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WO2003090869A1 - Modulateurs de lxr - Google Patents

Modulateurs de lxr Download PDF

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Publication number
WO2003090869A1
WO2003090869A1 PCT/US2003/012237 US0312237W WO03090869A1 WO 2003090869 A1 WO2003090869 A1 WO 2003090869A1 US 0312237 W US0312237 W US 0312237W WO 03090869 A1 WO03090869 A1 WO 03090869A1
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WO
WIPO (PCT)
Prior art keywords
substituted
alkyl
membered
aryl
amino
Prior art date
Application number
PCT/US2003/012237
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English (en)
Inventor
Thomas Arrhenius
Jie-Fei Cheng
Yujin Huang
Alex M. Nadzan
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
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Publication date
Application filed by Chugai Seiyaku Kabushiki Kaisha filed Critical Chugai Seiyaku Kabushiki Kaisha
Priority to AU2003228614A priority Critical patent/AU2003228614A1/en
Publication of WO2003090869A1 publication Critical patent/WO2003090869A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/02—Halogenated hydrocarbons
    • A61K31/035—Halogenated hydrocarbons having aliphatic unsaturation
    • 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
    • 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
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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

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., 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.
  • HDL high density lipoprotein
  • 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 modulaots would be useful in methods of increasing ABCA1 , SREBP-1 c, and apoE expression, increasing HDL cholesterol and treating LXR mediated diseases or conditions such as hypercholesterolemia and cardiovascular diseases.
  • W is independently chosen from: a five membered substituted non-aromatic heterocyclic ring containing one double bond having the following formulae (I a) and (I b):
  • B, D and E represent atoms selected from C, N, O or S; a six membered substituted non-aromatic heterocyclic ring containing zero to two double bonds having the following formulae (I c) and (I d):
  • D , E and B represent atoms selected from C, N, O or S, and G represents atoms selected from C or N ;
  • Ri is independently chosen from halo, haloalkyl, hydroxy, thiol, substituted thiol, sulfonyl, sulfinyl, nitro, cyano, amino, substituted amino, C ⁇ -C 6 alkyl and d- C ⁇ alkoxy, and when R-i is hydroxy, CrC 6 alkoxy, thiol, substituted thiol, amino, substituted amino, or C- ⁇ -C 6 alkyl, such radical may be combined with R 2 or R ⁇ 4 to form a ring of 5-7 members when R-i is positioned next to R 2 or
  • R 2 is selected from -N(R 3 )C(O)R 4 , -C(O)NR 4 R 5 , -N(R 3 )C(O)NR 4 R 5 , N(R 3 )SO 2 R 7 , -N(R 3 )SO 2 NR 4 R 3, -N(R 3 )C(O)OR 4, -C(O)OR 4 , -C(S)OR 4 , -SR 3, Phenyl,
  • R 3 is hydrogen, alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, acyl, or may form a ring of 5-7 members with R 4 or R 5 ;
  • R 4 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 6 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 , R 10 , R 11 and R- ⁇ 2 may be equal or different and are selected from hydrogen, alkyl, aryl, heterocyclyl, nitro, cyano, carboxylic acid, ester, amides, halo, hydroxyl, amino, substituted amino, alkoxy, acyl, ureido, sulfonamido, sulfamido, sulfonyl, sulfinyl, or guanadinyl;
  • R ⁇ 3 is hydrogen, alkyl, aryl, ester, heterocyclyl, acyl, sulfonyl, ureido, or guanadinyl;
  • R i4 is selected from -NR
  • A is O, S, or NR 3 ; m is from zero to three;
  • 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, Cl, l or CF 3 ; the corresponding enantiomers, diastereoisomers or tautomers, or a pharmaceutically acceptable salt, or a prodrug thereof in a pharmaceutically-acceptable carrier.
  • a preferred embodiment of the present invention relates to those compounds (I) wherein X is CF 3 ; Y is hydrogen; and Z is F.
  • Another preferred embodiment of the present invention relates to those compounds (I), wherein Ri is hydrogen.
  • Still another preferred embodiment of the present invention relates to those compounds (I), wherein W is selected from a five or six membered substituted aromatic heterocyclic ring containing one heteroatom and having the following formulae:
  • Yet another preferred embodiment of the present invention relates to those compounds (II g), (II h), (II i), (II j) and (II k) wherein R ⁇ 4 is selected from the following groups:
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , Rn, R 12 and R ⁇ 3 are as defined above.
  • Still another preferred embodiment of the present invention relates to those compounds (I) wherein W is a five or six membered substituted aromatic heterocyclic ring containing at least two heteroatoms with the proviso that the pyrazole ring is not included and having the following formulae (II m), (II n) and (II o):
  • R 2 is as defined as above and D , E and B represent atoms selected from C, N, O or S, and G represents atoms selected from C or N; Yet another preferred embodiment of the present invention relates to those compounds (II m), (II n) and (II o), wherein R 2 is chosen from the following groups:
  • R 2 is more preferably chosen from following group:
  • R is chosen from substituted aryl and R 3 is chosen from substituted arylalkyl;
  • Still another preferred embodiment of the present invention relates to those compounds (I), wherein W is chosen from a five membered substituted non- aromatic heterocyclic ring containing one double bond and having the following formula:
  • B, D and E represents a heteroatom selected from O, S and N;
  • the preferred five numbered substituted non- aromatic heterocyclic rings have the following formulae:
  • a more preferred non- aromatic heterocyclic ring has the following formula, wherein E represents a hetero atom selected from O, S or N:
  • the most preferred non-aromatic heterocyclic ring has the following formula:
  • R 2 is preferably selected from the following groups:
  • R 3 , R , R 5 , Re, R7, R 8 , Rg, R10, R11, R12 and R- ⁇ 3 are as defined above.
  • R 2 groups of compound (I m) most preferred are the following:
  • 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.
  • 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.
  • amido means a H-CON- or alkyl-CON-, aryl-CON- or heterocyclyl-CON group wherein the alkyl, aryl or heterocyclyl group is as herein described.
  • 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
  • heteroaryl it is referred to as "heteroaryl”
  • Preferred are monocyclic heterocycles of 5 or 6 members.
  • preferred 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.
  • heteroaryl examples include thienyl, pyrridyl, furyl, oxazolyl, oxadiazolyl, pyrollyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyhdazinyl, 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.
  • Preferred 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 alkylSO 2 , arylSO 2 or heterocyclyl- SO 2 group wherein the alkyl, aryl or heterocyclyl are defined as above.
  • sulfamido means an alkyl-N-S(O) 2 N-, aryl-NS(O) 2 N- or heterocyclyl-NS(O) 2 N- group wherein the alkyl, aryl or heterocyclcyl group is as herein described.
  • sulfonamido means an alkyl-S(O) 2 N-, aryl-S(O) 2 N- or heterocyclyl- S(O) 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 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.
  • 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.
  • 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 87/05297, Johnston et al., published September 11 , 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, 11th 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 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. If the subject compound is to be injected, 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.
  • 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.
  • Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981 ); and Ansel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).
  • 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.
  • 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.
  • 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 croscar
  • 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.
  • 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.
  • R Alkyl,Aryl,-COR6, -COOR 4 , -S(0) 2 R 7 etc.
  • 1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-yn-2-ol or 1 ,1 ,1-trifluoro-2-trifluoromethyl- but-2-en-2-ol can afford relevant hexafluoroisopropanol derivatives of five membered heterocycles (IV) or (V).
  • hexafluoroisopropanol derivatives of five membered heterocycles (IX) or (X) can be synthesized from the cycloaddition of dipoles containing hexafluoroisopropanol (VI) with alkynes (VII) or alkenes (VIII).
  • nitrile oxides (XII) for example (Scheme 1 b), cycloaddition of nitrile oxides (XII) with 1 ,1 ,1- trifluoro-2-trifluoromethyl-but-3-yn-2-ol or 1 ,1 ,1 -trifluoro-2-trifluoromethyl-but-2- en-2-ol provides respectively the hexafluoroisopropanol derivatives of isoxazole (XIII) or isoxazoline (XIV).
  • the nitrile oxide (XII) can be formed in situ from an aldoxime (XI), which is prepared from the condensation of aldehyde with hydroxyamine, by treatment with a chlorinating or brominating agent and a weak base.
  • Scheme 2 describes a method for preparation of hexafluoroisopropanol derivatives (XIX) by reacting aromatic heterocycles (XVIII) with hexafluoroacetone. For instance, reaction of 2-alkylamino-1 , 3-thiazoles or amino-1 ,3-thiazoles (XX) with hexafluoroacetone hydrate under heating conditions yields the hexafluoroisopropanol derivatives of 1 , 3-thiazole (XXI).
  • amides amides
  • XXVI amidophsphates
  • XXVII sulfonamides
  • ureas ureas
  • carbamates XXV,
  • amide derivatives of isoxazoline or isoxazole are prepared from the coupling of acid derivatives (XXX) with amines in the presence of a coupling reagent such as (benzotriazol-1- yloxy)tris(dimethylamino) phosphonium hexafluorophosphate (Bop) and a base.
  • a coupling reagent such as (benzotriazol-1- yloxy)tris(dimethylamino) phosphonium hexafluorophosphate (Bop) and a base.
  • alcohol (XXXIV), hydrazone (XXXV), and oxime (XXXVI) derivatives of isoxazoline or isoxazole can be prepared via a common ketone/aldehyde intermediate (XXXIII), which is prepared from 1 ,3-dipolar reaction of the relevant nitrile oxide (XXXII) with 1 ,1 ,1-trifluoro-2-trifluoromethyl-but-3-yn-2-ol or 1 ,1 ,1-trifluoro-2- trifluoromethyl-but-2-en-2-ol.
  • XXXIII common ketone/aldehyde intermediate
  • hexafluoroisopropanol derivatives (XXXXIV) of six membered heterocyclic rings containing one to four nitrogen atoms can be prepared by the method presented in Scheme 7.
  • XXXXV 5-bromo-2-aminopyrimidine derivative
  • n-butyllithium results in halogen-lithium exchange and subsequent reaction of the corresponding lithium intermediate with hexafluoroacetone affords hexafluoroisopropanol pyrimidine derivative (XXXVI).
  • Scheme 8 depicts the method of synthesis of alkynyl hexafluoroisopropanol derivatives.
  • reaction of hexafluoroacetone with alkynyl lithiums (XXXXVII), prepared by the treatment of alkynes with n-butyl lithium, gives rise to alkynyl hexafluoroisopropanol derivatives (XXXXVIII).
  • 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 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.
  • H 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. The following abbreviations have the indicated meanings:
  • Lawesson's reagent 2,4-bis(4-methoxyphenyl)-1 , 3,2,4- dithiadiphosphetane-2,4-disulfide
  • MgSO magnesium sulfate
  • NaHCO 3 sodium bicarbonate
  • NBS N-bromosuccinimide
  • Ph phenyl
  • Step 2 To a mixture of the residue from step 1 in 0.5 ml of toluene was added isopropyl isocyanate (30 ⁇ L, 0.3 mmol). The reaction mixture was heated at 110 °C in a pressure tube overnight. The organic solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried (MgS0 ) and concentrated to dryness. The crude product was purified by preparative TLC

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Abstract

L'invention concerne des méthodes de traitement de certaines maladies ou états pathologiques à médiation assurée par le récepteur X du foie (LXR), par administration d'une composition contenant en tant qu'ingrédient actif un composé représenté par la formule (I). Plus spécifiquement, l'invention concerne des méthodes de traitement de maladies cardio-vasculaires et de l'athérosclérose à travers l'administration d'un composé qui module l'activité de LXR.
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WO2012033353A2 (fr) 2010-09-07 2012-03-15 서울대학교 산학협력단 Composés de sesterterpène et leur utilisation
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US11214536B2 (en) 2017-11-21 2022-01-04 Inspirna, Inc. Polymorphs and uses thereof
US12084472B2 (en) 2015-12-18 2024-09-10 Ardelyx, Inc. Substituted 4-phenyl pyridine compounds as non-systemic TGR5 agonists

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US7196089B2 (en) 2003-01-29 2007-03-27 Asterand Uk Limited EP4 receptor antagonists
US7507754B2 (en) 2003-01-29 2009-03-24 Asterand Uk Limited EP4 receptor antagonists
US7528157B2 (en) 2003-01-29 2009-05-05 Asterand Uk Limited EP4 receptor antagonists
US7417068B2 (en) 2003-10-16 2008-08-26 Asterand Uk Limited EP4 receptor antagonists
US7569602B2 (en) 2003-10-16 2009-08-04 Asterand Uk Limited Furan derivatives as EP4 receptor antagonists
WO2005121093A1 (fr) 2004-05-07 2005-12-22 Laboratoires Fournier S.A. Modulateurs des recepteurs lxr
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
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
US7601725B2 (en) 2004-07-16 2009-10-13 Sunesis Pharmaceuticals, Inc. Thienopyrimidines useful as Aurora kinase inhibitors
US7989179B2 (en) 2005-06-28 2011-08-02 Daiichi Sankyo Company, Limited LXR ligand testing method
WO2012033353A2 (fr) 2010-09-07 2012-03-15 서울대학교 산학협력단 Composés de sesterterpène et leur utilisation
CN102367260A (zh) * 2011-12-12 2012-03-07 南京药石药物研发有限公司 2-氨基嘧啶-5-硼酸的合成方法
US10669296B2 (en) 2014-01-10 2020-06-02 Rgenix, Inc. LXR agonists and uses thereof
JPWO2016017467A1 (ja) * 2014-07-28 2017-04-27 住友化学株式会社 アミド化合物及びその有害節足動物防除用途
EP3178322A4 (fr) * 2014-07-28 2018-02-28 Sumitomo Chemical Company Limited Composé amide et son utilisation pour la lutte contre les arthropodes nuisibles
US10251396B2 (en) 2014-07-28 2019-04-09 Sumitomo Chemical Company, Limited Amide compound and use of same for noxious arthropod control
EP3178323A4 (fr) * 2014-07-29 2018-02-07 Sumitomo Chemical Company, Limited Agent de lutte contre les arthropodes nuisibles contenant un composé amide
US10968246B2 (en) 2015-12-18 2021-04-06 Ardelyx, Inc. Substituted 4-phenyl pyridine compounds as non-systemic TGR5 agonists
US10392413B2 (en) 2015-12-18 2019-08-27 Ardelyx, Inc. Substituted 4-phenyl pyridine compounds as non-systemic TGR5 agonists
US12084472B2 (en) 2015-12-18 2024-09-10 Ardelyx, Inc. Substituted 4-phenyl pyridine compounds as non-systemic TGR5 agonists
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
US12258303B2 (en) 2019-12-13 2025-03-25 Inspirna, Inc. Metal salts and uses thereof

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