WO2009026345A1 - Composés de thiazolidinone et procédés de préparation et d'utilisation de ceux-ci - Google Patents

Composés de thiazolidinone et procédés de préparation et d'utilisation de ceux-ci Download PDF

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WO2009026345A1
WO2009026345A1 PCT/US2008/073683 US2008073683W WO2009026345A1 WO 2009026345 A1 WO2009026345 A1 WO 2009026345A1 US 2008073683 W US2008073683 W US 2008073683W WO 2009026345 A1 WO2009026345 A1 WO 2009026345A1
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Prior art keywords
quinolin
compound
thiazolidine
dione
mmol
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PCT/US2008/073683
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English (en)
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Glenn Noronha
Jianguo Cao
Chun P. Chow
Joel Renick
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Targegen Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • PI3K phosphatidylinositol-3-kinase pathway plays an important role in cellular signaling. In addition to the key role that PI3Ks play in cell proliferation and survival, they have been implicated in disease states involving vasculostasis, vascularization, membrane trafficking, glucose transport, neurite outgrowth, membrane ruffling, superoxide production, actin reorganization, and chemotaxis. Further, the PI3K pathway is stimulated as a physiological consequence of many growth factors and regulators.
  • PI3Ks are lipid kinases, consist of eight identified members, and are divided into three sub-families based on their sub- structures and substrate specificities. Class I PI3Ks are further divided into two sub-classes, Class IA and Class IB. Class IA consists of pi 10a, pi lO ⁇ , and pi 105 as catalytic sub-units and these are activated in tyrosine kinase receptor signaling. Class IB contains only the pi 10 ⁇ sub-unit, which is mostly activated by seven trans-membrane G-protein coupled receptors (GPCRs) via its regulatory sub-unit plOl and G-protein ⁇ sub- units.
  • GPCRs trans-membrane G-protein coupled receptors
  • Class II PI3Ks have the ⁇ , ⁇ , and ⁇ isoforms.
  • Class III PI3Ks include the phophatidylinositol specific 3-kinases. Overall the PI3K pathways play important roles in various disease states on account of their pivotal role in cell signaling.
  • PI3K signaling is important to many aspects of cell growth and survival. Because the PI3K pathway is stimulated as a physiological consequence of many growth factors and regulators, it is quite frequently targeted by genomic aberrations including mutation, amplification and rearrangement, The activation of the PI3K pathway results in a disturbance of control of cell growth and survival, which contributes to a competitive growth advantage, metastatic competence and, often resistance to therapy. This makes the PI3Ks an attractive target for the development of novel anticancer agents.
  • PI3Ks play a role in vasculostasis.
  • Compromised vasculostasis has serious pathologic consequences. Examples where excessive vascular permeability leads to particularly deleterious effects include pulmonary edema, cerebral edema, and cardiac edema. In general, however, edema in any tissue or organ leads to some loss of normal function, and therefore to the risk of morbidity or even mortality.
  • excessive endothelial proliferation may damage tissues, such as the retina in proliferative retinopathies, or fuel unwanted tissue growth, such as with tumor growth. Many pathologic and disease situations are marked by multiple dysregulations in vasculostasis.
  • Angio genesis encompasses both enhanced vascular proliferation and permeability, as newly-formed blood vessels do not generally exhibit the same level of vascular barrier function as well-established or mature vessels. Examples of such hyper-permeable vasculature can be found in cancers, vasculo proliferative diseases, retinal diseases, and rheumatoid arthritis.
  • the connection between angiogenesis and hyperpermeability may partly result from the dual action of factors such as vascular endothelial growth factor (VEGF), which induces both endothelial proliferation and vascular permeability.
  • VEGF vascular endothelial growth factor
  • the PI3K family may also play an important role in inflammatory responses, and in respiratory diseases. Therefore, in addition to direct roles in regulating vasculostasis, the PI3K family can also influence situations in which vasculostasis is compromised, including ischemia and ischemia-reperfusion injury, through their control of leukocyte functioning. Maintaining or restoring vasculostasis should be beneficial to overall patient outcome where such indications as, for example, inflammation, allergic diseases, cancer, cerebral stroke, myocardial infarction, pulmonary and cardiac insufficiency, renal failure, and retinopathies, are present.
  • This disclosure is generally directed to compounds that include a thiazolidinone moiety.
  • this disclosure also directed to compounds that are phosphoinositide 3-kinase (PI3K) enzyme or pathway inhibitors or modulators.
  • PI3K phosphoinositide 3-kinase
  • compounds are provided that inhibit a PI3K, with an IC50 of about 200 nM or less, about 50 nM or less, from about 1 nM to about 50 nM, or about 10 nM or less.
  • the compound may inhibit one or more of PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , or PI3K ⁇ .
  • a method of treating an respiratory or ocular disorder comprising administering to a patient in need thereof an effective amount of a compound disclosed herein.
  • a method of treating cancer comprising administrating to a patient in need thereof an effective amount of a compound of any of the disclosed compounds.
  • a method for inhibiting tumor cell growth, tumor cell proliferation, or tumorigenesis comprising administering to a patient in need thereof an effective amount of a compound of any of the disclosed compounds..
  • methods for treating pain, diabetes, inflammation, platelet aggregation, ischemic heart disease, sclerosis, restenosis, disorders, HIV, bone resorption, cancer, non-small cell lung cancer, or brain cancer, comprising administering to a patient in need thereof an effective amount of any of the disclosed compounds.
  • the present disclosure is directed in part towards novel compounds and compositions that inhibit PI3K and methods of making and using the same.
  • Such compounds may inhibit one or more of the phosphoinositide-3-kinase family, including PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , and/or PI3K ⁇ .
  • therapeutic agent refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substance that acts locally or systemically in a subject.
  • therapeutic agents also referred to as “drugs”
  • drug are described in well-known literature references such as the Merck Index, the Physicians Desk Reference, and The Pharmacological Basis of Therapeutics, and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
  • therapeutic effect is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance.
  • the term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and/or conditions in an animal or human.
  • therapeutically-effective amount means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment.
  • the therapeutically effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • compositions of the present invention may be administered in a sufficient amount to produce a at a reasonable benefit/risk ratio applicable to such treatment.
  • modulation is art-recognized and refers to up regulation (i.e., activation or stimulation), down regulation (i.e., inhibition or suppression) of a response, or the two in combination or apart.
  • a "patient,” “subject” or “host” to be treated by the subject method may mean either a human or non-human animal.
  • the term “treating” is art-recognized and refers to curing as well as ameliorating at least one symptom of any condition or disease.
  • the term “prodrug” is art-recognized and is intended to encompass compounds which, under physiological conditions, are converted into the agents of the present invention.
  • a common method for making a prodrug is to select moieties which are hydrolyzed under physiological conditions to provide the desired compound. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal or the target organ or cell.
  • alkyl is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 3 O for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer, e.g. from 1 to 6 carbons.
  • cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.
  • alkyl is also defined to include halosubstituted alkyls.
  • alkyl (or “lower alkyl”) includes “substituted alkyls”, which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • Such substituents may include, for example, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.
  • a carbonyl such as a carboxyl, an alkoxy
  • the moieties substituted on the hydrocarbon chain may themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CN and the like. Exemplary substituted alkyls are described below.
  • Cycloalkyls may be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl- substituted alkyls, -CN, and the like.
  • aralkyl is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • lower alkyl refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • heteroatom is art-recognized and refers to an atom of any element other than carbon or hydrogen.
  • Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • aryl is art-recognized and refers to 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "heteroaryl” or “heteroaromatics.”
  • the aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like.
  • aryl or aromatic, also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyl s.
  • ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4- disubstituted benzenes, respectively.
  • 1,2-dimethylbenzene and ortho- dimethylbenzene are synonymous.
  • heterocyclyl or “heterocyclic group” are art-recognized and refer to 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles may also be polycycles.
  • Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, o
  • the heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,
  • polycyclyl or “polycyclic group” are art-recognized and refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl
  • carrier is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
  • nitro is art-recognized and refers to -NO2; the term “halogen” is art- recognized and refers to -F, -Cl, -Br or -I; the term “sulfhydryl” is art-recognized and refers to - SH; the term “hydroxyl” means -OH; and the term “sulfonyl” is art-recognized and refers to - SO2 " .
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:
  • R51 R52 wherein R50, R51 and R52 each independently represent a hydrogen, an alkyl, an alkenyl, - (CH2)m-R61, or R50 and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.
  • only one of R50 or R51 may be a carbonyl, e.g., R50, R51 and the nitrogen together do not form an imide.
  • R50 and R51 each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m- R61.
  • alkylamine includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.
  • amino is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula:
  • acylamino is art-recognized and refers to a moiety that may be represented by the general formula:
  • R50 is as defined above
  • R54 represents a hydrogen, an alkyl, an alkenyl or - (CH 2 ) m -R61, where m and R61 are as defined above.
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2)m-R61, wherein m and R61 are defined above.
  • Representative alkylthio groups include methylthio, ethyl thio, and the like.
  • carbonyl is art recognized and includes such moieties as may be represented by the general formulas:
  • X50 is a bond or represents an oxygen or a sulfur
  • R55 and R56 represents a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R61or a pharmaceutically acceptable salt
  • R56 represents a hydrogen, an alkyl, an alkenyl or -(CH 2 ) m -R61, where m and R61 are defined above.
  • X50 is an oxygen and R55 or R56 is not hydrogen
  • the formula represents an "ester”.
  • X50 is an oxygen
  • R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a "carboxylic acid".
  • X50 is an oxygen, and R56 is hydrogen
  • the formula represents a "formate".
  • the oxygen atom of the above formula is replaced by sulfur
  • the formula represents a "thiolcarbonyl” group.
  • X50 is a sulfur and R55 or R56 is not hydrogen
  • the formula represents a "thiolester.”
  • X50 is a sulfur and R55 is hydrogen
  • the formula represents a "thiolcarboxylic acid.”
  • X50 is a sulfur and R56 is hydrogen
  • the formula represents a "thiolformate.”
  • X50 is a bond, and R55 is not hydrogen
  • the above formula represents a "ketone” group.
  • X50 is a bond, and R55 is hydrogen
  • the above formula represents an "aldehyde” group.
  • each expression e.g. alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • polymers of the present invention may also be optically active.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically- active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • the term "substituted" is also contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67 th Ed., 1986-87, inside cover.
  • the term "hydrocarbon” is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom.
  • the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds that may be substituted or unsubstituted.
  • pharmaceutically-acceptable salts is art-recognized and refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds, including, for example, those contained in compositions of the present invention.
  • pharmaceutically acceptable carrier refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient.
  • materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • systemic administration refers to the administration of a subject composition, therapeutic or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • parenteral administration and “administered parenterally” are art- recognized and refer to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.
  • a 1 is a nine or ten membered bicyclic heterocycle, for example a nine or ten membered bicyclic aromatic heterocycle, containing one to three heteroatoms chosen from nitrogen, oxygen or sulfur optionally substituted by one to four substituents each independently selected from halo, hydroxyl, or alkyl;
  • a 2 is an heterocycle group, for example an aromatic heterocyclic group, which may contain an heteroatom chosen from sulfur or oxygen;
  • X is O, S or NR 12 ;
  • R 1 is selected from the group consisting of H, amide, ester, carbamate or alkyl
  • a 2 is optionally substituted by one to four substituents each independently selected from the group consisting of halo, hydroxyl, mercapto, nitro, formyl, formamido, carboxy, cyano, amino, amide, carbamoyl, sulphamoyl, ureido, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, thiocarbonyl, N-alkylureido, N-alkylamino, N-alkylsulphamoyl, N- alkylcarbamoyl, N-arylamide, N-alkylamide, aryl, heterocycle, or cycloalkyl, wherein said alkyl, alkenyl, alkynyl or alkoxy may be optionally substituted by one or more groups selected from R a , and wherein said aryl, heterocycle or cycloalkyl may each be optionally substituted by one or
  • R a is independently selected from halo, hydroxyl, nitro, formyl, formamido, alkyl, alkoxy, carboxyl, cyano, amino, amido, carbamoyl, sulphamoyl, ureido, aryl, heterocycle, or cycloalkyl.
  • R 12 is selected from the group consisting of alkyl, alkenyl, alkynl, aryl, heterocycle, or cycloalkyl.
  • the moieties of R 12 may be optionally substituted by one, two, or three substituents selected from the group consisting of halo, hydroxyl, nitro, formyl, formamido, alkyoxy, alkyl, carboxyl, cyano, amino, amido, carbamoyl, sulphamoyl, ureido, aryl, heterocycle, or cycloalkyl.
  • R 12 may be CF 3 .
  • a 1 may be, in some embodiments, a nine or ten membered aromatic bicyclic heterocycle containing one to three heteroatoms chosen, for each occurrence, from nitrogen or oxygen.
  • a 1 is selected from the group consisting of: indolyl, naphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzofuryl, benzthienyl, cinnolinyl, and pteridinyl.
  • a 1 can be selected from quinolinyl or quinazolinyl.
  • a 2 may be selected from thiopene, furan, pyran, chromene, isothiazole, isoxazole, benzothiophene, 2,3-dihydrothieno[3,4-b][l,4]dioxine, 4,5,6,7-tetrahydrothieno[3,4-c]pyridine, or benzofuran.
  • a 2 may be substituted on a ring carbon with 1 or 2 substituents each independently chosen from: halo, carboxyl, cyano, amino, amide, formyl, formamido, alkoxy, carbamoyl, sulphamoyl, ureido, an optionally substituted alkyl (for example CF 3 ), an optionally substituted aryl, or an optionally substituted heterocycle group.
  • a 2 can be substituted on a ring carbon with 1 or 2 substituents each independently chosen from halo, methyl, phenyl, or isoxazole, wherein said phenyl and isoxazole are optionally substituted on a ring carbon by 1 or 2 substituents chosen from halo, alkyl, aryl or heterocycle.
  • a disclosed compound is represented by formula Ia or Ib:
  • Y is CR b or N
  • Z is S or O
  • R 2 , R 3 , R 4 are each independently selected from the group consisting of H, halo, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, cyano, carboxyl, N-arylamido, aryl, and heterocycle, or R 2 and R 3 , or R 3 and R 4 , form, together with the carbon atoms to which they are attached, a 5 or 6 carbocycle or heterocycle ring, wherein any of said alkyl, alkenyl, alkynyl, carbocycle, aryl, or heterocycle can be optionally substituted with halo, hydroxyl, cyano, alkoxy, ureido, sulphamoyl, N-alkylsulphamoyl, alkyl, aryl, heterocycle or alkylheterocycle.
  • R 3 may be phenyl or N-phenylacetamide wherein the phenyl is optionally substituted with hydroxyl, alkyl, N-alkylsulphamoyl, alkoxy, or an alkylmorpholino.
  • R b is selected from H, halo, hydroxyl, or alkyl.
  • Z is S or O.
  • R 2 is H.
  • R 3 and R 4 are each independently selected from H, -CH 2 OH, -CH 2 CH 2 OH, CH 3 , phenyl, F, Cl, CO 2 H,-C(O)NH-phenyl, -C(O)NCH 2 CH 2 -pyrrolidine, or dimethylisoxazole, wherein the phenyl is optionally substituted by, for example, one or two substituents selected from the group consisting of halo, cyano, hydroxyl, alkyl, alkoxy, N-alkylsulphamoyl, and sulphamoyl.
  • R 3 and R 4 taken together with the ring carbons on which they are attached, form a bicyclic ring such as benzofuran, benzothiophene, 2,3-dihydro- thieno[3,4b][l,4]dioxin or 4,5,6,7-tetrahydrothieno[3,2-c]pyridine.
  • Such bicyclic rings may be substituted by, for example, one or two substituents selected from the group consisting of halo, hydroxyl, cyano, and alkyl.
  • X may be, for example NR 12 , wherein R 12 is phenyl optionally substituted by one or two halogen moities; or X may be, for example, O.
  • Re is selected from the group consisting of:
  • X is O, S or NR 12 ;
  • W is, independently for each occurrence, CR b , N-alkyl, NH, N-C(O)-alkyl, N-C(O)- heterocycle, N-C(O)-N-alkyl, N-C(O)-N-heterocycle, O or S;
  • Z is, independently for each occurrence, S or O;
  • R b is selected from H, halo, hydroxyl, or alkyl
  • R 1 is H or alkyl
  • R 7 is H or alkyl
  • Rg and Rg are each independently selected from H, Cl, F, alkyl, alkynl, alkenyl, carboxyl, cyano, hydroxyl, hydroxyalkyl, formyl, formamido, amido, amine, sulphamoyl, N-
  • n is an integer from 0 to 8.
  • R 1O is independently selected for each occurrence from H, Cl, F, hydroxyl, cynao, or alkyl;
  • R 11 is selected from group consisting of heterocycle, aryl, or cycloalkyl; wherein R 11 is optionally substituted at one to four substituents each independently selected from halo, hydroxyl, carboxyl, sulphamoyl, N-alkylsulphamoyl, -alkyl-heterocycle, -alkyl-carbocycle or alkyl;
  • R 12 is selected from the group consisting of alkyl, aryl, heterocycle, or cycloalkyl, wherein R 12 may be optionally substituted by one, two, or three substituents selected from the group consisting of halo, hydroxyl, nitro, formyl, formamido, alkyoxy, alkyl, carboxyl, cyano, amino, amido, carbamoyl, sulphamoyl, ureido, aryl, heterocycle, or cycloalkyl;
  • R 13 is alkylene, alkenylene, or alkynyl
  • formula II may be represented by:
  • n is 1 to 3, or 1 to 5, for example, m may be 1, 2, 3, 4, or 5.
  • R 1O at each occurrence is H.
  • R 11 may be substituted at one or two positions by methyl.
  • R 11 is chosen from: pyrrolindyl, phenyl, isoxazole, or thiazolidinedione.
  • R 7 is H or methyl.
  • Rg may be H, methyl, or ethyl. .
  • Rg may be chosen, for example, from: H, Cl, phenyl, co 2H , or 3,5-dimethyl-isoxazol- 4-yl.
  • compositions of the present invention will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration, and the form of the subject composition. Any of the subject formulations may be administered in a single dose or in divided doses. Dosages for the compositions of the present invention may be readily determined by techniques known to those of skill in the art or as taught herein.
  • the dosage of the subject compounds will generally be in the range of about 0.01 ng to about 10 g per kg body weight, specifically in the range of about 1 ng to about 0.1 g per kg, and more specifically in the range of about 100 ng to about 10 mg per kg.
  • An effective dose or amount, and any possible affects on the timing of administration of the formulation may need to be identified for any particular composition of the present invention. This may be accomplished by routine experiment as described herein, using one or more groups of animals (preferably at least 5 animals per group), or in human trials if appropriate.
  • the effectiveness of any subject composition and method of treatment or prevention may be assessed by administering the composition and assessing the effect of the administration by measuring one or more applicable indices, and comparing the post-treatment values of these indices to the values of the same indices prior to treatment.
  • the health of the patient may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period.
  • Treatment including composition, amounts, times of administration and formulation, may be optimized according to the results of such monitoring.
  • the patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters.
  • Adjustments to the amount(s) of subject composition administered and possibly to the time of administration may be made based on these reevaluations.
  • Treatment may be initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum therapeutic effect is attained.
  • compositions may reduce the required dosage for any individual agent contained in the compositions because the onset and duration of effect of the different agents may be complimentary.
  • Toxicity and therapeutic efficacy of subject compositions may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 and the ED50.
  • the data obtained from the cell culture assays and animal studies may be used in formulating a range of dosage for use in humans.
  • the dosage of any subject composition lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose may be estimated initially from cell culture assays.
  • compositions of the present invention may be administered by various means, depending on their intended use, as is well known in the art.
  • compositions of the present invention may be formulated as tablets, capsules, granules, powders or syrups.
  • formulations of the present invention may be administered parenterally as injections (intravenous, intramuscular or subcutaneous), drop infusion preparations, suppositories or administration intranasally (for example, to deliver a dosage to the brain via the nose or to deliver a dosage to the nose directly) or by inhalation (e.g. to treat a condition of the respiratory tract or to pretreat or vaccinate via the respiratory tract).
  • compositions of the present invention may be formulated as eyedrops or eye ointments. These formulations may be prepared by conventional means, and, if desired, the compositions may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
  • any conventional additive such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may be present in the formulated agents.
  • Subject compositions may be suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of composition that may be combined with a carrier material to produce a single dose vary depending upon the subject being treated, and the particular mode of administration.
  • Methods of preparing these formulations include the step of bringing into association compositions of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association agents with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), each containing a predetermined amount of a subject composition thereof as an active ingredient.
  • Compositions of the present invention may also be administered as a bolus, electuary, or paste.
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example,
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing
  • Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non- irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • suitable non- irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Compositions and compounds of the present invention may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (T weens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • Dosages for administration by nasal delivery e.g. delivered to or via the nasal cavity, can be applied as drops, ointments, gels, mists/sprays (aqueous or nonaqueous), aerosols
  • compositions for inhalation and/or delivery to the nose may contain from 1% to 20% by weight of a penetrator enhancer (for example, surfactants, e.g. sugar esters, sugar ethers, carbohydrate esters) which may allow enhanced nose permeability of the active agent.
  • a penetrator enhancer for example, surfactants, e.g. sugar esters, sugar ethers, carbohydrate esters
  • Dosages for administration by inhalation or by delivered to or via the lung can be applied as mists/sprays (aqueous or nonaqueous), aerosols (liquids, suspensions or dry powders),liquids or suspensions (aqueous or nonaqueous), powders, or combinations thereof.
  • Such delivery can be achieved by commercially available devices such as 1) nebulizers, 2) metered dose inhalers, 3) dry powder inhalers, 4) soft mist inhalers, or by instillation or insufflation, or other mechanisms and/or devices known in the art.
  • compositions of this invention suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate and cyclodextrins.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • Treatment or amelioration of disease states and pathological conditions that implicate PI3K pathways are contemplated herein, and such treatment comprises administering one or more of the disclosed compounds, such as those recited in Formulas I or II, or a composition as described herein comprising a disclosed compound.
  • Methods of treating a patient suffering from diseases such as myocardial infarction, stroke, congestive heart failure, ischemia or reperfusion injury, vascular leakage syndrome (VLS), cancer, arthritis, (for example rheumatoid arthritis), or other arthropathy, eye diseases including uveitis, retinopathy or vitreoretinal disease, macular degeneration, autoimmune diseases, vascular leakage syndrome, inflammatory diseases, edema, transplant rejection, burn, respiratory diseases such as acute respiratory distress syndrome (ARDS), asthma, and chronic obstructive pulmonary disorder (COPD), and transplant rejection are contemplated, and may comprise administering a disclosed compound, such as those recited in Formulas I or II, or a composition comprising a disclosed compound.
  • diseases such as myocardial infarction, stroke, congestive heart failure, ischemia or reperfusion injury, vascular leakage syndrome (VLS), cancer, arthritis, (for example rheumatoid arthritis), or other arthropathy,
  • Compounds and compositions disclosed herein, e.g. that inhibit vascular permeability may be used in a co-therapy to reduce the deleterious side-effects of such therapies.
  • edema formation may cause uneven delivery of therapeutic agents to diseased tissues, therefore vasculostatic agents that inhibit vascular permeability could be used in a co-therapy approach to enhance delivery and efficacy of such therapies.
  • exemplary methods of treating cancers include treatment of myeloma.
  • Acute and/or prophylactic treatment of the interruption of blood flow by pathologic conditions such as thrombus formation, or medical intervention such as cardioplegia, organ transplantation, and angioplasty, or physical trauma, using disclosed compounds is also contemplated.
  • a microwave vial was charged with 4 (0.10 g, 0.40 mmol), thiazolidine-2,4-dione (0.70 g, 0.59 mmol), and Cs 2 CO 3 (0.26 g, 0.79 mmol) in ethanol (2 mL).
  • the reaction mixture was heated for 30 min at 150 0 C in a Biotage microwave reactor.
  • the resulting mixture was separated by preparative HPLC. Fractions that contained the desired product were combined, neutralized with saturated Na 2 CO 3 , and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO 4 , and concentrated to afford the title compound as a yellow solid (0.082 g, 59%).
  • a microwave vial was charged with 5 (0.12 g, 0.42 mmol), thiazolidine-2,4-dione (0.73 g, 0.62 mmol), and Cs 2 CO 3 (0.27 g, 0.83 mmol) in ethanol (3 mL).
  • the reaction mixture was heated for 30 min at 150 0 C in a Biotage microwave reactor. Precipitate from the resulting mixture was filtered and washed with ethanol (10 mL) followed by H 2 O (10 mL) to afford the title compound as an orange solid (0.066 g, 41%).
  • a microwave vial was charged with 7 (0.2 g, 0.74 mmol), thiazolidine-2,4-dione (0.15 g, 1.11 mmol), Cs 2 CO 3 (0.48 g, 1.49 mmol) in ethanol (4.5 mL).
  • the reaction mixture was heated for 30 min at 150 0 C in a Biotage microwave reactor. Upon cooling to room temperature, the reaction mixture added MeOH (50 mL). Precipitate from the resulting mixture was filtered to afford the title compound as a brown solid (0.079 g, 29%).
  • reaction mixture was purified on a flash chromatography (SiO 2 , 10% ethyl acetate in hexanes to 100% ethyl acetate over 15 minutes) to afford the title compound (0.37 g, 61%) as a pale yellow solid.
  • Example 29 Preparation of: 5- ⁇ 6-[(Z)-(2,4-Dioxo-l,3-thiazolidin-5-ylidine)methyl]quinolin-4- yl ⁇ -,/V-(2-pyrrolidin- 1 -ylethyl)thiophene-2-carboxamide:
  • Chlorobenzene (1000 mL) and PPA (280 g) were combined and heated to reflux (130 0 C).
  • the solution of compound 20 (130 g, 0.48 mol) in chlorobenzene (300 mL) was added drop wise to the mixture over 1.5 h.
  • the reaction mixture was refluxed for 3-4 h and then cooled.
  • the solvent was decanted from the residue and toluene (400 mLx2 ) was added to the residue, stirred and decanted.
  • the chlorobenzene/toluene extracts were combined and concentrated under vacuum, and the residue was then taken up with PE (800 mL) and water (400 mL).
  • Example 34 Preparation of: Benzo[b]thiophene-6-carbonitrile (23) and Benzo[b]thiophene-4- carbonitrile (24)
  • the reaction mixture was poured into 2 mL water and 6 mL ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate (3x18 mL). The combined organic layers were washed with water (2 mL), brine (4 mL), dried (Na 2 SO 4 ), and concentrated in vacuo. The crude residue was triturated in ethyl acetate (3 mL) and then fully precipitated with petroleum ether (6 mL) to afford the title compound as an off-white solid (206 mg, 46%). The material was used as is for the next reaction.
  • the reaction mixture was poured into 2 mL water and 6 mL ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate (3x18 mL). The combined organic layers were washed with water (2 mL), brine (4 mL), dried (Na 2 SO 4 ), and concentrated in vacuo. The crude residue was triturated in ethyl acetate (3 mL) and then fully precipitated with petroleum ether (6 mL) to afford the title compound as a mustard colored solid (168 mg, 48%). The material was used as is for the next reaction.
  • reaction mixture Upon completion, the reaction mixture was poured into ice water. The resulting mixture was acidified to pH ⁇ 2 with 1 N HCl. The aqueous layer was extracted with MTBE (1000 mL x X). The combined organic layers were washed with brine, dried over sodium sulfate, and then concentrated. The crude product was crystallized from dichloromethane to give the compound (28 g, 34.5%) as a light yellow solid.
  • a microwave vial was charged with 57 (0.130 g, 0.37 mmol), thiazolidine-2,4-dione (0.071 g, 0.55 mmol), and Cs 2 CO 3 (0.24 g, 0.73 mmol) in ethanol (2 mL).
  • the reaction mixture was heated 30 min at 150 0 C in a Biotage microwave reactor.
  • the resulting mixture concentrated and purified by silica gel chromatography (CH 2 Cl 2 :Me0H 100:0 to 90: 10 gradient) to afford the title compound in a 1:1 ratio of E and Z isomers as an orange solid (0.033 g, 20 %).
  • a microwave vial was charged with 58 (0.273 g, 0.73 mmol), thiazolidine-2,4-dione (0.143 g, 1.1 mmol), and Cs 2 CO 3 (0.476 g, 1.46 mmol) in ethanol (4 mL).
  • the reaction mixture was heated 30 min at 150 0 C in a Biotage microwave reactor.
  • the resulting mixture concentrated and purified by silica gel chromatography (CH 2 Cl 2 :Me0H 100:0 to 90: 10 gradient) to afford the title compound as an orange solid (0.033 g, 20 %).
  • a microwave vial was charged with 59 (0.150 g, 0.40 mmol), thiazolidine-2,4-dione (0.070 g, 0.60 mmol), and Cs 2 CO 3 (0.260 g, 0.80 mmol) in ethanol (4 mL).
  • the reaction mixture was heated 30 min at 150 0 C in a Biotage microwave reactor.
  • the resulting mixture concentrated and purified by HPLC to afford the title compound as a brown solid (0.024 g, 13 %).
  • a microwave vial was charged with 65 (0.200 g, 0.44 mmol), thiazolidine-2,4-dione (0.085 g, 0.66 mmol), and Cs 2 CO 3 (0.46 g, 1.3 mmol) in ethanol (4 mL).
  • the reaction mixture was heated 30 min at 150 0 C in a Biotage microwave reactor.
  • the resulting mixture concentrated and purified by silica gel chromatography (CH 2 Cl 2 :Me0H 100:0 to 50:50 gradient) to afford the title compound a yellow solid (0.103 g, 42%).
  • a microwave vial was charged with 65 (0.275 g, 0.58 mmol), thiazolidine-2,4-dione (0.113 g, 0.87 mmol), and Cs 2 CO 3 (0.64 g, 1.8 mmol) in ethanol (3 mL).
  • the reaction mixture was heated 30 min at 150 0 C in a Biotage microwave reactor.
  • the resulting mixture concentrated and purified by silica gel chromatography (CH 2 Cl 2 IMeOH 100:0 to 50:50 gradient) to afford the title compound a yellow solid (0.180 g, 56%).
  • a microwave vial was charged with 66 (0.140 g, 0.52 mmol), thiazolidine-2,4-dione (0.204 g, 1.57 mmol), and Cs 2 CO 3 (1.11 g, 3.14 mmol) in ethanol (4 mL).
  • the reaction mixture was heated 30 min at 160 0 C in a Biotage microwave reactor.
  • the resulting mixture concentrated and purified by silica gel chromatography (CH 2 Cl 2 :Me0H 100:0 to 0:100 gradient) to afford the title compound a brown solid (0.042 g, 17%).
  • a microwave vial was charged with 67 (0.32 g, 0.82 mmol), thiazolidine-2,4-dione (0.161 g, 1.24 mmol), and Cs 2 CO 3 (0.805 g, 2.47 mmol) in ethanol (6 mL).
  • the reaction mixture was heated 30 min at 160 0 C in a Biotage microwave reactor.
  • the resulting mixture concentrated and purified by preparative HPLC to afford the title compound a brown solid (0.202 g, 50%).
  • Example 84 Complicatedple 84103 Preparation of tert-Butyl-(3-ethynyl-phenoxy)-dimethyl- silane (68)
  • a microwave vial was charged with 72 (0.50 g, 3.3 mmol), chloro-acetic acid (0.32 g, 3.4 mmol), and sodium acetate (0.30 g, 3.7 mmol) in acetic acid (3 mL).
  • the reaction mixture was heated for 20 min at 150 0 C in a Biotage microwave reactor. Water was added (20 mL) and the resulting solid filtered to afford the title compound (a 1/1 mixture of E/Z isomers) as a yellow solid (0.46 g, 73%).
  • a microwave vial was charged with 74 (0.85 g, 4.1 mmol), chloro-acetic acid (0.45 g, 4.7 mmol), and sodium acetate (0.40 g, 4.9 mmol) in acetic acid (6 mL).
  • the reaction mixture was heated for 20 min at 150 0 C in a Biotage microwave reactor. Water was added (20 mL) to the reaction mixture and the resulting solid filtered to afford the title compound as a white solid (0.71 g, 70%).
  • a microwave vial was charged with 3 (50 mg, 0.21 mmol), 75 (70 mg, 0.29 mmol), and Cs 2 CO 3 (0.13 g, 0.40 mmol) in ethanol (4 mL). The reaction mixture was heated for 30 min at 140 0 C in a Biotage microwave reactor. The resulting solid was filtered, washed with ethanol followed by water to afford the title compound as an orange solid (55 mg, 57%).
  • IC 50 values for compounds against the isoforms of PI3-Kinase were generated using either luminescence or fluorescence polarization based assays.
  • a four order of magnitude serial dilution of the compounds was introduced into a buffered solution containing appropriate amounts of either PI3-kinase isoform, ATP (3 ⁇ M for luminescence or 25 ⁇ M for fluorescence polarization) and PIP3 (50 ⁇ M for luminescence and 10 ⁇ M for fluorescence polarization); the reaction was then allowed to proceed for an appropriate time.
  • Example 96 ELISA for C5a-induced phosphorylation of AKT in Raw 264.7 macrophages.
  • Raw 264.7 mouse macrophage cells (ATCC#TIB-71) were cultured in DMEM containing 10% heat inactivated serum and IX penicillin/streptomycin. 7.5xl0 4 cells were seeded into a 96 well plate were allowed to adhere overnight. Cells were then washed one time with serum-free medium, and then incubated under serum-free conditions for 3-4 hours at 37°C/5%CO 2 . Cells were pretreated with the indicated compound (10 ⁇ M - 0.0045 ⁇ M) for 1 h, followed by stimulation with 0.5 ⁇ g/ml C5a (Sigma) for 5 min. Cells were immediately placed on ice, and washed one time with cold PBS.
  • Cells were lysed with 65 ⁇ L of 1% Triton- X-100 lysis buffer containing protease inhibitors (Cell Signaling Technology) and further incubated in this solubilization buffer for 20-30 min on ice with mild agitation. Lysates were then centrifuged at 5000 rpm at 4 0 C for 10-15 min. Thereafter, an ELISA specific for phosphorylated AKT (pAKT-Ser473) (Cell Signaling Technology) was performed. Absorbance was measured at 450-540 nm.
  • Example 97 VEGF-induced hRMVEC proliferation assay
  • hRMVECs early passage human retinal microvascular endothelial cells (hRMVECs) cells (Cell Systems, Kirkland, WA) were plated at a density of -1.5 x 10 3 cells/well in a 96-well plate (Corning, Corning, NY), and allowed to adhere for ⁇ 6 hours or overnight. Medium was then changed into CSC-Maintenance Medium (Cell Systems, Kirkland, WA) and further incubated for at least 24 h - 48 h at 37°C/5% CO 2 .
  • CSC-Maintenance Medium Cell Systems, Kirkland, WA
  • this specialized medium contains 10% FBS but no growth factor, and renders proliferating cells into a quiescent state.
  • the cells were then pre-treated with varying concentrations of the indicated compound (20 ⁇ M - 0.00914 ⁇ M or 10 ⁇ M - 0.00457 ⁇ M or DMSO (as a vehicle control) prepared in basal CSC-medium containing 10% FBS and 50 ⁇ g/ml heparin for -60 minutes at 37°C/5% CO 2 .
  • Human recombinant VEGF (Peprotech, Rocky Hill, NJ) was then added to a final concentration of 50 ng/ml.
  • cellular proliferation was quantified using the Cell Proliferation Kit (Roche, Alameda, CA) as described by the manufacturer. Briefly, for one 96-well plate, 100 ⁇ L of electron-coupling reagent was added to 5 mL of XTT labeling solution. 50 ⁇ L of this solution was then added to each well, and the reaction was allowed to develop at 37°C/5% CO 2 . The colored formazan product that is generated by metabolically active cells was measured spectrophotometrically using the SpectraMax spectrophotometer (Molecular Devices, Sunnyvale, CA) at 492 nm with correction at 690 nm.
  • SpectraMax spectrophotometer Molecular Devices, Sunnyvale, CA
  • IV and PO intravenous and oral dose formulations were prepared fresh.
  • PO intravenous and oral dose formulations were prepared fresh.
  • PO intravenous solutions containing appropriate excipients or suspended in 0.5% MC and 0.05% Tween80.
  • IV formulation the compounds were solubilized in an aqueous vehicle containing suitable excipients. The IV formulation was aseptically filtered through 0.22um filters.
  • Rats Six jugular vein cannulated male Sprague-Dawley rats ( ⁇ 300g) with were divided into three groups with three rats in IV dose group and three rats in the PO dose group. Animals were allowed food and water ad libitum. The study was conducted at TargeGen. (San Diego, CA).
  • Blood samples (approximately 500 ⁇ L per time point) were serially collected via jugular vein cannula and transferred into tubes containing sodium heparin anticoagulant at 0.083, 0.25, 0.5, 1, 3, 5, 7, and 24 hours post-dose for IV dose; and at 0.5, 1, 3, 5, 7, and 24 hours post dose for PO doses. Blood was maintained in an ice and water mixture prior to centrifugation to obtain plasma. Plasma samples are transferred to a -2O 0 C freezer and stored until analysis.
  • Matrix calibration standards and QC samples were prepared by spiking the compound into blank rat plasma (Valley Biomedical Inc., Lot # L51663). The final concentrations of a selected compound were 0, 1, 5, 10, 50, 100, 500, 1000, 2500 and 5000 ng/niL for calibration standards, and 2.50, 25.0, 250 and 2500 for QC samples.
  • Plasma samples were processed using a standard protocol. The samples were analyzed using a LC/MS/MS Waters Quattro LC by standard determined conditions. Chromatogram signals were integrated and calibrated using MassLynx 3.0. Pharmacokinetic parameters were estimated using WinNonlin (version 4.1) from mean plasma concentration- time profiles. The values for the maximum plasma concentration (C max ) and the time to maximum concentration (T max ) were determined from measure plasma concentrations. The area under the curves, AUC ( i ast) and AUC (inf ) were calculated from plasma concentration-time profiles using the linear trapezoidal rule.
  • the PK evaluation in mice utilized the same procedures described above except the number of mice was three per time point per dosed group and the blood samples were collected by cardiac puncture.
  • Table 2 provides data from a mouse PK model with IV and PO arms.
  • Example 99 Protocol for ocular exposure following topical instillation
  • Table 3 shows ocular PK data for selected compounds with low oral availability
  • Example 101 Murine model of ocular edema and neovascularization
  • a murine model of ocular edema and neovasularization was used to assess compound activity. Laser energy is used to rupture the Bruch's membrane, after which edema and neovascularization develop within the choroid. (Tobe T. et al. (1998) Am J Pathol 153:1641-1646). Optical coherence tomography (OCT) was then used 7-9 days post-lasering to quantify the area of laser lesion sites, as a measure of edema and neovascularization.
  • OCT optical coherence tomography
  • Example 102 Cell data against for selected compounds against various cancer cell lines

Abstract

L'invention concerne des composés de thiazolidinone, et des procédés de préparation et d'utilisation de ceux-ci. De tels composés peuvent être utilisés dans des troubles inflammatoires ou véhiculés par l'immunité. L'invention concerne le traitement de troubles respiratoires ou oculaires, le traitement de l'arthrite, ou peut être utilisée pour traiter le cancer, tel que le cancer de la prostate ou du sein, ou un myélome multiple.
PCT/US2008/073683 2007-08-20 2008-08-20 Composés de thiazolidinone et procédés de préparation et d'utilisation de ceux-ci WO2009026345A1 (fr)

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US95683107P 2007-08-20 2007-08-20
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US2078608P 2008-01-14 2008-01-14
US61/020,786 2008-01-14
US2221708P 2008-01-18 2008-01-18
US61/022,217 2008-01-18
US5142408P 2008-05-08 2008-05-08
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WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
US8372971B2 (en) 2004-08-25 2013-02-12 Targegen, Inc. Heterocyclic compounds and methods of use
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US8481536B2 (en) 2004-04-08 2013-07-09 Targegen, Inc. Benzotriazine inhibitors of kinases
WO2014068070A1 (fr) 2012-10-31 2014-05-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés pour prévenir le syndrome des antiphospholipides (sapl)
WO2016059220A1 (fr) 2014-10-16 2016-04-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Agents d'activation du tcr à utiliser dans le traitement de la lla-t

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ES2766751T3 (es) 2012-04-20 2020-06-15 Gb006 Inc Composiciones para la regulación de integrinas

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WO2007030360A2 (fr) * 2005-09-07 2007-03-15 Laboratoires Serono S.A. Inhibiteurs pi3k utiles dans le traitement de l'endometriose

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US20040138199A1 (en) * 2002-12-20 2004-07-15 Gogliotti Rocco Dean Benzoxazines and derivatives thereof as therapeutic agents
WO2007030360A2 (fr) * 2005-09-07 2007-03-15 Laboratoires Serono S.A. Inhibiteurs pi3k utiles dans le traitement de l'endometriose

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8481536B2 (en) 2004-04-08 2013-07-09 Targegen, Inc. Benzotriazine inhibitors of kinases
US8372971B2 (en) 2004-08-25 2013-02-12 Targegen, Inc. Heterocyclic compounds and methods of use
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014068070A1 (fr) 2012-10-31 2014-05-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés pour prévenir le syndrome des antiphospholipides (sapl)
WO2016059220A1 (fr) 2014-10-16 2016-04-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Agents d'activation du tcr à utiliser dans le traitement de la lla-t

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