WO2003090732A1 - Modulateurs lxr pour le traitement des maladies cardio-vasculaires - Google Patents

Modulateurs lxr pour le traitement des maladies cardio-vasculaires Download PDF

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Publication number
WO2003090732A1
WO2003090732A1 PCT/US2003/012391 US0312391W WO03090732A1 WO 2003090732 A1 WO2003090732 A1 WO 2003090732A1 US 0312391 W US0312391 W US 0312391W WO 03090732 A1 WO03090732 A1 WO 03090732A1
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alkyl
aryl
mmol
hydrogen
amino
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PCT/US2003/012391
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English (en)
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Thomas Arrhenius
Jie-Fei Cheng
Alex M. Nadzan
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Chugai Seiyaku Kabushiki Kaisha
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Priority to AU2003223684A priority Critical patent/AU2003223684A1/en
Publication of WO2003090732A1 publication Critical patent/WO2003090732A1/fr

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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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to methods for treatment of certain diseases or conditions mediated by Liver X Receptor (LXR) by the administration of a composition containing as an active ingredient a compound according to Formula I.
  • LXR Liver X Receptor
  • the invention relates to methods for treatment of cardiovascular diseases and atherosclerosis through the administration of a compound which modulates LXR activity.
  • LXRs Liver X receptors
  • LXR ⁇ and LXR ⁇ are nuclear receptors that regulate the expression of cytochrome P450 7A (CYP7A1), and thus the metabolism of several important lipids, including cholesterol and bile acids.
  • LXRs were first identified as orphan members of the nuclear receptor superfamily (Song et al., Proc. Natl. Acad. Sci. 191 :10809-10813 (1994). Willy et al., Genes Dev. 9:1033-1045 (1995)).
  • LXR ⁇ is expressed most highly in the liver and to a lesser extent in the kidney, small intestine, spleen and adrenal gland. On the contrary, LXR ⁇ is ubiquitously expressed.
  • Naturally occurring or synthetic oxysterols such as 22(R)- hydroxycholesterol, 24(S)-hydroxycholesterol, and 24(S),25-epoxycholesterol are believed to be transcriptional activators of LXR ⁇ and ⁇ . These oxysterols exist at concentrations that activate LXRs in tissues (e.g. liver, brain and placenta) where both cholesterol metabolism and LXR expression are high.
  • LXRs bind to the ATP binding cassette transporter-1 (ABCA1 ) gene promoter and increases expression of the gene to result in increased ABCA1 protein.
  • ABCA1 is a membrane bound transport protein which is involved in the regulation of cholesterol efflux from extrahepatic cells onto nascent HDL particles.
  • Humans with mutations in the gene ABCA1 have low levels of high density lipoprotein (HDL) and a concomitant increased risk of cardiovascular diseases such as atherosclerosis, myocardial infarction and ischemic stroke (Brooks-Wilson et al, Nat. Genet. 22: 336-345 (1999), Bodzioch et al., Nat. Genet.
  • HDL high density lipoprotein
  • LXR ⁇ and ⁇ agonists were demonstrated to increase ABCA1 gene expression which resulted in increased HDL cholesterol, and decreased absorption of cholesterol and thereby decreased the risk of cardiovascular diseases (Sparrow et al., J. Biol. Chem. 277:10021-10027 (2002).
  • LXRs signaling pathways play a central role in the control of macrophage cholesterol efflux through the coordinate regulation of ABCA1 and ABCG1 and surface constituent of plasma lipoprotein apolipoprotein E (apoE) gene expression.
  • apoE plasma lipoprotein apolipoprotein E
  • LXR/RXR heterodimers regulate apoE transcription directly, through interaction with a conserved LXR response element present in both ME.1 and ME.2.
  • the ability of oxysterol and synthetic ligands to regulate apoE expression in adipose tissue and peritoneal macrophages is reduced in LXR ⁇ -/- or LXR ⁇ -/- mice and abolished in double knockouts.
  • LXRs also play an important role in fatty acid metabolism by activating the sterol regulatory element-binding protein-1c (SREBP-1c) gene (Tobin, et al., J. Biol. Chem. 277:10691-10697 (2002).
  • SREBP-1c sterol regulatory element-binding protein-1c
  • transcription of the SREBP-1c gene is stimulated by naturally occurring oxysterols, like 24(S),25-expoxycholesterol and 22(R)-hydroxycholesterol, that bind to LXR ⁇ and ⁇ .
  • LXRs are also activated by T0901317, a synthetic nonsteroidal compound.
  • SREBP-1c mRNA declined dramatically when cultured rat hepatoma cells were treated with inhibitors of 3-hydroxy-3- methylglutaryl coenzyme reductase, which block the synthesis of endogenous LXR ligands. This inhibition was reversed when the cells were incubated with either T0901317 or mevalonate, the product of the reductase reaction.
  • LXR modulators would be useful in methods of increasing ABCA1 , SREBP-1c, and apoE expression, increasing HDL cholesterol and treating LXR mediated diseases or conditions such as hypercholesterolemia and cardiovascular diseases.
  • R-i is independently chosen from halo, haloalkyl, hydroxy, thiol, substituted thiol, sulfonyl, sulfinyl, nitro, cyano, amino, substituted amino, CrC 6 alkyl and C- t - C 6 alkoxy, and when R-i is hydroxy, C-i-C ⁇ alkoxy, thiol, substituted thiol, amino, substituted amino, or C C 6 alkyl, such radical may be combined with
  • R 2 to form a ring of 5-7 members when R-i is ortho to R 2 ;
  • R 3 is hydrogen, alkyl, aryl, heterocyclyl, acyl, or may form a ring of 5-7 members with R 4 or R 5 ;
  • R is hydrogen, alkyl, aryl, heterocyclyl, acyl, or may form a ring of 5-7 members with R 5 or R 3 ;
  • R 5 is hydrogen, alkyl, aryl, or heterocyclyl, acyl or may form a ring of 5-7 members with R 3 or R 4 ;
  • R ⁇ and R may be equal or different and are selected from hydrogen, alkyl, aryl, or heterocylcyl;
  • R 8 is hydrogen, alkyl, aryl, heterocylcyl, amino or substituted amino;
  • R 9 , R1 0 , R11 and R ⁇ 2 may be equal or different and are selected from hydrogen, alkyl, aryl, heterocyclyl, nitro, cyano, carboxylic acid, ester, amide, halo, hydroxyl, amino, substituted amino, alkoxy, acyl, ureido, sulfonamido, sulfamido, sulfonyl, sulfinyl, or guanadinyl;
  • R- ⁇ 3 is hydrogen, alkyl, aryl, heterocycly
  • X is H, CF 2 Z, or CF 3 , or together with Y forms a double bond when A is O; Y is hydrogen, or together with X forms a double bond when A is O; Z is F, Br, CI, l or CF 3; their prodrugs and pharmaceutically acceptable salts.
  • the enantiomers, diasteromers, or tautomers of the compound (I) are also encompassed in the present invention.
  • the compounds of this invention have the following general structures (la and lb):
  • R**, R 2 , A, m, X, Y, and Z are as defined above. More preferred compounds are depicted in the following general structures (lc and Id):
  • alkyl means a cyclic, branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, pentyl, and adamantyl.
  • Alkyl groups can either be unsubstituted or substituted with one or more substituents, e.g., halogen, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • alkyl groups will comprise 1 to 12 carbon atoms, preferably 1 to 10, and more preferably 1 to 8 carbon atoms or cyclic groups containing three to eight carbons.
  • lower alkyl means a subset of alkyl, and thus is a hydrocarbon substituent, which is linear, cyclic or branched.
  • Preferred lower alkyls are of 1 to about 6 carbons, and may be branched or linear, and may include cyclic substituents, either as part or all of their structure. Examples of lower alkyl include butyl, propyl, isopropyl, ethyl, and methyl.
  • radicals using the terminology "lower” refer to radicals preferably with 1 to about 6 carbons in the alkyl portion of the radical.
  • aryl means a substituted or unsubstituted aromatic radical having a single-ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which can be optionally unsubstituted or substituted with amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents, and which may or may not include one or more heteroatoms.
  • Preferred carbocyclic aryl is phenyl.
  • heteroaryl is clearly contemplated in the term “aryl”.
  • aryl represents a heterocycle, it is referred to as “heteroaryl”, and has one or more heteroatom(s).
  • Preferred are monocyclic heterocycles of 5 or 6 members.
  • heteroaryl is a monovalent unsaturated aromatic group having a single ring and having at least one hetero atom, such as N, O, or S, within the ring, which can optionally be unsubstituted or substituted with amino, cyano, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, aryl, halo, mercapto, oxo (hence forming a carbonyl.) and other substituents.
  • hetero atom such as N, O, or S
  • heteroaryl examples include thienyl, pyrridyl, furyl, oxazolyl, oxadiazolyl, pyrollyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl and others.
  • substitution on the aryl ring is within the scope of this invention.
  • the radical is called substituted aryl.
  • Preferred substitution patterns in five membered rings are substituted in the 2 position relative to the connection to the claimed molecule.
  • substituents include those commonly found in aryl compounds, such as alkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkyl, mercapto and the like.
  • acyl means an H-CO- or alkyl-CO-, aryl-CO- or heterocyclyl-CO- group wherein the alkyl, aryl or heterocyclcyl group is as herein described.
  • acyls contain a lower alkyl.
  • exemplary alkyl acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, t-butylacetyl, butanoyl and palmitoyl.
  • halo is a chloro, bromo, fluoro or iodo atom radical. Chloro, bromo and fluoro are preferred halides. The term “halo” also contemplates terms sometimes referred to as “halogen", or "halide”.
  • haloalkyl means a hydrocarbon substituent, which is linear or branched or cyclic alkyl, alkenyl or alkynyl substiuted with chloro, bromo, fluoro or iodo atom(s). Most preferred of these are fluoroalkyls, wherein one or more of the hydrogen atoms have been substituted by fluoro. Preferred haloalkyls are of 1 to about 5 carbons in length, More preferred haloalkyls are 1 to about 4 carbons, and most preferred are 1 to 3 carbons in length.
  • haloalkylene means a diradical variant of haloalkyl, such diradicals may act as spacers between radicals, other atoms, or between the parent ring and another functional group.
  • linker CHF-CHF is a haloakylene diradical.
  • heterocyclyl means heterocyclic radicals, which are saturated or unsaturated. These may be substituted or unsubstituted, and are attached to other via any available valence, preferably any available carbon or nitrogen. More preferred heterocycles are of 5 or 6 members. In six membered non-aromatic monocyclic heterocycles, the heteroatom(s) are selected from one up to three of O, N or S, and wherein when the heterocycle is five membered and non-aromatic, preferably it has one or two heteroatoms selected from O, N, or S.
  • substituted amino means an amino radical which is substituted by one or two alkyl, aryl, or heterocyclyl groups, wherein the alkyl, aryl or heterocyclyl are defined as above.
  • substituted thiol means RS- group wherein R is an alkyl, an aryl, or a heterocyclyl group, wherein the alkyl, aryl or heterocyclyl are defined as above.
  • sulfonyl means an alkylS0 2 , arylS0 2 or heterocyclyl-
  • S0 2 group wherein the alkyl, aryl or heterocyclyl are defined as above.
  • sulfamido means an alkyl-N-S(0) 2 N-, aryl-NS(0) 2 N- or heterocyclyl-NS(0) 2 N- group wherein the alkyl, aryl or heterocyclcyl group is as herein described.
  • sulfonamido means an alkyl-S(0) 2 N-, aryl-S(0) 2 N- or heterocyclyl- S(0) 2 N- group wherein the alkyl, aryl or heterocyclcyl group is as herein described.
  • ureido means an alkyl-NCON-, aryl-NCON- or heterocyclyl-NCON- group wherein the alkyl, aryl or heterocyclcyl group is as herein described
  • a "radical” may form a ring with another radical as described herein.
  • radicals are combined, the skilled artisan will understand that there are no unsatisfied valences in such a case, but that specific substitutions, for example a bond for a hydrogen, is made. Hence certain radicals can be described as forming rings together.
  • rings having from 3-7 members, more preferably 5 or 6 members.
  • ring or “rings” when formed by the combination of two radicals refers to heterocyclic or carbocyclic radicals, and such radicals may be saturated, unsaturated, or aromatic.
  • preferred heterocyclic ring systems include heterocyclic rings, such as morpholinyl, piperdinyl, imidazolyl, pyrrolidinyl, and pyridinyl.
  • a "pharmaceutically-acceptable salt” is an anionic salt formed at any acidic (e.g., carboxyl) group, or a cationic salt formed at any basic (e.g., amino) group.
  • salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published September 1 1 , 1987 (incorporated by reference herein).
  • Preferred counter-ions of salts formable at acidic groups can include cations of salts, such as the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium) and organic salts.
  • Preferred salts formable at basic sites include anions such as the halides (such as chloride salts).
  • halides such as chloride salts
  • the skilled artisan is aware that a great number and variation of salts may be used, and examples exist in the literature of either organic or inorganic salts useful in this manner.
  • prodrugs can be provided as biohydrolyzable prodrugs, as they are understood in the art.
  • Prodrug as used herein is any compound wherein when it is exposed to the biological processes in an organism, is hydrolyzed, metabolized, derivatized or the like, to yield an active substance having the desired activity.
  • prodrugs may or may not have any activity as prodrugs. It is the intent that the prodrugs described herein have no deleterious effect on the subject to be treated when dosed in safe and effective amounts. These include for example, biohydrolyzable amides and esters.
  • a “biohydrolyzable amide” is an amide compound which does not essentially interfere with the activity of the compound, or that is readily converted in vivo by a cell, tissue, or human, mammal, or animal subject to yield an active compound of the invention.
  • a “biohydrolyzable ester” refers to an ester compound of the invention that does not interfere with the activity of these compounds or that is readily converted by an animal to yield an active formula (I) compound.
  • biohydrolyzable prodrugs are understood by the skilled artisan and are embodied in regulatory guidelines.
  • optical isomer Inasmuch as the compounds of the invention may contain optical centers, "optical isomer”, “stereoisomer”, “enantiomer,” “diastereomer,” as referred to herein have the standard art recognized meanings (cf. Hawleys Condensed Chemical Dictionary, 1 1th Ed.) and are included in the compounds claimed, whether as racemates, or their optical isomers, stereoisomers, enantiomers, diastereomers.
  • cardiovascular diseases include arrhthymia, atrial fibrillation, congestive heart failure, coronary artery disease, hypertension, myocardial infarction, stroke, ventricular fibrillation, among others, particularly cardiovascular ischemia such as angina pectoris and those conditions mediated by LXR.
  • compositions of the present invention comprise: (a) a safe and therapeutically effective amount of a LXR activating compound (I), prodrug or pharmaceutical salt thereof; and (b) a pharmaceutically-acceptable carrier.
  • LXR related therapy As discussed above, numerous diseases can be mediated by LXR related therapy. Thus, the compounds of this invention are useful in therapy with regard to conditions involving this LXR activity.
  • the compounds of this invention can therefore be formulated into pharmaceutical compositions for use in prophylaxis, management and treatment of these conditions.
  • Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.
  • a "safe and therapeutically effective amount" of a compound of the present invention is an amount that is effective, to modulate LXR activity, in a subject, a tissue, or a cell, and preferably in an animal, more preferably in a mammal, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio, when used in the manner of this invention.
  • the specific "safe and therapeutically effective amount” will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of treatment, the nature of concurrent therapy (if any), the specific dosage form to be used, the carrier employed, the solubility of the compound therein, and the dosage regimen desired for the composition.
  • compositions of the subject invention contain a pharmaceutically-acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a mammal.
  • compatible means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations.
  • Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration preferably to an animal, preferably mammal being treated.
  • substances which can serve as pharmaceutically- acceptable carriers or components thereof, are 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 methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water
  • the preferred pharmaceutically- acceptable carrier is sterile, physiological saline, with blood-compatible suspending agent, the pH of which has been adjusted to about 7.4.
  • pharmaceutically-acceptable carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water.
  • Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil.
  • the pharmaceutically-acceptable carrier in compositions for parenteral administration, comprises at least about 90% by weight of the total composition.
  • the compositions of this invention are preferably provided in unit dosage form.
  • a "unit dosage form” is a composition of this invention containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. (The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day, and are expected to be given more than once during a course of therapy, though a single administration is not specifically excluded.
  • compositions preferably contain from about 5 mg (milligrams), more preferably from about 10 mg to about 1000 mg, more preferably to about 500 mg, most preferably to about 300 mg, of the selected compound.
  • the compositions of this invention may be in any of a variety of forms, suitable (for example) for oral, nasal, rectal, topical (including transdermal), ocular, intracereberally, intravenous, intramuscular, or parenteral administration.
  • oral and nasal compositions comprise compositions that are administered by inhalation, and made using available methodologies.
  • a variety of pharmaceutically-acceptable carriers well-known in the art may be used. These include solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances.
  • Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
  • the pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for peroral administration are well-known in the art.
  • Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc.
  • Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture.
  • Coloring agents such as the FD&C dyes, can be added for appearance.
  • Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.
  • Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be readily made by a person skilled in the art.
  • Peroral compositions also include liquid solutions, emulsions, suspensions, and the like.
  • the pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591 , tragacanth and sodium alginate;
  • typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
  • Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above. Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action.
  • dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
  • compositions of the subject invention may optionally include other drug actives.
  • compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms.
  • Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • compositions of this invention can also be administered topically to a subject, e.g., by the direct application or spreading of the composition on the epidermal or epithelial tissue of the subject, or transdermally via a "patch".
  • Such compositions include, for example, lotions, creams, solutions, gels and solids.
  • These topical compositions preferably comprise a safe and effective amount, usually at least about 0.1 %, and preferably from about 1 % to about 5%, of the compound.
  • Suitable carriers for topical administration preferably remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water.
  • the carrier is organic in nature and capable of having dispersed or dissolved therein the compound.
  • the carrier may include pharmaceutically-acceptable emollient, emulsifiers, thickening agents, solvents and the like.
  • the compounds and compositions of this invention can be administered topically or systemically.
  • Systemic application includes any method of introducing compound into the tissues of the body, e.g., intra-articular, intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual administration, inhalation, rectal, or oral administration.
  • the compounds of the present invention are preferably administered orally.
  • the specific dosage of the compound to be administered, as well as the duration of treatment is to be individualised by the treating clinicians. Typically, for a human adult (weighing approximately 70 kilograms), from about 5 mg, preferably from about 10 mg to about 3000 mg, more preferably to about 1000 mg, more preferably to about 300 mg, of the selected compound is administered per day. It is understood that these dosage ranges are by way of example only, and that daily administration can be adjusted depending on the factors listed above. In all of the foregoing, of course, the compounds of the invention can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication.
  • novel compounds or compositions of this invention are useful when dosed together with another active and can be combined in a single dosage form or composition.
  • compositions can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • aniline derivative II which either is commercially available or prepared easily via literature procedure, was converted into its corresponding N-substituted phenylhexafluoroisopropanol aniline derivatives III. The latter were transformed into the corresponding urea IV, which is subsequently converted into the targeted molecule thioureas (V). Thioureas V could be also prepared directly from compound III via thiocarbamoyl chloride intermediate followed by the reaction with primary or secondary amines. When treated with cyanide or phosphoryl chloride, the aniline compound III gave the corresponding guanidines or phosphonamides respectively, under reaction conditions depicted in the above scheme.
  • Non-cyclic or cyclic derivatives including ketones (XV), oximes (XVI), hydrazone/carbazide (XX), alcohols (XIX) and isoxazoles/isoxazolines/isoxazolidines (XVII, XVIII), were prepared via a common ketone/aldehyde intermediate (XV), which was prepared from the
  • Scheme 4 summarizes the preparation of isoxazole related compounds.
  • 2-hydroxyhexafluoroisoproyl-bromobenzene (XXI) was converted into the corresponding boronic acid (ester), which underwent Suzuki coupling with halogenated isoxazole compounds to provide XXIII or XXIV. Further modification led to compound XXV to XXIX as shown in Scheme 4.
  • Scheme 5 2-hydroxyhexafluoroisoproyl-bromobenzene
  • A O or NR 13
  • Scheme 8 described an example for preparation of opening chain compounds such as XXXXII or pyrazole/pyrizoline compounds.
  • the aldehyde XV was converted into halohydrazone such as chlorohydrazone XXXXI, which reacted with amine to give the open chain product XXXXII or to give pyrazoline compound XXXXII when it reacted with an olefin.
  • the pyrazoline compounds could be oxidized into their corresponding pyrazoles XXXXV under oxidative conditions.
  • Phosphorus-containing compounds such as XXXXVI and XXXXVII were prepared from the brominated precursor XXI. Coupling of bromobenzene derivative with phosphite in the presence of NiCI 2 gave rise to the phosphorate derivative XXXXVI. In the presence of palladium catalyst, the coupling of bromobenzene derivative with phosphonate provided the phosphorus compound XXXXVII.
  • trifluormethylketone derivatives were prepared from a commercially available nitrobenzoate XXXXVIII. Reaction of the nitrobenzoate with trifluoromethyl trimethyl silane provided the desired trifluormethyl ketone functionality. After reduction of the nitro group, the resulting aniline XXXXIX was converted into amide derivative L under the conventional conditions. Alkylation of anilide L was conducted in an indirect fashion. Thus, trifluoromethyl ketone functionality in L was reduced into its corresponding trifluoromethyl alcohol Lll with NaBH 4 . Subsequent alkylation with R 4 X in the presence of NaH afforded the alkylated anilide Lll. Oxidation of the alcohol intermediate gave the desired trifluoromethyl ketone product Llll.
  • LXR modulator refers to compounds which achieve at least 50% activation or inhibition of LXR relative to 24(S)25- epoxycholesterol, the positive control, or which stimulate the expression of the responsive genes, such as ABCA1 genes, in a cell system.
  • THP-1 cells were maintained in suspension for passage and growth in PRMI 1640 (Invitrogen) containing 10% FBS (Irvine Scientific, Santa Ana, CA), 100 units/ml penicillin/1 OOug/ml streptomycin (Irvine Scientific), 1 mM sodium pyruvate (Invitrogen) and 55 uM ⁇ - mercaptoethanol (Sigma). Passaging was performed every 3-4 days at a 1 :4 dilution. For experiments, 1X106 cells/well were plated in 6-well plates in media supplemented with 100 ng/ml phorbol 12-myristate-13-acetate (PMA, Sigma) to induce differentiation.
  • PMA phorbol 12-myristate-13-acetate
  • THP-1 cells were maintained in this media for 5-days prior to treatment with LXR agonists. Generally, the culture media was replaced with media containing vehicle (DMSO or ethanol) or 1-10 uM drugs at 0 h. THP-1 cells were dosed a second time at 24 h and then harvested for RNA isolation 24 h later.
  • vehicle DMSO or ethanol
  • 1-10 uM drugs at 0 h.
  • RNA samples were diluted to 100 ug/ml and treated with 40 units/ml RNA-free Dnase I (Ambion, Austin, TX) for 30 min at 37°C followed by inactivation at 75oC for 5 min. Samples were quantitated by spectrophotometry or with the RiboGreen assay (Molecular Probes, Eugee, OR) and diluted to a concentration of 10ng/ul. Samples were assayed in duplicate 25-ul reactions using 35ng of RNA/reaction with PerkinElmer chemistry on an ABI Prism 7700 (Applied Biosystems).
  • Gene specific primers were used at 7.5 or 22.5 pmd/reaction and optimized for each gene examined, and the gene-specific fluorescently tagged probe was used at 5 pmol/reaction.
  • the probe is degraded by Taq polymerase during the amplification phase, releasing the fluorescent tag from its quenched state; amplification data is expressed as the number of PCR cycles required to elevate the fluorescence signal beyond a threshold intensity level.
  • Fold induction values were calculated by subtracting the mean threshold cycle number for each treatment group from the mean threshold cycle number of the vehicle group and raising 2 to the power of this difference. As shown in Table A, LXR modulating activity was determined from the magnitude of gene expression induction as compared to a control (DMSO).
  • nuclear magnetic resonance spectra is measured in CDCI 3 or other indicated solvents on a Varian NMR spectrometer (Unity Plus 400, 400 MHz for 1 H) unless otherwise indicated and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane.
  • the peak multiplicities are denoted as follows, s, singlet; d, doublet; t, triplet; m, multiplet.
  • CDI carbonyl diimidazole
  • DIBAL diisobutylaluminum hydride
  • DMAP 4-(dimethylamino)-pyridine
  • EDCI or EDAC 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloric acid
  • ESIMS electron spray mass spectrometry
  • HMTA hexamethylenetetramine
  • Lawesson's reagent 2,4-bis(4-methoxyphenyl)-1 ,3,2,4- dithiadiphosphetane-2,4-disulfide
  • LHMDS lithium bis(trimethylsilyl)amide
  • MgS0 4 magnesium sulfate
  • NaHC0 3 sodium bicarbonate
  • Na 2 C0 3 sodium carbonate
  • NBS N-bromosuccinimide
  • NCS N-chlorosuccinimide
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • the alkylated intermediate (110 mg, 0.207 mmol) and Lawesson's reagent (320 mg, 0.832 mmol) are mixed in toluene (3 mL) and the reaction mixture is heated at 120 °C for 6 hrs. The organic solvent is removed under reduced pressure and the residue is purified by preparative TLC (CH 2 CI 2 :MeCN, 20:1 ) to afford the title compound as white foam (24 mg, 21%).
  • Step 2 The acyl chloride obtained above in acetone (25 mL) is added to a solution of ⁇ /,0-dimethyl hydroxyamine ( 20 mmol) in saturated Na 2 C0 3 (25 mL) at room temperature. The reaction mixture is stirred at the temperature for 16 hours and acidified with concentrated HCI. The organic solvent is removed under reduced pressure and the aqueous layer is extracted with EtOAc. The combined organic extract is washed with 1 N HCI, saturated NaHC0 3 and brine and dried over MgS0 4 . After removal the solvent, the ⁇ /-methoxymethyl amide (Weinreb amide) is obtained in pure form (5.8 g).
  • Step 3 n-Propylmagnesium bromide (3 mL) is added to a solution of the Weinreb amide intermediate obtained above (662 mg, 2 mmol) in THF (6 mL) at 0°C under an argon atmosphere. The reaction mixture is stirred at 0°C for 30 minutes and then at the room temperature for 4 hours. The reaction mixture is poured into ice cold 1 N HCI and extracted with EtOAc. The combined organic solvent is washed with saturated NaHC0 3 , brine and dried over MgS0 4 . The solvent is removed under reduced pressure to afford the title compound (620.7 mg). 1 H NMR 51.00 (t, 3H), 1.78 (qt, 2H), 2.95 (t, 2H), 7.80 (d, 2H), 8.00 (d, 2H); ESIMS: t ⁇ /z 313 (M-H).
  • the benzaldehyde intermediate (1.0 g) and hydroxyamine hydrochloric acid (1.27 g) are mixed in MeOH (8 mL). The reaction mixture is stirred at room temperature for 12 hours. The solvent is removed under reduced pressure and the residue is partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc. The combined organic solvent is washed with brine and dried MgS0 . Removal of solvent affords the oxime intermediate (1.1 g).
  • Step 2 To the solution of the acid intermediate (150 mg, 0.406 mmol) in THF (2 mL) is added 1 M solution of oxalyl chloride in CH 2 CI 2 (812 ⁇ L) under nitrogen atmosphere, and followed by 4 drops of DMF. The reaction mixture is stirred at room temperature for 1 h. After removal of the solvent under reduced pressure, the residue is dissolved in THF (1 mL) and added the solution of N,0- dimethylhydroxylamine hydrochloride (80 mg, 0.812 mmol) and triethyl amine (113 ⁇ L, 0.812 mmol) in THF (1 mL). The reaction mixture is stirred at room temperature for 2 hrs before being quenched with 1 N HCI solution.
  • N,0- dimethylhydroxylamine hydrochloride 80 mg, 0.812 mmol
  • triethyl amine 113 ⁇ L, 0.812 mmol
  • the aldehyde intermediate (13 mg, 0.037 mmol) and (carbethoxy methylene)triphenylphosphorane (14 mg, 0.04 mmol) are mixed in toluene (1 mL).
  • the reaction mixture is stirred at 90 °C for 3 hrs before condensed under reduced pressure.
  • the residue is purified by preparative TLC (hexane:Acetone, 2:1 ) to afford the title compound as white solid (13 mg, 81%).
  • Step 3 Sodium hydride (18mg 0.45mmol) is added to the solution of 2-[4-(5-Amino-3- phenyl-isoxazol-4-yl)-phenyl]-1 ,1 ,1 ,3,3,3-hexafluoro-propan-2-ol in DMF at 0°C under argon atmosphere.
  • the reaction mixture is stirred at room temperature under argon atmosphere for 30 minutes before adding isobutyryl chloride (23.8ul, 0.23mmol).
  • the solution is allowed to stir for 8 hours and diluted with EtOAc.
  • the organic layer is washed with H 2 0 brine and dried over MgS04. Concentration and purification by preparative TLC afford the title compound.
  • Step 2 The residue obtained (54 mg) was dissolved in acetic acid (1 ml) and ammonium acetate (77 mg, 1 mmol) was added. The reaction mixture was stirred under reflux condition for 3 hrs. After being diluted with water, the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over MgS04. The solvent was evaporated off under reduced pressure. The residue was purified by preparative TLC (Hexane: EtOAc, 2:1 ) to afford the title compound (24 mg, 46%).
  • Dimethyl sulfide (90 mg, 1.45 mmol) is added to a solution of N- chlorosuccinimide (107 mg, 0.805 mmol) in CH 2 CI 2 (5.5 mL) at 0°C. The mixture is stirred at 0°C for 5 minutes, then cooled to -70°C. To the solution is added dropwise a solution of methyl hydrazone (145 mg, 0.483 mmol) from above in CH 2 CI 2 (1 mL). The mixture is stirred for 4.5 h, gradually allowing the temperature to warm to 0°C. The reaction is quenched with cold water and extracted with CH 2 CI 2 . The organic layer is washed with water and brine, then dried over MgS0 .
  • Dimethyl sulfide (338 mg, 5.43 mmol) is added to a solution of N- chlorosuccinimide (404 mg, 3.02 mmol) in CH 2 CI 2 (21 mL) at 0°C.
  • the mixture is stirred at 0°C for 5 minutes, then cooled to -70°C.
  • To the solution is added dropwise a solution of phenyl hydrazone (656 mg, 1.81 mmol) from above in CH 2 CI 2 (3 mL).
  • the mixture is stirred for 2 h, gradually allowing the temperature to warm to 0°C.
  • the reaction is quenched with cold water and extracted with CH 2 CI 2 .
  • the organic layer is washed with water and brine, then dried over MgS0 4 .
  • Step l Methyl 4-nitrobenzoate (4.0 g, 22.0 mmol) is dissolved in anhydrous CH 2 CI 2 (80 mL) under Argon atmosphere. The solution is then cooled to -78°C. (Trifluoromethyl) thmethylsilane (4.08 mL, 27.6 mmol) is added to the solution followed by solid tetrabutylammoniumfluoride (560 ⁇ L, 0.56 mmol). The light pink solution is then allowed to slowly warm to r.t. and stir for 20 h. The orange solution is washed with water, brine, dried over MgS0 and evaporated under reduced pressure.
  • Trifluoromethyl) thmethylsilane (4.08 mL, 27.6 mmol) is added to the solution followed by solid tetrabutylammoniumfluoride (560 ⁇ L, 0.56 mmol).
  • the light pink solution is then allowed to slowly warm to r.t. and stir for 20 h.
  • Step 2 4-Nitro-2',2',2',-trifluoroacetophenone (3.05 g, 13.9 mmol), glacial acetic acid (30 mL, 500 mmol), and Iron powder (4.7 g, 83 mmol) are added to 95% ethanol (63 mL). The mixture is then heated reflux for 17 h. The brown mixture is then filtered through Celite and evaporated under reduced pressure. The residue is co-evaporated twice with toluene to remove any remaining acetic acid. The brown solid is mixed with chloroform and filtered through a pad of silica gel to remove polar impurities, to afford the title compound as yellow solid (2.08 g, 79.1 %).

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Abstract

La présente invention porte sur des procédés de traitement de certaines maladies ou certains états induits par le récepteur X du foie (LXR), ces procédés consistant à administrer une composition contenant comme ingrédient actif un composé de formule (I). Cette invention porte notamment sur des procédés de traitement de maladies cardio-vasculaires et de l'athérosclérose, ces procédés consistant à administrer un composé qui module l'activité de LXR.
PCT/US2003/012391 2002-04-23 2003-04-21 Modulateurs lxr pour le traitement des maladies cardio-vasculaires WO2003090732A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092856A1 (fr) * 2004-03-26 2005-10-06 F. Hoffmann-La Roche Ag Tetrahydrocarbazoles et derives
WO2006000323A1 (fr) * 2004-06-28 2006-01-05 F.Hoffmann-La Roche Ag Nouveaux derives d'hexafluoroisopropanol
WO2006066779A1 (fr) * 2004-12-22 2006-06-29 F.Hoffmann-La Roche Ag Derives de cyclohexane
EP1764075A1 (fr) * 2004-07-02 2007-03-21 Sankyo Company, Limited Inhibiteur de la production de facteur tissulaire
JP2008514661A (ja) * 2004-10-01 2008-05-08 エフ．ホフマン−ラ ロシュ アーゲー ヘキサフルオロイソプロパノール置換エーテル誘導体
WO2010023317A1 (fr) * 2008-08-29 2010-03-04 Galderma Research & Development Nouveaux hexafluoro-2-biphénylisopropanols modulant les récepteurs de type lxr, procédé pour leur synthèse et leur emploi en tant que médicament en médecine humaine et vétérinaire et en cosmétique
JP2010512342A (ja) * 2006-12-08 2010-04-22 エグゼリクシス， インコーポレイテッド Ｌｘｒおよびｆｘｒのモジュレーター
WO2012033353A2 (fr) 2010-09-07 2012-03-15 서울대학교 산학협력단 Composés de sesterterpène et leur utilisation
US8637512B2 (en) 2002-07-29 2014-01-28 Glaxo Group Limited Formulations and method of treatment
US9144547B2 (en) 2002-02-12 2015-09-29 Glaxo Group Limited Oral dosage form for controlled drug release
WO2017123568A2 (fr) 2016-01-11 2017-07-20 The Rockefeller University Méthodes pour le traitement de troubles associés à des cellules suppressives dérivées de cellules myéloïdes
US10669296B2 (en) 2014-01-10 2020-06-02 Rgenix, Inc. LXR agonists and uses thereof
US11174220B2 (en) 2019-12-13 2021-11-16 Inspirna, Inc. Metal salts and uses thereof
US11214536B2 (en) 2017-11-21 2022-01-04 Inspirna, Inc. Polymorphs and uses thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000054759A2 (fr) * 1999-03-15 2000-09-21 Tularik Inc. Modulateurs du lxr
WO2001003705A1 (fr) * 1999-07-08 2001-01-18 Tularik Inc. Compositions et methodes permettant d'augmenter les taux de hdl cholesterol
WO2002058690A2 (fr) * 2001-01-26 2002-08-01 Chugai Seiyaku Kabushiki Kaisha Procedes relatifs au traitement de maladies par le biais d'inhibiteurs de malonyl-coa decarboxylase
WO2002064136A2 (fr) * 2001-01-26 2002-08-22 Chugai Seiyaku Kabushiki Kaisha Inhibiteurs de malonyl-coa decarboxylase utiles en tant que modulateurs metaboliques
US20030073614A1 (en) * 2001-10-17 2003-04-17 Schulman Ira G. Methods for affecting various diseases utilizing LXR compounds

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000054759A2 (fr) * 1999-03-15 2000-09-21 Tularik Inc. Modulateurs du lxr
WO2001003705A1 (fr) * 1999-07-08 2001-01-18 Tularik Inc. Compositions et methodes permettant d'augmenter les taux de hdl cholesterol
WO2002058690A2 (fr) * 2001-01-26 2002-08-01 Chugai Seiyaku Kabushiki Kaisha Procedes relatifs au traitement de maladies par le biais d'inhibiteurs de malonyl-coa decarboxylase
WO2002064136A2 (fr) * 2001-01-26 2002-08-22 Chugai Seiyaku Kabushiki Kaisha Inhibiteurs de malonyl-coa decarboxylase utiles en tant que modulateurs metaboliques
US20030073614A1 (en) * 2001-10-17 2003-04-17 Schulman Ira G. Methods for affecting various diseases utilizing LXR compounds

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9144547B2 (en) 2002-02-12 2015-09-29 Glaxo Group Limited Oral dosage form for controlled drug release
US8637512B2 (en) 2002-07-29 2014-01-28 Glaxo Group Limited Formulations and method of treatment
KR100803478B1 (ko) * 2004-03-26 2008-02-14 에프. 호프만-라 로슈 아게 테트라하이드로카바졸 및 유도체
JP4705630B2 (ja) * 2004-03-26 2011-06-22 エフ．ホフマン−ラ ロシュ アーゲー テトラヒドロカルバゾール及び誘導体
WO2005092856A1 (fr) * 2004-03-26 2005-10-06 F. Hoffmann-La Roche Ag Tetrahydrocarbazoles et derives
US7906546B2 (en) 2004-03-26 2011-03-15 Hoffmann-La Roche Inc. Tetrahydrocarbazoles and derivatives
JP2007530480A (ja) * 2004-03-26 2007-11-01 エフ．ホフマン−ラ　ロシュ　アーゲー テトラヒドロカルバゾール及び誘導体
JP2008504313A (ja) * 2004-06-28 2008-02-14 エフ．ホフマン−ラ　ロシュ　アーゲー 新規なヘキサフルオロイソプロパノール誘導体
US7259178B2 (en) 2004-06-28 2007-08-21 Hoffmann-La Roche Inc. Hexafluoroisopropanol derivatives
JP4809338B2 (ja) * 2004-06-28 2011-11-09 エフ．ホフマン−ラ ロシュ アーゲー 新規なヘキサフルオロイソプロパノール誘導体
AU2005256394B2 (en) * 2004-06-28 2008-07-17 F. Hoffmann-La Roche Ag Novel hexafluoroisopropanol derivatives
US7608721B2 (en) 2004-06-28 2009-10-27 Hoffmann-La Roche Inc. Hexafluoroisopropanol derivatives
WO2006000323A1 (fr) * 2004-06-28 2006-01-05 F.Hoffmann-La Roche Ag Nouveaux derives d'hexafluoroisopropanol
US7897815B2 (en) 2004-06-28 2011-03-01 Hoffmann-La Roche Inc. Hexafluoroisopropanol derivatives
JPWO2006004030A1 (ja) * 2004-07-02 2008-04-24 三共株式会社 組織因子産生抑制剤
EP1764075A1 (fr) * 2004-07-02 2007-03-21 Sankyo Company, Limited Inhibiteur de la production de facteur tissulaire
JP5575357B2 (ja) * 2004-07-02 2014-08-20 第一三共株式会社 組織因子産生抑制剤
EP1764075A4 (fr) * 2004-07-02 2010-08-04 Sankyo Co Inhibiteur de la production de facteur tissulaire
JP2008514661A (ja) * 2004-10-01 2008-05-08 エフ．ホフマン−ラ ロシュ アーゲー ヘキサフルオロイソプロパノール置換エーテル誘導体
US7253282B2 (en) 2004-12-22 2007-08-07 Hoffman-La Roche Inc. Hexafluoroisopropanol substituted cyclohexane derivatives
WO2006066779A1 (fr) * 2004-12-22 2006-06-29 F.Hoffmann-La Roche Ag Derives de cyclohexane
JP2010512342A (ja) * 2006-12-08 2010-04-22 エグゼリクシス， インコーポレイテッド Ｌｘｒおよびｆｘｒのモジュレーター
FR2935380A1 (fr) * 2008-08-29 2010-03-05 Galderma Res & Dev Nouveaux composes hexafluoro-2-biphenyl-isopropanol, modulateurs des recepteurs de type lxrs, leur procede de preparation et leur application comme medicaments en medecine humaine ou veterinaire ainsi qu'en cosmetique.
WO2010023317A1 (fr) * 2008-08-29 2010-03-04 Galderma Research & Development Nouveaux hexafluoro-2-biphénylisopropanols modulant les récepteurs de type lxr, procédé pour leur synthèse et leur emploi en tant que médicament en médecine humaine et vétérinaire et en cosmétique
WO2012033353A2 (fr) 2010-09-07 2012-03-15 서울대학교 산학협력단 Composés de sesterterpène et leur utilisation
US10669296B2 (en) 2014-01-10 2020-06-02 Rgenix, Inc. LXR agonists and uses thereof
WO2017123568A2 (fr) 2016-01-11 2017-07-20 The Rockefeller University Méthodes pour le traitement de troubles associés à des cellules suppressives dérivées de cellules myéloïdes
US11214536B2 (en) 2017-11-21 2022-01-04 Inspirna, Inc. Polymorphs and uses thereof
US11174220B2 (en) 2019-12-13 2021-11-16 Inspirna, Inc. Metal salts and uses thereof
US11459292B2 (en) 2019-12-13 2022-10-04 Inspirna, Inc. Metal salts and uses thereof
US11878956B2 (en) 2019-12-13 2024-01-23 Inspirna, Inc. Metal salts and uses thereof

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