WO2003090746A1 - 1,3-thiazoles utilises en tant que modulateurs du lxr pour le traitement de maladies cardiovasculaires - Google Patents

1,3-thiazoles utilises en tant que modulateurs du lxr pour le traitement de maladies cardiovasculaires Download PDF

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Publication number
WO2003090746A1
WO2003090746A1 PCT/US2003/012250 US0312250W WO03090746A1 WO 2003090746 A1 WO2003090746 A1 WO 2003090746A1 US 0312250 W US0312250 W US 0312250W WO 03090746 A1 WO03090746 A1 WO 03090746A1
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alkyl
substituted
heteroatoms
aryl
substituents
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PCT/US2003/012250
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English (en)
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Thomas Arrhenius
Jie-Fei Cheng
Alex M. Nadzan
Mark Wilson
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Chugai Seiyaku Kabushiki Kaisha
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Priority to AU2003222667A priority Critical patent/AU2003222667A1/en
Publication of WO2003090746A1 publication Critical patent/WO2003090746A1/fr

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • A61K31/425Thiazoles
    • A61K31/429Thiazoles condensed with heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs 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 Iipids, 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., Gene Deve. 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. 22: 347-351 (1999); and Rust 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 agonists 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.
  • the present invention relates to the use of compounds of the following structure (I):
  • the present invention relates to the use of compounds of the following structure (I): wherein Y is selected from S or O;
  • Ri and R 2 are different, and each is independently selected from hydrogen, halogen, hydroxy, nitro, cyano, C1-C12 alkyl, substituted C ⁇ -C-
  • ring D is a substituted or unsubstituted monocyclic 3-7 membered ring containing zero to three heteroatoms, wherein such heteroatoms are selected from O, N, or S, wherein such substituents are independently chosen from Rg, and R 3 and R 4 , taken together can form a substituted or unsubstituted monocyclic 3-7 membered ring containing zero to three heteroatoms, wherein such heteroatoms are selected from O, N, or S, wherein such substituents are independently chosen from Rg, or Ri and R 2 taken together can form a monocyclic 5-7 membered substituted or unsubstituted ring containing zero to three heteroatoms, wherein such heteroatoms are selected from O, N, or S, and such substituents are independently selected from Re and R 7 ; R 3 is selected from hydrogen, hydroxy, C ⁇ -C- ⁇ 2 alkyl, substituted C 1 -C 12 alkyl, alkylamino, aryl, Ci-C-i 2
  • Re and R are different, and independently selected from Ri and R 2 , with the improviso that R 6 and R 7 can not be taken together to form a ring;
  • R 8 is selected from hydrogen, C- ⁇ -C ⁇ 2 alkyl, substituted C 1 -C 12 alkyl, heterocyclyl, or aryl;
  • R 9 is selected from hydrogen, halogen, -CN -C(0)CF 3 , -S(0) n CF 3 , -C(0)CH 2 F, -
  • R 10 is selected from C- 1 -C12 alkyl, substituted d-C ⁇ 2 alkyl, heterocyclyl, or aryl;
  • R 1 1 is selected from C 1 -C12 alkyl, substituted C 1 -C 1 2 alkyl, heterocyclyl, or aryl;
  • A is a bond, -NR 4 -, or -CR 4 R 5 -;
  • B is a bond, -NR 4 -, -CR 4 H-, -CR 4 (OH)- or -CR 4 R 5 -;
  • L is a bond, -0-, -C(O)-, -NR 5 -, -CR 4 H-,.CR 4 (OH)-, or -CR 4 R 5 -, -NHNR 5 -;
  • Q is a bond, -NR 4 -, -C(O)-, -O- or -CR 4 R 5 -;
  • X is O, S, NR 4> NOR 4 , NCN, NN0 2l CR 8 N0 2) CR 8 CN, C(CN) 2> CR 8 Rn, or N-
  • V is -OH, -SH, -CN; m is zero, one, two or three; n is one or two; its corresponding enantiomers, diastereoisomers or tautomers, or a pharmaceutically acceptable salt, or a prodrug thereof in an pharmaceutically- acceptable carrier.
  • Y is S.
  • Ri and R 2 taken together form a substituted five to seven membered ring containing zero to three heteroatoms selected from N, O, or S, wherein such substituents are independently chosen from R 6 and R 7 .
  • Re and R are selected from -CR 8 (V)Rn or - CH2CR ⁇ (V)R ⁇ , wherein V is either -OH and -CN, -P(0)(OR 4 )R 3) -P(0)(R 3 ) 2 , or a group of the following formulae:
  • ring formed from Ri and R 2 is a 6- membered aryl containing zero to three nitrogens which is substituted according to the following formulae:
  • Y is S, and U is selected from C or N.
  • R 6 and R 7 are different, and selected from H or a group of the following formulae:
  • alkyl means a straight chain alkane, alkene, or alkyne substituent containing only carbon and hydrogen, such as methyl, ethyl, butyl, pentyl, heptyl and the like.
  • alkyl groups will comprise 1 to 12 carbon atoms, preferably 1 to 10, and more preferably 2 to 8 carbon atoms.
  • substituted alkyl means a hydrocarbon substituent, which is linear, cyclic or branched, in which one or more hydrogen atoms are substituted by carboxy, hydroxy, alkoxy, cyano, nitro, carbonyl, aryl, carboxyalkyl, mercapto, amino, amido, ureido, carbamoyl, sulfonamido, sulfamido, or halogen.
  • Preferred substituted alkyls have their alkyl spacers (i.e., portion which is alkyl) of 1 to about 5 carbons, and may be branched or linear, and may include cyclic substituents, either as part or all of their structure.
  • substituted alkyls include 4-carboxybutyl, pyridin-2-ylmethyl, and 1 ,3-thiazol-2- ylmethyl, benzyl, phenethyl, and trifluoromethyl.
  • substituted alkyl may be combined with other art accepted terms.
  • substituted alkoxy means alkoxy as understood in the art, wherein the alkyl portion of the substituent is substituted.
  • branched alkyl means a subset of “alkyl”, and thus is a hydrocarbon substituent, which is branched.
  • Preferred branched alkyls are of 3 to about 12 carbons, and may include cycloalkyl within their structure. Examples of branched alkyl include isopropyl, isobutyl, 1 ,2-dimethyl-propyl, cyclopentyl methyl and the like.
  • branched alkyl may be combined with other art accepted terms.
  • branched alkoxy means alkoxy as understood in the art, wherein the alkyl portion of the substituent is branched.
  • cycloalkyl is a hydrocarbon substituent that is cyclic, and can be substituted or unsubstituted. Where it is substituted, one or more hydrogen atoms are substituted by carboxy, hydroxy, alkoxy, cyano, nitro, carbonyl, aryl, carboxyalkyl, mercapto, amino, amido, ureido, carbamoyl, sulfonamido, sulfamido, or halogen.
  • Preferred cyclic alkyls are of 3 to about 7 carbons. Examples of cycloalkyl include cyclopropyl, cyclopentyl, 4-fluoro- cyclohexyl, 2,3-dihydroxy-cyclopentyl, and the like.
  • alkylene is an alkyl diradical, i.e., an alkyl that has open valences on two different carbon atoms.
  • (alkylene)Rj is an alkyl diradical attached at one carbon and having substituent R ⁇ attached at another carbon, which may be one or more carbons away from the point of attachment.
  • Alkylene can be linear, branched, or cyclic. Examples of alkylene include -CH 2 -, CH 2 CH 2 -, -(CH 2 )4-, -(cyclohexyl)-, and the like.
  • aryl is a substituted or unsubstituted aromatic, i.e., H ⁇ ckel 4n + 2 rule applies, radical having a single-ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which may contain zero to 4 heteroatoms.
  • heteroaryl is clearly contemplated in the term “aryl”.
  • Preferred carbocyclic aryl is phenyl.
  • Preferred monocyclic heterocycles, i.e., heteroaryls are 5 or 6 membered rings.
  • aryl represents an aromatic heterocycle
  • heteroaryl or “heteroaromatic”
  • Preferred numbers of such heteroatoms are from one to three N atoms, and preferably when “heteroaryl” is a heterocycle of five members, it has one or two heteroatoms selected from O, N, or S.
  • preferred heterocycles have up to three, more preferably two or less, heteroatoms present in the aromatic ring. The skilled artisan will recognize that among heteroaryl, there are both five and six membered rings.
  • heteroaryl examples include; thienyl, pyridyl, pyrimidyl, pyridazyl, furyl, oxazolyl, imidazolyl, thiazolyl, oxadiazilyl, triazinyl, triazolyl, thiadiazolyl, and others, which the skilled artisan will recognize.
  • substitution on the aryl ring is within the scope of this invention. Where substitution occurs, the radical is referred to as "substituted aryl”.
  • substituents include those commonly found in aryl compounds, such as alkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkyl, mercapto and the like. Such substituents are prepared using known methodologies. These substituents may be attached at various positions of the aryl ring, and wherein a given placement is preferred, such placement is indicated by "o,/77,p-Rj-aryl". Thus, if substituent R is attached at the para position of the aryl, then this is indicated as “p-Rj-substituted aryl".
  • halogen is a chloro, bromo, fluoro or iodo atom radical. Chloro, bromo and fluoro are preferred halogens. The term “halogen” also contemplates terms sometimes referred to as “halo” or "halide”.
  • alkylamino is an amine radical in which at least one hydrogen atom on the nitrogen has been replaced with alkyl. Preferred examples include ethylamino, butylamino, isopropylamino, and the like.
  • the alkyl component may be linear, branched, cyclic, substituted, saturated, or unsatu rated.
  • alkylsulfanyl is a thiol radical in which the hydrogen atom on sulfur has been replaced with alkyl. Preferred examples include ethylsulfanyl, butylsulfanyl, isopropylsulfanyl, and the like.
  • the alkyl component may be linear, branched, cyclic, substituted, saturated, or unsaturated.
  • alkoxy is a hydoxyl radical in which the hydrogen atom on oxygen has been replaced with alkyl. Preferred examples include ethoxy, butoxy, benzyloxy, and the like.
  • the alkyl component may be linear, branched, cyclic, substituted, saturated, or unsaturated.
  • heterocycle(s) means ring systems, preferably of 3-7 members, which are saturated or unsaturated, and non-aromatic. These may be substituted or unsubstituted, and are attached to other parts of the molecule via any available valence, preferably any available carbon or nitrogen. More preferred heterocycles are of 5 or 6 members. In six-membered monocyclic heterocycles, the heteroatom(s) are from one to three of O, S, or N, and wherein when the heterocycle is five-membered, preferably it has one or two heteroatoms selected from O, N, or S.
  • heterocyclyl means radical heterocycles. These may be substituted or unsubstituted, and are attached to other via any available valence, preferably any available carbon or nitrogen.
  • sulfamido means an alkyl-N-S(0) 2 N-, aryj-NS(0) N- or heterocyclyl-NS(0) 2 N- group wherein the alkyl, aryl or heterocyclyl group is as defined herein above.
  • 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 heterocyclyl group is as herein described.
  • a substituent referred to as a radical in this specification may form a ring with another radical as described herein.
  • radicals When such 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.
  • certain radicals can be described as forming rings together. The skilled artisan will recognize that such rings can and are readily formed by routine chemical reactions, and it is within the purview of the skilled artisan to both envision such rings and the methods of their formations.
  • Preferred are rings having from 3-7 members, more preferably 5 or 6 members.
  • Compounds described herein may have cyclic structures therein, such as a ring Ri and R 2 .
  • ring 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 pyridyl.
  • Preferred functionalities represented by this structure include amides, ureas, thioureas, carbamates, esters, thioesters, amidines, ketones, oximes, nitroolefines, hydroxyguanidines and guanidines. More preferred functionalities include ureas, thioureas, amides, and carbamates.
  • prodrugs are compounds 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 (l) compound.
  • Such biohydrolyzable prodrugs are understood by the skilled artisan and are embodied in regulatory guidelines.
  • compositions herein also specifically contemplate pharmaceutically acceptable salts, whether cationic or anionic.
  • 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. Many such salts are known in the art, as described in World Patent Publication
  • 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).
  • 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.
  • Optical isomer Inasmuch as the compounds of the invention may contain one or more stereogenic 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, and diastereomers.
  • the compounds of the invention may exist as "regio-isomers", specifically those compounds of formula I that have several relative orientations of the heteroatoms within ring C, reference to such isomers has the standard art recognized meaning (cf. Hawleys Condensed Chemical Dictionary, 11th Ed.) and are included in the compounds claimed.
  • cardiovascular diseases include arrhthymia, atrial fibrillation, congestive heart failure, coronary artery disease, hypertension, myocardial infarction, stroke, ventricular fibrillation, among others, particularly cardiovascular ischemia and those conditions modulated by LXR.
  • compositions of the present invention comprise:
  • 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 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 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
  • a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.
  • 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.
  • 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.
  • oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, 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.
  • 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.
  • Other 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 emolients, 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 individualized 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.
  • 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.
  • additional drugs or excipients as appropriate for the indication.
  • the invention may be used in conjunction with beta-blockers, calcium antagonists, ACE inhibitors, diuretics, angiotensin receptor inhibitors, or known cardiovascular drugs or therapies.
  • 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 system, such as small unilamellar vesicles, large unilamellar vesicles, and mutilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphayidylcholines.
  • 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/100ug/ml streptomycin (Irvine Scientific), 1mM 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-welI 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 pmol/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.
  • LXR modulating activity was determined from the magnitude of gene expression induction as compared to a control (DMSO).
  • Compounds showing significant induction of the ABCA1 gene in a THP-1 cell system, as compared to the control (DMSO) demonstrates that the compounds of the present invention are useful LXR modulators for increasing ABCA1 expression, increasing HDL cholesterol and treating LXR mediated diseases or conditions such as hypercholesterolemia and cardiovascular diseases.
  • Table A Gene Expression Induction.
  • amino-2-mercaptobenzothiazole(s) 1 which are commercially available or easily prepared using known methods, are condensed with aldehydes or ketones and reduced with sodium cyanoborohydride to afford the corresponding /V-alkylaniline(s) 2.
  • R 9 alkyl, aryl, hetrocyclyl
  • the pyrimidine and pyridine scaffold(s) 10 are obtained as shown in Scheme 3. Iterative displacement of the chlorines in 8 (which are commercially available or prepared using known methods) by sodium diethyldithiocarbamate, and a primary amine (R 4 NH 2 ), respectively give intermediate(s) 9, which upon reduction/thiolysis with basic sodium sulfide and condensation with potassium xanthic acid salt afford 10.
  • DIBAL diisobutylaluminum hydride
  • DMSO dimethylsulfoxide
  • ECAC 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloric acid
  • Et 3 N triethylamine
  • EtOAc ethyl acetate
  • HMTA hexamethylenetetramine
  • LHDMS lithium bis(trimethylsilyl)amide
  • MgS0 magnesium sulfate
  • NBS N-bromosuccinimide
  • NCS N-chlorosuccinimide
  • 6-[(2-methylpropyl)amino]-1 ,3-benzothiazole-2-thiol (Table 1 , Example 1-1 ): Into a 500 ml round bottomed flask were added 6-amino-1 ,3-benzothiazole-2- thiol (5.0 g, 0.03 mol), hexanal (3.0 g, 0.03 mol), methanol (250 ml), glacial acetic acid (2.5 ml), water (1 ml), and NaCNBH 3 (1.9 g, 0.03 mol). The mixture was stirred for 4 h, filtered, and the filtrate was concentrated to give light yellow solid.
  • Step 1 Into a 1 L flask were added 2,6-dichIoro-3-nitropyridine (15.01g, 77.78 mmol) and anhydrous THF. The solution was cooled in an ice-water bath for 10 min and degassed by evacuation/purging with Ar. A solution of sodium diethyldithiocarbamate (19.34g, 85.8 mmol) in 275 mL THF was prepared and degassed, and then added dropwise over 30 min to the solution of the chloropyridine. The solution was stirred at 0 degrees for 5 h, then allowed to warm to room temperature.
  • Step 2 Into a 250 mL round bottomed flask were added the product obtained in step 1 (12.38 g, 40.48 mmol), K 2 C0 3 (5.64 g, 40.8 mmol), and acetonitrile (100 mL). Isopropylamine (3.5 mL, 40.5 mmol) was added over 5 min, and the solution was stirred overnight. The reaction solution was filtered through a 2-cm pad of Celite, concentrated, and the residue was taken up in EtOAc and washed 3x with 1 M citric acid, then brine. The organic fraction was dried (Mg S0 4 ), filtered, and concentrated to afford an orange-red oil.
  • Step 4 Into a 250 mL round bottomed flask containing the crude product obtained in step 3 (-13.8 mmol) was added ethyl xanthic acid, potassium salt (3.42 g, 21.3 mmol), and EtOH (100 mL). The reaction mixture was refluxed 5 h under Ar, then cooled to ca. 40 degrees and decolorized with charcoal. Filtration through a 2-cm pad of Celite gave a light brown cake, which was dissolved in a minimal amount of water and acidified with acetic acid to afford the crude product as a tan solid.

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Abstract

L'invention concerne des méthodes permettant de traiter certaines maladies ou affections induites par le récepteur X du foie (LXR), par administration d'une composition contenant, en tant que principe actif, un composé représenté par la formule I. Plus particulièrement, l'invention concerne des méthodes permettant de traiter des maladies cardiovasculaires et l'athérosclérose par administration d'un composé modulant l'activité du LXR.
PCT/US2003/012250 2002-04-23 2003-04-21 1,3-thiazoles utilises en tant que modulateurs du lxr pour le traitement de maladies cardiovasculaires WO2003090746A1 (fr)

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Cited By (8)

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WO2005092856A1 (fr) * 2004-03-26 2005-10-06 F. Hoffmann-La Roche Ag Tetrahydrocarbazoles et derives
WO2005121093A1 (fr) 2004-05-07 2005-12-22 Laboratoires Fournier S.A. Modulateurs des recepteurs lxr
WO2012033353A2 (fr) 2010-09-07 2012-03-15 서울대학교 산학협력단 Composés de sesterterpène et leur utilisation
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
JP2019522035A (ja) * 2016-07-29 2019-08-08 ルピン・リミテッド Malt1阻害剤としての置換チアゾロ−ピリジン化合物
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

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WO2000069810A1 (fr) * 1999-05-17 2000-11-23 Novo Nordisk A/S Antagonistes/agonistes inverses de glucagon
WO2002066034A1 (fr) * 2001-02-20 2002-08-29 Chugai Seiyaku Kabushiki Kaisha Methode de traitement de maladies metaboliques dans lesquelles sont utilises des inhibiteurs de malonyl-coa decarboxylase
US20030073614A1 (en) * 2001-10-17 2003-04-17 Schulman Ira G. Methods for affecting various diseases utilizing LXR compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000069810A1 (fr) * 1999-05-17 2000-11-23 Novo Nordisk A/S Antagonistes/agonistes inverses de glucagon
WO2002066034A1 (fr) * 2001-02-20 2002-08-29 Chugai Seiyaku Kabushiki Kaisha Methode de traitement de maladies metaboliques dans lesquelles sont utilises des inhibiteurs de malonyl-coa decarboxylase
WO2002066035A2 (fr) * 2001-02-20 2002-08-29 Chugai Seiyaku Kabushiki Kaisha Azoles en inhibiteurs de la décarboxylase des malonyl-coa, convenant comme modulateurs métaboliques
US20030073614A1 (en) * 2001-10-17 2003-04-17 Schulman Ira G. Methods for affecting various diseases utilizing LXR compounds

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US7906546B2 (en) 2004-03-26 2011-03-15 Hoffmann-La Roche Inc. Tetrahydrocarbazoles and derivatives
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
WO2005121093A1 (fr) 2004-05-07 2005-12-22 Laboratoires Fournier S.A. Modulateurs des recepteurs lxr
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
JP2019522035A (ja) * 2016-07-29 2019-08-08 ルピン・リミテッド Malt1阻害剤としての置換チアゾロ−ピリジン化合物
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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