pharmaceutical compositions can include pharmaceutically acceptable carriers, excipients, and/or stabilizers are nontoxicto recipients at dosages and/or concentrations used to practice the methods disclosed herein.
  • the pharmaceutically acceptable excipient can include, but is not limited to a diluent, a binder, a filler, a buffering agent, a pH modifying agent, a disi ntegrant, a dispersant, a preservative, a lubricant, or a coloring agent.
  • concentrations and types of excipients utilized to form pharmaceutical compositions disclosed herein and contemplated herein can be selected according to known principles of pharmaceutical science and knowledge in the art.
  • the excipient can be a diluent.
  • the diluent can be compressible (i.e., plastically deformable) or abrasively brittle.
  • suitable compressible diluents can include, but are not limited to, microcrystalline cellulose (MCC), cellulose derivatives, cellulose powder, cellulose esters (i.e., acetate and butyrate mixed esters), ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, corn starch, phosphated corn starch, pregelatinized com starch, rice starch, potato starch, tapioca starch, starch -lactose, starch-calcium carbonate, sodium starch glycolate, glucose, fructose, lactose, lactose monohydrate, sucrose, xylose, lactitol, mannitol, malitol,
  • the excipient can be a binder.
  • Suitable binders include, but are not limited to, starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof.
  • the excipient can be a filler.
  • suitable fillers include, but are not limited to, carbohydrates, inorganic compounds, and polyvinylpyrrolidone.
  • the filler can be calcium sulfate, both di- and tri-basic, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, lactose, sucrose, mannitol, or sorbitol.
  • the excipient can be a buffering agent.
  • suitable buffering agents include, but are not limited to, phosphates, carbonates, citrates, tris buffers, polysaccharide buffers, and buffered saline salts (e.g., Tris buffered saline, or phosphate buffered saline).
  • the excipient can be a pH modifier.
  • the pH modifying agent can be sodium carbonate, sodium bicarbonate, sodium citrate, citric acid, or phosphoric acid.
  • the excipient can be a disintegrant.
  • the disintegrant can be non -effervescent or effervescent.
  • Suitable examples of non- effervescentdisintegrants include, but are not limited to, starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pecitin, and tragacanth.
  • suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid and sodium bicarbonate in combination with tartaric acid.
  • the excipient can be a dispersant or dispersing enhancing agent.
  • Suitable dispersants can include, but are not limited to, starch, alginicacid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, amorphous silicate, and microcrystalline cellulose.
  • the excipient can be a preservative.
  • suitable preservatives include antioxidants, such as BHA, BHT, vitamin A, vitamin C, vitamin E, or retinyl palmitate, citric acid, sodium citrate; chelators such as EDTA or EGTA; and antimicrobials, such as parabens, chlorobutanol, or phenol.
  • the excipient can be a lubricant.
  • suitable lubricants include minerals such as talc or silica; and fats such as vegetable stearin, magnesium stearate, or stearic acid.
  • the excipient can be a coloring agent.
  • Suitable color additives include, but are not limited to, food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).
  • Other pharmaceutically acceptable carriers, excipients, and/or stabilizers can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3- pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or ly
  • the regimen of administration can affect what constitutes an effective amount. Further, several divided dosages as well as staggered dosages, can be administered daily or sequentially, or the dose can be continuously infused, orcan be a bolus injection. Further, the dosages of the compound(s) described herein can be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
  • Compounds described herein may be used in the treatment of states, disorders or diseases as described herein, or for the manufacture of pharmaceutical compositions for use in the treatment of these diseases for example a cardiovascular or cholesterol related disorder. Methods of use of the compounds described herein in the treatment of these diseases, or pharmaceutical preparations having the compounds described herein for the treatment of these diseases.
  • phrases “pharmaceutically acceptable excipient” includes any pharmaceutically acceptable material, composition, or vehicle, suitable for administering the compounds described herein to mammals.
  • the excipient includes liquid or solid filler, a diluent, a binder a buffering agent, a pH modifying agent, a disintegrant, a dispersant, a preservative, a lubricant or wetting agent, taste-masking agent, an antioxidant, carrier, adjuvant, stabilizing agent, emulsifying agent, solution promoter, salt, solubilizer, antifoaming agent, surfactant, a flavoring agent, a coloring agent, solvent or encapsulating material or any combination thereof.
  • compositions of the disclosure may optionally comprise one or more additional drug or therapeutically active agent in addition to the at least one factor disclosed herein.
  • additional drug or therapeutically active agent in addition to the at least one factor disclosed herein.
  • the excipient may be a dispersant or dispersing enhancing agent.
  • Suitable dispersants may include, but are not limited to, starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, iso-amorphous silicate, and microcrystalline cellulose.
  • the excipient may be a preservative.
  • suitable preservatives include antioxidants, such as BHA, BHT, vitamin A, vitamin C, vitamin E, or retinyl palmitate, citric acid, sodium citrate; chelators such as EDTA or EGTA; and antimicrobials, such as parabens, chlorobutanol, or phenol.
  • theexcipient may be a lubricant.
  • suitable lubricants include minerals such astalc or silica; andfats such as vegetable stearin, magnesium stearate, or stearic acid.
  • Some additional examples of materials which can serve as pharmaceutically acceptable excipients include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, saffloweroil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isot
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and per-fuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (B HA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, a-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (B HA), butylated hydroxytoluene (BHT), lec
  • the weight fraction of the excipient or combination of excipients in the composition may be about 99% or less, about 97% or less, about 95% or less, about 90% or less, about 85% or less, about 80% or less, about75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10% or less, about 5% or less, about 2%, or about 1 % or less of the total weight of the composition.
  • compositions described herein can be formulated by any conventional manner using one or more pharmaceutically acceptable carriers or excipients as described in, for example, Remington’s Pharmaceutical Sciences (A.R. Gennaro, Ed.), 21st edition, ISBN: 0781746736 (2005), incorporated herein by reference in its entirety.
  • Such formulations will contain a therapeutically effective amountof a biologically active factor described herein, which can be in purifiedform, together with a suitable amount of carrier so as to provide the form for proper administration to the subject.
  • Formulations described herein includethosesuitableforparenteral, oral, intraadiposal, intraarterial, intraarticular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intrapericardial, intraperitoneal, intrapleural, intraprostatical, intrarectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intravascular, intravitreal , liposomal, local, mucosal, parenteral, rectal, subconjunctival, subcutaneous, sublingual, topical, trans buccal, and transdermal route.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methodswell known in the art of pharmacy.
  • the amount of active ingredient that can be combined with an excipient material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amountwill rangefrom aboutl percentto aboutninety-ninepercentof active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound as described herein with the excipient and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound described herein with liquid excipients, or finely divided solid excipients, or both, and then, if necessary, shaping the product.
  • Formulations described herein suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amountofa compound described herein as an active ingredient.
  • a compound described herein may also be administered as a bolus, electuary, or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosph ate, and/oranyofthe following: fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicicacid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginicacid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetylene glycol, glycerol
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions described here-in may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or micro-spheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dis-solved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds described herein include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, or elixirs.
  • the liquid dosage forms may contain inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butyleneglycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing
  • the oral compositions can also include adjuvants such as wetting agents, emu Isifying agents, suspending agents, sweeten ing, flavoring, coloring, perfuming, preservative agents, or combinations thereof.
  • adjuvants such as wetting agents, emu Isifying agents, suspending agents, sweeten ing, flavoring, coloring, perfuming, preservative agents, or combinations thereof.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • compositions described herein suitable for parenteral administration comprise one or more compounds described herein in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutionsordispersionsjust priorto use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonicwith the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous excipients examples includewater, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Properfluidity can be maintained, forexample, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, or combinations thereof. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate andgelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, or combinations thereof.
  • Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents,
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • the preparations described herein may be given orally, parenterally, topically, or rectally. They are of course given by forms suitableforeach administration route. For example, they are ad-ministered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc., administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral and/or IV administration is preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection or infusion.
  • systemic administration means the administration of a compound, drug or other material otherthan directly in to the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • these compounds may be administered to humans and other animals for therapy by any suitable route of administration, including parenteral, oral, intraadiposal, intraarterial, intraarticular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intrapericardial, intraperitoneal, intrapleural, intraprostatical, intrarectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intravascular, intravitreal , liposomal, local, mucosal, parenteral, rectal, subconjunctival, subcutaneous, sublingual, topical, trans buccal, and transdermal route.
  • parenteral oral, intraadiposal, intraarterial, intraarticular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intrapericardial, intraperitoneal, intrapleural, intraprostatical, intrarectal, intrathecal, intratracheal, intratu
  • the compounds described herein which may be used in a suitable hydrated form, and/or the pharmaceutical compositions described herein, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound described herein employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds described herein employed in the pharmaceutical composition at levels lower than th at required in order to achieve the desired therapeuticeffectand gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound described herein will be that amountof the compoundthatis the lowest dose effective to producea therapeutic effect. Such an effective dose will generallydepend upon thefactors described herein.
  • the total daily dose of compound described herein may be from about 5 mg to about 850 mg.
  • the dose may be about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about225 mg, about 230 mg, about235 mg, about240 mg, about245 mg, about250 mg, about255 mg, about265 mg, about 270 mg, about275 mg, about280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about345 mg, about350 mg, about 355 mg, about365 mg, about370 mg, about 375
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • a compound described herein While it is possible for a compound described herein to be administered alone, it may be administered in combination with other active composition.
  • ком ⁇ онент is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound described herein anda combination partnermay be administered independentlyat the same time or separately within time intervals th at especially allow th at the combination partners show a cooperative, e.g., synergistic, effect, or any combination thereof.
  • the compounds described herein may be administered, simultaneously or sequentially, with an anti-inflammatory, antiproliferative, antibiotics, NSAIDs, painkillers, chemotherapeutic agent, immunosuppressant, other drugs, or salt thereof.
  • the current disclosure encompasses methods of making (synthesizing) the compound or salt thereof comprising any one of the compounds disclosed herein. In some aspects, the compound or salt thereof comprising any one of the compounds 1 -17 provided in Table 1 .
  • Analytical techniques including but not limited to 1 H, 13 C, 19 F NMR, thin layer chromatography, and LC/MS may be used to monitor the reactions and to characterize the reaction intermediates and desired final products.
  • methods of making the compounds include reacting a substituted pyridine carboxamide with an amine in the presence of a base in a solvent for a specific reaction time under an appropriate temperature.
  • suitable bases include DIPEA, ammonia, or combinations thereof.
  • suitable solvents include DMSO, dioxane, DMF, or combinationsthereof.
  • the specific reaction time may be from about5 hrs to about48 hrs. The specific reaction time may be about 5 hrs, about 6 hrs, about?
  • the appropriate temperature may be from about 25°C to about 150°C.
  • the appropriate temperature may be 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31 °C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41 °C, 42°C, 43°C, 44°C, 45°C, 46°C,
  • Salts of the compounds described herein having at least one salt-forming group may be prepared in a manner known per se.
  • salts of the compounds described herein having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used.
  • metal compounds such as alkali metal salts of suitable organic carboxylic acids
  • organic alkali metal or alkaline earth metal compounds such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate
  • corresponding calcium compounds or with ammonia or a suitable organic amine such as sodium or potassium hydroxide, carbonate or
  • Acid addition salts of the compounds described herein are obtained in customary manner, e.g., by treating the compounds with an acid or a suitable anion exchange reagent.
  • Internal salts of the compounds described herein containing acid and basic saltforming groups e.g., a free carboxy group and a free amino group, may be formed, e.g., by the neutralization of salts, such as acid addition salts, to the isoelectric point, e.g., with weak bases, or by treatment with ion exchangers.
  • Salts can be converted in customary manner into the free compounds; metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a su itable basic agent.
  • Figure 1 illustrates the general chemical reaction for the formation of the disclosed compounds.
  • Figure 2 illustrates examples of sample chloro-/V-substituted-3-pyridinecarboxamide in one or more embodiments of the present disclosure.
  • Example 3 Synthesis of N-cyclohexyl-2-((pyridin-4- ylmethyl)amino)nicotinamide (TQYY-3) (Compound s) [00187] 0.1 mmol of 2-chloro-/V-[4-(1 -cyanocyclopentyl)phenyl] -3- pyridinecarboxamide and 0.2 mmol of 4-picolylaminewere reacted according to the general procedure. The reaction mixture was purified using preparative TLC (pTLC) in a 2:1 hexanes to acetone solvent mixture. The reaction and purification formed 10.4 mg of compound TQYY-3 with a 34% yield.
  • pTLC preparative TLC
  • Table 2 provides the 1 H, 13 C, 19 F NMR and LC-MS characterization of the synthesized compounds. Appendix A, incorporated by reference herein in its entirety, provides the NMR spectra of compounds 1-17 is Table 2.
  • Table 3 provides the physical state, melting point, and Rf value in an appropriate solvent of the compound of Table 1 , listed as compounds 1-17:
  • HMGCR HMG CoA reductase
  • mice Chow-fed mice were subjected to daily treatments by oral gavage with vehicle (corn oil) or Apatinib (200 pg/g of body weight)for fourconsecutive days.
  • vehicle corn oil
  • Apatinib 200 pg/g of body weight
  • FIG. 4 the results show that treatment with Apatinib led to a significant decrease in the amount of hepatic HMGCR as determined by immunoblot analysis.
  • the level of UBIAD1 was also reduced by Apatinib treatment, which is consistent with enhanced translocation of UBIAD1 to the Golgi from which it is subjected to basal autophagic degradation.
  • Apatinib modulates the ERAD of HMGCR and ER-to-Golgi trafficking of UBIAD1 in livers of mice through mechanisms similar to those we observed in cultured cells.
  • Apatinib causes reduction in levels of HMGCR and UBIADI in livers of mice.
  • Male C57BL/6 mice (10 weeks of age) fed chow diet ad libitum were subjected to daily oral gavage with vehicle (corn oil) or Apatinib (200 pg/g of body weight) for four consecutive days. The mice were sacrificed and livers were harvested for subcellular fractionation. Aliquots of resulting membranefractionswered to SDS-PAGE, followed by immunoblot analysis with antibodies against the indicated proteins (FIG. 4).

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Abstract

L'invention concerne des composés, des compositions et des procédés de fabrication et d'utilisation des composés pour le traitement de maladies cardiovasculaires ou de troubles liés au cholestérol provoqués par des mutations de l'UBIAD1. D'un point de vue mécanique, ces composés s'avèrent être des activateurs allostériques du gène UBIAD1 et améliorent son affinité pour GGpp.
PCT/US2024/039362 2023-07-24 2024-07-24 Petites molécules empêchant l'accumulation induite par statine de hmg coa réductase Pending WO2025024564A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060166891A1 (en) * 2003-04-22 2006-07-27 Sircar Jagadish C Mediators of reverse cholesterol transport for the treatment of hypercholesterolemia
US20190321465A1 (en) * 2015-09-09 2019-10-24 Tsinghua University Mevalonate pathway inhibitor as highly-efficient vaccine adjuvant
US20200282052A1 (en) * 2017-11-10 2020-09-10 Elevar Therapeutics, Inc. A combination therapy with apatinib for the treatment of cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060166891A1 (en) * 2003-04-22 2006-07-27 Sircar Jagadish C Mediators of reverse cholesterol transport for the treatment of hypercholesterolemia
US20190321465A1 (en) * 2015-09-09 2019-10-24 Tsinghua University Mevalonate pathway inhibitor as highly-efficient vaccine adjuvant
US20200282052A1 (en) * 2017-11-10 2020-09-10 Elevar Therapeutics, Inc. A combination therapy with apatinib for the treatment of cancer

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