WO2012027579A1 - Dérivés de triterpénoïdes synthétiques - Google Patents

Dérivés de triterpénoïdes synthétiques Download PDF

Info

Publication number
WO2012027579A1
WO2012027579A1 PCT/US2011/049163 US2011049163W WO2012027579A1 WO 2012027579 A1 WO2012027579 A1 WO 2012027579A1 US 2011049163 W US2011049163 W US 2011049163W WO 2012027579 A1 WO2012027579 A1 WO 2012027579A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
acute
disease
syndrome
deuterium
Prior art date
Application number
PCT/US2011/049163
Other languages
English (en)
Inventor
Julie F. Liu
Original Assignee
Concert Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Concert Pharmaceuticals, Inc. filed Critical Concert Pharmaceuticals, Inc.
Publication of WO2012027579A1 publication Critical patent/WO2012027579A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom

Definitions

  • ADME absorption, distribution, metabolism and/or excretion
  • ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites.
  • some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent.
  • modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.
  • a metabolic inhibitor will be co -administered with a drug that is cleared too rapidly.
  • a drug that is cleared too rapidly.
  • the FDA recommends that these drugs be co- dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al.,
  • a potentially attractive strategy for improving a drug's metabolic properties is deuterium modification.
  • Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the AD ME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability.
  • the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.
  • Varespladib methyl and varespladib inhibit a novel enzyme target known as secretory phospholipase A2, or sPLA2. Elevated levels of sPLA2 have been implicated in a variety of acute inflammatory conditions, including Acute Coronary Syndrome and Acute Chest Syndrome, as well as chronic diseases such as stable Coronary Artery Disease.
  • Varespladib methyl is currently undergoing Phase 3 clinical trial evaluation for Acute Coronary Syndrome (also laiown as unstable angina pectoris). Varespladib methyl is also undergoing Phase 3 evaluation for the treatment of mixed dyslipidemia and has been evaluated in Phase 2 trials for the treatment of stable coronary artery disease (atherosclerosis). The methyl ester is hydrolyzed in vivo to varespladib.
  • Varespladib is in a Phase 2 program in Acute Chest Syndrome, an
  • This invention relates to novel derivatives of varespladib, esters thereof and pharmaceutically acceptable salts thereof.
  • This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by
  • treat means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.
  • a disease e.g., a disease or disorder delineated herein
  • Disease means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
  • varespladib or varespladib methyl will inherently contain small amounts of deuterated isotopologues.
  • concentration of naturally abundant stable hydrogen and carbon isotopes is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this invention. See, for instance, Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al, Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen”
  • the position is understood to have hydrogen at its natural abundance isotopic composition.
  • a position is designated specifically as “D” or “deuterium”
  • the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium).
  • a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • isotopologue refers to a species that differs from a specific compound of this invention only in the isotopic composition thereof.
  • a compound represented by a particular chemical structure containing indicated deuterium atoms will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure.
  • the relative amount of such isotopologues in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound.
  • the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%), less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.
  • the invention also provides salts of the compounds of the invention.
  • a salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.
  • the compound is a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention.
  • pharmaceutically acceptable counterion is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.
  • Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids.
  • inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylprop
  • the pharmaceutically acceptable salt may also be a salt of a compound of the present invention having an acidic functional group, such as a carboxylic acid functional group, and a base.
  • exemplary bases include, but are not limited to, hydroxide of alkali metals including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(Ci-C6)-alkylamine), such as N,N-dimethyl-N-(2 -hydroxy ethyl)amine or tri-(2-hydroxyethyl)amine; N-
  • the compounds of the present invention may contain an asymmetric carbon atom, for example, as the result of deuterium substitution or otherwise.
  • compounds of this invention can exist as either individual enantiomers, or mixtures of the two enantiomers. Accordingly, a compound of the present invention may exist as either a racemic mixture or a scalemic mixture, or as individual respective stereoisomers that are substantially free from another possible stereoisomer.
  • stereoisomers as used herein means less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers and most preferably less than 2% of other stereoisomers are present.
  • Methods of obtaining or synthesizing an individual stereoisomer for a given compound are known in the art and may be applied as practicable to final compounds or to starting material or intermediates.
  • stable compounds refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).
  • Substituted with deuterium refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.
  • each R may be referred to specifically (e.g., R 1 , R 2 , R 3 , etc.). Unless otherwise indicated, when a variable is referred to generally, it is meant to include all specific embodiments of that particular variable.
  • R 1 is -CD 3 , -CD 2 H, -CD3 ⁇ 4, -CH 3 , or H;
  • R 2 is ethyl optionally substituted with deuterium
  • R is phenyl optionally substituted with deuterium
  • Y la and Y lb are independently H or D;
  • R 1 is -CH 3 or H
  • R 2 is -C3 ⁇ 4CH 3
  • each of Y la and s H; then R is substituted with at least one deuterium.
  • Y la and Y lb are the same. In one aspect of this embodiment, Y la and Y lb are each deuterium. In another aspect, Y la and Y lb are each hydrogen. In one aspect of this embodiment, R 1 is -CD 3 , -CH 3 , or H. In one aspect of this embodiment, R 2 is -CD 2 CD 3 , -CD 2 CH 3 or -CH 2 CD 3 . In another aspect of this embodiment, R 2 is -CH 2 CH 3 . In one aspect of this embodiment, R 3 is
  • R is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R 1 is -CD 3 , or -CH 3 .
  • R 2 is -CD 2 CD 3 , -CD 2 CH 3 , -CH 2 CD 3 or -CH 2 CH 3 .
  • R 2 is -CD 2 CD 3 , -CD 2 CH 3 , -CH 2 CD 3 or -CH 2 C3 ⁇ 4;
  • R 3 is
  • R 1 is H. In one aspect of this
  • R 2 is -CD 2 CD 3 , -CD 2 CH 3 , -CH 2 CD 3 or -CH 2 CH 3 .
  • R is -CD 2 CD 3 or -CH 2 CH 3 ;
  • R J is
  • Y la and Y lb are the same.
  • any atom not designated as deuterium in any of the embodiments set forth above for a compound of Formula I is present at its natural isotopic abundance.
  • the compound of Formula I is a compound wherein Y la and Y lb are the same, and the compound is selected from any one of the compounds set forth in Table 1 :
  • R 2 is -CD 2 CD 3 , -CD 2 CH 3 , or -CH 2 CD 3
  • R 2 is -CD 2 CD 3 , -CD 2 CH 3 , -CH 2 CD 3 or -CH 2 CH 3 , with the proviso that if R 2 is -CH 2 CH 3 and Y la and Y lb are each H, then R 3 is
  • R 1 is -CD 3 , -CH 3 , or H
  • R 3 is Y l a and Y are independently H or D
  • R is -CD 2 CD 3 , -CD 2 CH 3 , -CH 2 CD 3 or -CH 2 CH 3 , with the proviso that if 1 is -CH 3 or H
  • R 2 is -CH 2 C3 ⁇ 4
  • Y la
  • any atom not designated as deuterium in Formula Ila-d is present at its natural isotopic abundance.
  • Compounds of Formula I and II may be prepared in a manner analogous to those described in Sanz et al., Smart et al., WO '306, WO '929 and WO '923, in each case by replacing as needed the reagents and/or reactants described in the schemes and the examples with suitable deuterated counterparts to obtain derivatives of varespladib or varespladib ester having the deuteration patterns disclosed herein.
  • Scheme 1 illustrates one possible route to compounds of Formula I in a manner analogous to that described by Sanz et al. and in WO '306.
  • Scheme 1 A Synthetic Route to Compounds of Formula I
  • deuterated counterparts of the reagents and/or reactants described in the Schemes 1 and 2 and examples of the articles and literature identified herein may be commercially available deuterated compounds, such as the following:
  • CD 3 CD 2 ⁇ — H s CH3CD2 ⁇ — H and CD 3 CH2 ⁇ H ; gach disclosed in Saussey, J. et al. Spectrochimica Acta, Part A: Molecular and Biomolecular
  • CD 3 CH 2 -H i s a lso disclosed in Zatsepina, N. N. et al., Reaktsionnaya Sposobnost Organicheskikh Soedinenii (1974), 11(2), 399-415; Saur, O. et al., Spectrochimica Acta, Part A: Molecular and
  • the invention also provides pyrogen-free pharmaceutical compositions comprising an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt of said compound; and a pharmaceutically acceptable carrier.
  • the carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.
  • compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes,
  • polyethylene-polyoxypropylene-block polymers polyethylene glycol and wool fat.
  • solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions may be enhanced by methods well-known in the art.
  • One method includes the use of lipid excipients in the formulation. See "Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly
  • Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this invention optionally formulated with a poloxamer, such as LUTROLTM and PLURONICTM (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See United States patent 7,014,866; and United States patent publications 20060094744 and 20060079502.
  • compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques).
  • Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000).
  • Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients.
  • ingredients such as the carrier that constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc.
  • Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.
  • carriers that are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
  • compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • suitable dispersing or wetting agents such as, for example, Tween 80
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in
  • 1,3-butanediol 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, e.g.: Rabinowitz JD and Zaffaroni AC, US Patent 6,803,031, assigned to Alexza Molecular Delivery Corporation.
  • Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.
  • Application of the subject therapeutics may be local, so as to be administered at the site of interest.
  • Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.
  • the compounds of this invention may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters.
  • an implantable medical device such as prostheses, artificial valves, vascular grafts, stents, or catheters.
  • Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in US Patents 6,099,562; 5,886,026; and 5,304,121.
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluoro silicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
  • Coatings for invasive devices are to be included within the defmition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.
  • the invention provides a method of coating an implantable medical device comprising the step of contacting said device with the coating composition described above. It will be obvious to those skilled in the art that the coating of the device will occur prior to implantation into a mammal.
  • the invention provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this invention.
  • Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers.
  • the invention provides an implantable medical device coated with a compound or a composition comprising a compound of this invention, such that said compound is therapeutically active.
  • the invention provides an implantable drug release device impregnated with or containing a compound or a composition comprising a compound of this invention, such that said compound is released from said device and is therapeutically active.
  • composition of this invention may be painted onto the organ, or a composition of this invention may be applied in any other convenient way.
  • a composition of this invention further comprises a second therapeutic agent.
  • the second therapeutic agent may be selected from any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered with a compound having the same mechanism of action as varespladib or varespladib methyl.
  • Such agents include those indicated as being useful in combination with varespladib or varespladib methyl, including but not limited to, those described in U.S. Patent No. 5,654,326.
  • the second therapeutic agent is selected from an antiinflammatory agent, atrial naturetic factor (for use in treating acute renal failure), a statin, a bile acid sequestrant, a fibrate, niacin, a niacin derivative, a cholesterol absorption inhibitor, a cholesterol ester transfer protein (CETP) inhibitor, a microsomal triglyceride transfer protein (MTP) inhibitor, a squalene synthase inhibitor, an ACE inhibitor, and angiotensin II receptor antagonist, a beta adrenergic blocker, a calcium channel blocker, an antithrombotic, an antibiotic, a steroid such as a glucocorticosteroid, an immunosuppressive agent, and an agent for controlling diarrhea.
  • atrial naturetic factor for use in treating acute renal failure
  • a statin for use in treating acute renal failure
  • a statin for use in treating acute renal failure
  • a statin for use in treating acute renal failure
  • a statin for use in treating acute renal failure
  • the invention provides separate dosage forms of a compound of this invention and one or more of any of the above-described second therapeutic agents, wherein the compound and second therapeutic agent are associated with one another.
  • association with one another means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).
  • the compound of the present invention is present in an effective amount.
  • the term is a pharmaceutical composition of the invention.
  • an “effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat the target disorder.
  • an effective amount of a compound of this invention can range from about 0.1 mg to about 500 mg per day.
  • the daily dose is from about 1 mg to about 300 mg of the compound.
  • the daily dose is from about 10 mg to about 200 mg of the compound.
  • the daily dose is about 25 mg of the compound.
  • the daily dose is about 75 mg of the compound.
  • the daily dose is about 150 mg of the compound.
  • the daily dose is from about 0.1 mg to about 30 mg of the compound.
  • the daily dose is from about 0.5 mg to about 20 mg of the compound.
  • the daily dose is from about 1 mg to about 15 mg of the compound.
  • the daily dose is from about 1 mg to about 10 mg of the compound.
  • the daily dose is from about 1 mg to about 5 mg of the compound.
  • the pharmaceutically effective amount is a daily dose is 0.01 - 25 mg of compound per kg of body weight. In some embodiments, the daily dose is 0.05 - 20 mg of compound per kg of body weight. In some embodiments, the daily dose is 0.1 - 10 mg of compound per kg of body weight. In some embodiments, the daily dose is 0.1 - 5 mg of compound per kg of body weight. In some
  • the daily dose is 0.1 - 2.5 mg of compound per kg of body weight.
  • compositions that comprise a second therapeutic agent an effective amount of the second therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent.
  • an effective amount is between about 70% and 100% of the normal monotherapeutic dose.
  • the normal monofherapeutic dosages of these second therapeutic agents are well known in the art. See, e.g., Wells et al., eds.,
  • the invention provides a method of inhibiting sPLA2 in a cell, comprising contacting a cell with a compound of Formula I herein or a pharmaceutically acceptable salt thereof.
  • the invention provides a method of treating in a subject a disease or condition selected from acne, acute bronchitis, bronchiolitis, acute CHF, acute lung injury, acute coronary syndrome, acute chest syndrome, acute renal failure, allergic conjunctivitis, allergic rhinitis, allograft rejection, Alzheimer's disease, AMI/reperfusion injury, angina, ankylosing spondylitis, apoptosis, ARDS, asthma, stable Coronary Artery Disease (atherosclerosis), atopic eczema,
  • the method of this invention is used to treat Acute Coronary Syndrome, stable Coronary Artery Disease (atherosclerosis) and mixed dyslipidemia in a subject in need thereof.
  • R 1 in the compound of Formula I is -CD 3 , -CD 2 H, -CDH 2 , or -CH 3 .
  • the method of this invention is used to treat Acute Chest Syndrome in a subject in need thereof.
  • Acute Chest Syndrome in a subject in need thereof.
  • R 1 in the compound of Formula I is H.
  • any of the above methods of treatment comprises the further step of co-administering to the subject in need thereof one or more second therapeutic agents.
  • the choice of second therapeutic agent is also dependent upon the particular disease or condition to be treated. Examples of second therapeutic agents that may be employed in the methods of this invention are those set forth above for use in combination compositions comprising a compound of this invention and a second therapeutic agent.
  • the combination therapies of this invention include a method of treating in a subject a disease selected from Acute Coronary Syndrome, Acute Chest Syndrome, stable Coronary Artery Disease, and mixed dyslipidemia comprising administering to a subject an effective amount of the compound of Formula I herein or a pharmaceutically acceptable salt thereof and one or more of the second therapeutic agents set forth above.
  • co-administered means that the second therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an second therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In such combination therapy treatment, both the compounds of this invention and the second therapeutic agent(s) are administered by conventional methods.
  • composition of this invention comprising both a compound of the invention and a second therapeutic agent, to a subject does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this invention to said subject at another time during a course of treatment.
  • Effective amounts of these second therapeutic agents are well known to those skilled in the art and guidance for dosing may be found in patents and published patent applications referenced herein, as well as in Wells et al., eds., Pharaiacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and other medical texts. However, it is well within the skilled artisan's purview to determine the second therapeutic agent's optimal effective-amount range.
  • the effective amount of the compound of this invention is less than its effective amount would be where the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.
  • the invention provides the use of a compound of Formula I alone or together with one or more of the above-described second therapeutic agents in the manufacture of a medicament, either as a single composition or as separate dosage forms, for treatment or prevention in a subject of a disease, disorder or symptom set forth above.
  • Another aspect of the invention is a compound of Formula I for use in the treatment or prevention in a subject of a disease, disorder or symptom thereof delineated herein.
  • Microsomal Assay Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC (Lenexa, KS). ⁇ -nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl 2 ), and dimethyl sulfoxide (DMSO) are purchased from Sigma- Aldrich.
  • 7.5 mM stock solutions of test compounds are prepared in DMSO.
  • the 7.5 mM stock solutions are diluted to 12.5-50 ⁇ in acetonitrile (ACN).
  • ACN acetonitrile
  • the 20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl 2 .
  • the diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate.
  • a 10 ⁇ aliquot of the 12.5-50 ⁇ test compound is added to the microsomes and the mixture is pre-warmed for 10 minutes. Reactions are initiated by addition of pre-warmed NADPH solution.
  • the final reaction volume is 0.5 mL and contains 0.5 mg/niL human liver microsomes, 0.25-1.0 ⁇ test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCl 2 .
  • the reaction mixtures are incubated at 37 °C, and 50 ⁇ , aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 ⁇ of ice-cold ACN with internal standard to stop the reactions.
  • the plates are stored at 4 °C for 20 minutes after which 100 ⁇ , of water is added to the wells of the plate before centrifugation to pellet precipitated proteins.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux acides dioxooléanediénoïques, des esters et des sels pharmaceutiquement acceptables de ceux-ci. La présente invention concerne en outre des compositions comprenant un composé de la présente invention et l'utilisation de telles compositions dans des procédés de traitement de maladies et affections qui sont avantageusement traitées par administration de varespladib ou de varespladib méthyle.
PCT/US2011/049163 2010-08-26 2011-08-25 Dérivés de triterpénoïdes synthétiques WO2012027579A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US37740410P 2010-08-26 2010-08-26
US61/377,404 2010-08-26

Publications (1)

Publication Number Publication Date
WO2012027579A1 true WO2012027579A1 (fr) 2012-03-01

Family

ID=45723808

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/049163 WO2012027579A1 (fr) 2010-08-26 2011-08-25 Dérivés de triterpénoïdes synthétiques

Country Status (1)

Country Link
WO (1) WO2012027579A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7098237B1 (en) * 1998-10-14 2006-08-29 Shionogi & Co., Ltd. Remedies for ischemia reperfusion injury
US20090062369A1 (en) * 2007-08-31 2009-03-05 Joaquim Trias Use of secretory phospholipase a2 (spla2) inhibitors to decrease spla2 levels
US20100204282A1 (en) * 2007-02-05 2010-08-12 Hutchinson John H Reverse indoles as 5-lipoxygenase-activating protein (FLAP) inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7098237B1 (en) * 1998-10-14 2006-08-29 Shionogi & Co., Ltd. Remedies for ischemia reperfusion injury
US20100204282A1 (en) * 2007-02-05 2010-08-12 Hutchinson John H Reverse indoles as 5-lipoxygenase-activating protein (FLAP) inhibitors
US20090062369A1 (en) * 2007-08-31 2009-03-05 Joaquim Trias Use of secretory phospholipase a2 (spla2) inhibitors to decrease spla2 levels

Similar Documents

Publication Publication Date Title
AU2013296627B2 (en) Deuterated ibrutinib
AU2010260249B2 (en) Deuterated isoindoline-1,3-dione derivatives as PDE4 and TNF-alpha inhibitors
AU2014235462C1 (en) Deuterated palbociclib
WO2012151361A1 (fr) Dérivés de carbamoylpyridone
WO2011063001A1 (fr) Promédicaments de niacine et versions deutérisées de ceux-ci
AU2014205472B2 (en) Deuterated momelotinib
WO2014011971A2 (fr) Carfilzomib deutéré
WO2015179772A1 (fr) Composés phénylquinazolinone et phénylisoquinolinone deutérés
EP2935251A1 (fr) Inhibiteurs alk deutérés
WO2011017612A1 (fr) Dérivés de diphénylpyrazine substitués
US20130109707A1 (en) Fluorouracil derivatives
WO2015031741A1 (fr) Thiénotriazolodiazépines substituées
EP2968268A1 (fr) Inhibiteurs de l'enzyme udp-glucose : n-acyl-sphingosine glucosyltransférase
WO2012154728A1 (fr) N-butyl-bumétanide deutéré
WO2014159511A1 (fr) Pacritinib deutérié
WO2015009889A1 (fr) Dérivés deutériés d'intédanib et leur utilisation pour le traitement de troubles prolifératifs
WO2012027579A1 (fr) Dérivés de triterpénoïdes synthétiques
WO2010068480A1 (fr) Dérivés deutérés de diméboline
US9181190B2 (en) Deuterated vercirnon
WO2014152275A1 (fr) Dérivés modifiés par le deutérium de l'inhibiteur de polymérase ns5b tcm647055

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11820659

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11820659

Country of ref document: EP

Kind code of ref document: A1