US20110212961A1 - Pyrazole Derivatives as Kinase Inhibitors - Google Patents

Pyrazole Derivatives as Kinase Inhibitors Download PDF

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US20110212961A1
US20110212961A1 US13/103,811 US201113103811A US2011212961A1 US 20110212961 A1 US20110212961 A1 US 20110212961A1 US 201113103811 A US201113103811 A US 201113103811A US 2011212961 A1 US2011212961 A1 US 2011212961A1
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Maurizio Pellecchia
Surya De
Elisa Barile
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Sanford Burnham Prebys Medical Discovery Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates generally to compounds useful for the inhibition of kinases, and more specifically, to new pyrazole derivatives, including those comprising pyridine or pyrimidine moieties, that are useful as kinase inhibitors.
  • Inhibiting kinases such as PI3K and mTOR
  • PI3K and mTOR is one method of treating various diseases, disorders and pathologies.
  • some compounds that can be useful as inhibitors of certain kinases have been identified and synthesized.
  • no compounds have been reported that are capable of targeting and inhibiting kinases PI3 K-AKT-mTOR signaling pathway.
  • agents for the treatment of various diseases, disorders and pathologies, such as tumors, as well as for the pharmaceutical compositions including such agents.
  • Such agents can be based on inhibitors of kinases PI3 K-AKT-mTOR signaling pathway.
  • X is a six-member ring selected from the group consisting of an unsubstituted phenyl, a substituted phenyl, an unsubstituted pyridine, a substituted pyridine, an unsubstituted pyrimidine and a substituted pyrimidine;
  • Y is selected from the group consisting of H, an unsubstituted alkenyl, a substituted alkenyl, an unsubstituted alkynyl and a substituted alkynyl; and R is selected from the group consisting of H, an unsubstituted alkyl and a substituted alkyl.
  • R 1 is selected from a group consisting of a substituted alkenyl and a substituted alkynyl, wherein the substitutent(s) in each of the substituted alkenyl and the substituted alkynyl is(are) selected from the group consisting of an aryl, a substituted aryl, a heteroaryl, and a substituted heteroaryl;
  • R 2 is selected from a group consisting of a halogen, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted alkyl, a substituted alkyl, and (CH 2 ) n OR 6 ;
  • R 3 is selected from a group consisting of H, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted alkyl, and a substituted
  • compounds having the general structure IIIA or IIIB:
  • R 8 is selected from a group consisting of an unsubstituted aryl and a substituted aryl; each of R 9 , R 10 , R 11 , and R 12 is selected from a group consisting of an unsubstituted alkyl, a substituted alkyl, an acyl, an unsubstituted aryl, a substituted aryl, and a halogen; and Z is selected from a group consisting of C, O, and N.
  • compositions for the treatment of various disorders, diseases, and pathologies, such as cancer, the compositions comprising a compound having the general structure II, IIIA or IIIB, and a pharmaceutically acceptable carrier.
  • methods for the treatment of various disorders, diseases, and pathologies, such as cancer comprising administering to a subject in need thereof a pharmacologically effective dose of a pharmaceutical composition comprising a compound having the general structure II, IIIA or IIIB.
  • FIG. 1 shows the data on inhibition of PC3 cell proliferation by some compounds of the present invention, according to one embodiment of the present invention.
  • FIG. 2 shows the data on inhibition of U87 spheroid cell growth by some compounds of the present invention, according to one embodiment of the present invention.
  • FIG. 3 shows the data on inhibition of target kinase activities in U87 spheroid cell by some compounds of the present invention, according to one embodiment of the present invention.
  • FIG. 4 shows the data on inhibition of PC3 cell proliferation by some compounds of the present invention, according to another embodiment of the present invention.
  • FIG. 5 shows the data on inhibition of U87 spheroid cell growth by some compounds of the present invention, according to another embodiment of the present invention.
  • FIG. 6 shows the data on inhibition of target kinase activities in U87 spheroid cell by some compounds of the present invention, according to another embodiment of the present invention.
  • FIG. 7 shows the PI3K assay data, including compound 1 of the invention.
  • alkyl and “substituted alkyl” refer to substituted and unsubstituted C 1 -C 10 straight chain saturated aliphatic hydrocarbon groups, substituted and unsubstituted C 2 -C 10 straight chain unsaturated aliphatic hydrocarbon groups, substituted and unsubstituted C 4 -C 10 branched saturated aliphatic hydrocarbon groups, substituted and unsubstituted C 4 -C 10 branched unsaturated aliphatic hydrocarbon groups, substituted and unsubstituted C 3 -C 8 cyclic saturated aliphatic hydrocarbon groups, substituted and unsubstituted C 5 -C 8 cyclic unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • alkyl shall include but is not limited to: methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, ethenyl, propenyl, butenyl, penentyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, isopropyl (i-Pr), isobutyl (i-Bu), tert-butyl (t-Bu), sec-butyl (s-Bu), isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl,
  • Alkyl substituents are independently selected from a group consisting of halogen, —OH, —SH, —NH 2 , —CN, —NO 2 , ⁇ O, ⁇ CH 2 , trihalomethyl, carbamoyl, arylC 0-10 alkyl, heteroarylC 0-10 alkyl, C 1-10 alkyloxy, arylC 0-10 alkyloxy, arylC 1-10 alkylthio, arylC 0-10 alkylthio, C 1-10 alkylamino, arylC 0-10 alkylamino, N-aryl-N—C 0-10 alkylamino, C 1-10 alkylcarbonyl, arylC 0-10 alkylcarbonyl, C 1-10 alkylcarboxy, arylC 0-10 alkylcarboxy, C 1-10 alkylcarbonylamino, arylC 0-10 alkylcarbonylamino, tetrahydrofu
  • alkenyl refers to straight-chained or branched hydrocarbyl groups having at least one carbon-carbon double bond, and having between about 2 and about 12 carbon atoms
  • substituted alkenyl refers to alkenyl groups further bearing one or more substitutents described above
  • alkynyl refers to straight-chained or branched hydrocarbyl groups having at least one carbon-carbon triple bond, and having between about 2 and about 12 carbon atoms
  • substituted alkynyl refers to alkynyl groups further bearing one or more substitutents described above.
  • aryl refers to an unsubstituted, monosubstituted, disubstituted or trisubstituted monocyclic, polycyclic, biaryl aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e.g., 3-phenyl, 4-naphtyl and the like).
  • the aryl substituents are independently selected from a group consisting of halogen, —OH, —SH, —CN, —NO 2 , trihalomethyl, hydroxypyronyl, C 1-10 alkyl, arylC 0-10 alkyl, C 0-10 alkyloxyC 0-10 alkyl, arylC 0-10 alkyloxyC 0-10 alkyl, C 0-10 alkylthioC 0-10 alkyl, arylC 0-10 alkylthioC 0-10 alkyl, C 0-10 alkylaminoC 0-10 alkyl, arylC 0-10 alkylaminoC 0-10 alkyl, N-aryl-N—C 0-10 alkylaminoC 0-10 alkyl, C 1-10 alkylcarbonylC 0-10 alkyl, arylC 0-10 alkylcarbonylC 0-10 alkyl, C 1-10 alkylcarboxyC 0-10 al
  • aryl includes, but is not limited to, such specific groups as phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl and the like.
  • heteroaryl refers to a monovalent unsaturated group having a single ring or multiple condensed (also known as “fused”) rings, from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring.
  • heteroaryl groups in this invention can be optionally substituted with 1 to 3 substituents selected from a group consisting of: halogen, —OH, —SH, —CN, —NO 2 , trihalomethyl, hydroxypyronyl, C 1-10 alkyl, arylC 0-10 alkyl, C 0-10 alkyloxyC 0-10 alkyl, arylC 0-10 alkyloxyC 0-10 alkyl, C 0-10 alkylthioC 0-10 alkyl, arylC 0-10 alkylaminoC 0-10 alkyl, C 0-10 alkylaminoC 0-10 alkyl, arylC 0-10 alkylaminoC 0-10 alkyl, N-aryl-N—C 0-10 alkylaminoC 1-10 alkyl, C 1-10 alkylcarbonylC 0-10 alkyl, arylC 0-10 alkylcarbonylC 0-10 alkyl, C 1-10
  • heteroaryl includes, but is not limited to, such specific groups as thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl, pyrrolyl-2,5-dione, 3-pyrrolinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, indolizinyl, indazolyl, phthalimidyl (or isoindoly-1,3-dione), imidazolyl, 2H-imidazolinyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4
  • acyl refers to a radical —R—C( ⁇ O)—, i.e., to a radical derived from an organic acid by the removal of the carboxylic hydroxyl group.
  • Typical examples of acyl groups include acetyl and benzoyl moieties.
  • halogen refers to fluorine, chlorine, bromine, and iodine.
  • kinase refers to any enzyme that catalyzes the addition of phosphate groups to a protein residue; for example, serine and threonine kinases catalyze the addition of phosphate groups to serine and threonine residues.
  • an effective amount of a compound refers a non-toxic but sufficient amount of the compound that provides a desired effect. This amount may vary from subject to subject, depending on the species, age, and physical condition of the subject, the severity of the disease that is being treated, the particular compound used, its mode of administration, and the like. Therefore, it is difficult to generalize an exact “effective amount,” yet, a suitable effective amount may be determined by one of ordinary skill in the art.
  • pharmaceutically acceptable refers to a compound, additive or composition that is not biologically or otherwise undesirable.
  • the additive or composition may be administered to a subject along with a compound of the invention without causing any undesirable biological effects or interacting in an undesirable manner with any of the other components of the pharmaceutical composition in which it is contained.
  • salts includes hydrochloric salt, hydrobromic salt, hydroiodic salt, hydrofluoric salt, sulfuric salt, citric salt, maleic salt, acetic salt, lactic salt, nicotinic salt, succinic salt, oxalic salt, phosphoric salt, malonic salt, salicylic salt, phenylacetic salt, stearic salt, pyridine salt, ammonium salt, piperazine salt, diethylamine salt, nicotinamide salt, formic salt, urea salt, sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, lithium salt, cinnamic salt, methylamino salt, methanesulfonic salt, picric salt, tartaric salt, triethylamino salt, dimethylamino salt, tris(hydroxymethyl)aminomethane salt and the like. Additional pharmaceutically acceptable salts are known to those of skill in the art.
  • the term “patient” refers to organisms to be treated by the methods of the present invention. Such organisms include, but are not limited to, humans.
  • the term “subject” generally refers to an individual who will receive or who has received treatment for the treatment of a disease, disorder or pathology.
  • X is a six-member ring selected from the group consisting of an unsubstituted phenyl, a substituted phenyl, an unsubstituted pyridine, a substituted pyridine, an unsubstituted pyrimidine and a substituted pyrimidine;
  • Y is selected from the group consisting of H, an unsubstituted alkenyl, a substituted alkenyl, an unsubstituted alkynyl and a substituted alkynyl; and R is selected from the group consisting of H, an unsubstituted alkyl and a substituted alkyl.
  • the compounds of the general structure I may be derivatives of indazole, which are described in more detail below.
  • X may be an unsubstituted or substituted phenyl having at least one substitutent independently selected from the group consisting of an amino group, a substituted amido group, nitro group, an ester group, carboxyl group, and morpholino group.
  • the compounds of the general structure I may be derivatives of pyrazolopyridine, which are described in more detail below.
  • X may be an unsubstituted or substituted pyridine.
  • the compounds of the general structure I may be derivatives of pyrazolopyrimidine, which are described in more detail below.
  • X may be a substituted pyrimidine having at least one substitutent independently selected from the group consisting of a substituted amino group, morpholino group, piperazino group, and piperidino group.
  • Examples of some sub-genera that are within the purview of the present invention and are described by the general structure I include the structures where X is a moiety derived from substituted pyridine, such as compounds having the general structure II:
  • R 1 is selected from a group consisting of a substituted alkenyl and a substituted alkynyl, wherein the substitutent(s) in each of the substituted alkenyl and the substituted alkynyl is(are) selected from the group consisting of an aryl, a substituted aryl, a heteroaryl, and a substituted heteroaryl;
  • R 2 is selected from a group consisting of a halogen, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted alkyl, a substituted alkyl, and (CH 2 ) n OR 6 ;
  • R 3 is selected from a group consisting of H, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted alkyl, and a substituted
  • Examples of some other sub-genera that are within the purview of the present invention and are described by the general structure I include the structures, where X is a moiety derived from substituted pyrimidine, such as compounds having the general IIIA or IIIB:
  • R 8 is selected from a group consisting of an unsubstituted aryl and a substituted aryl; each of R 9 , R 10 , R 11 , and R 12 is selected from a group consisting of an unsubstituted alkyl, a substituted alkyl, an acyl, an unsubstituted aryl, a substituted aryl, and a halogen; and Z is selected from a group consisting of C, O, and N.
  • Non-limiting examples of some specific compounds that are within the purview of the present invention include the compounds 1-37:
  • the compounds of the present invention are capable of inhibiting kinase, for example, by selectively targeting at the kinases PI3 K-AKT-mTOR signal transduction pathway, for the treatment of various disorders, diseases, and pathologies, such as cancer.
  • the compounds having the structure I, including sub-genera II, IIIA and IIIB, or pharmaceutically acceptable salts thereof can be used for preparing pharmaceutical compositions, e.g., by combining these compounds and pharmaceutically acceptable carriers.
  • the pharmaceutical compositions can then be used in pharmacologically effective doses for the treatment of various disorders, diseases, and pathologies, such as cancer.
  • reaction schemes A and B Two such schemes, as applicable to compounds of the sub-genera II and IIIA are shown below as reaction schemes A and B, respectively.
  • salts of the compounds of the present invention may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the above-described compounds I, including the sub-genera II, IIIA and IIIB can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Useful dosages of the compounds I, including the sub-genera II, IIIA and IIIB can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to those having ordinary skill in the art who can, for example, be guided by the procedures described in U.S. Pat. No. 4,938,949.
  • the concentration of the compound(s) I, including the sub-genera II, IIIA and IIIB in a liquid composition, such as a lotion can be between about 0.1 and 25 mass %, such as between about 0.5 and 10 mass %.
  • concentration in a semi-solid or solid composition such as a gel or a powder can be between about 0.1 and 25 mass %, such as between about 0.5 and 2.5 mass %.
  • the amount of the compound(s) I, including the sub-genera II, IIIA and IIIB, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • a suitable dose can be in the range of between about 0.5 and 100 mg/kg, e.g., between about 10 and 75 mg/kg of body weight per day, such as between about 15 and 60 mg/kg/day.
  • the compound(s) I, including the sub-genera II, IIIA and IIIB can be conveniently administered in unit dosage form; for example, containing 5 to 1000 mg, such as 10 to 750 mg, for example, 50 to 500 mg of active ingredient per unit dosage form.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • FIGS. 1-7 further exemplify embodiments of the present invention, which are intended to further illustrate but not limit the invention.
  • FIG. 1 illustrates inhibition of PC3 cell proliferation by pyrazolopyridines (the above shown compounds of the sub-genera II).
  • FIG. 4 illustrates inhibition of PC3 cell proliferation by amininopyrimidines (the above shown compounds of the sub-genera IIIA). As can be seen from FIGS. 1 and 4 , a substantial degree of inhibition has been achieved.
  • FIG. 2 illustrates inhibition of U87 spheroid cell growth by pyrazolopyridines (the above shown compounds of the sub-genera II).
  • FIG. 5 illustrates inhibition of U87 spheroid cell growth by amininopyrimidines (the above shown compounds of the sub-genera IIIA).
  • FIG. 3 shows the data on inhibition of target kinase activities in U87 spheroid cell by pyrazolopyridines (the above shown compounds of the sub-genera II), while FIG. 6 shows the same for amininopyrimidines (the above shown compounds of the sub-genera IIIA).
  • Table 1 below provides shows the data on inhibition of PI3K and mTOR kinases by some compounds of the invention.

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Abstract

The present invention provides compounds having the general structure I, or a pharmaceutically acceptable salt thereof:
Figure US20110212961A1-20110901-C00001
wherein X is a six-member ring selected from phenyl, pyridine, or pyrimidine; Y is H, an alkenyl, a substituted alkenyl, or alkynyl, and R is H or alkyl. Pharmaceutical compositions for treating various disorders such as cancers, the compositions including compound I are also provided.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a divisional application of U.S. application Ser. No. 12/261,584 filed Oct. 30, 2008, now pending; which claims the benefit under 35 USC §119(e) to U.S. Application Ser. No. 60/984,302 filed Oct. 31, 2007, now expired. The disclosure of each of the prior applications is considered part of and is incorporated by reference in the disclosure of this application.
    • BACKGROUND OF THE INVENTION
  • 1. Field of the Invention
  • The invention relates generally to compounds useful for the inhibition of kinases, and more specifically, to new pyrazole derivatives, including those comprising pyridine or pyrimidine moieties, that are useful as kinase inhibitors.
  • 2. Background Information
  • Inhibiting kinases, such as PI3K and mTOR, is one method of treating various diseases, disorders and pathologies. Previously, some compounds that can be useful as inhibitors of certain kinases have been identified and synthesized. However, no compounds have been reported that are capable of targeting and inhibiting kinases PI3 K-AKT-mTOR signaling pathway.
    • SUMMARY OF THE INVENTION
  • Currently, there is a need for novel, potent, and selective agents for the treatment of various diseases, disorders and pathologies, such as tumors, as well as for the pharmaceutical compositions including such agents. Such agents can be based on inhibitors of kinases PI3 K-AKT-mTOR signaling pathway.
  • According to embodiments of the present invention, there are provided compounds having the general structure I, or pharmaceutically acceptable salts thereof:
  • Figure US20110212961A1-20110901-C00002
  • wherein X is a six-member ring selected from the group consisting of an unsubstituted phenyl, a substituted phenyl, an unsubstituted pyridine, a substituted pyridine, an unsubstituted pyrimidine and a substituted pyrimidine; Y is selected from the group consisting of H, an unsubstituted alkenyl, a substituted alkenyl, an unsubstituted alkynyl and a substituted alkynyl; and R is selected from the group consisting of H, an unsubstituted alkyl and a substituted alkyl.
  • According to one embodiment of the present invention, compounds are provided having the general structure II:
  • Figure US20110212961A1-20110901-C00003
  • wherein R1 is selected from a group consisting of a substituted alkenyl and a substituted alkynyl, wherein the substitutent(s) in each of the substituted alkenyl and the substituted alkynyl is(are) selected from the group consisting of an aryl, a substituted aryl, a heteroaryl, and a substituted heteroaryl; R2 is selected from a group consisting of a halogen, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted alkyl, a substituted alkyl, and (CH2)nOR6; R3 is selected from a group consisting of H, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted alkyl, and a substituted alkyl; R4 is selected from a group consisting of OH and OR7; each of R5, R6 and R7 is independently selected from a group consisting of an unsubstituted alkyl and a substituted alkyl; and n is an integer having the value of 1, 2, or 3.
  • According to embodiments of the present invention, compounds are provided having the general structure IIIA or IIIB:
  • Figure US20110212961A1-20110901-C00004
  • wherein R8 is selected from a group consisting of an unsubstituted aryl and a substituted aryl; each of R9, R10, R11, and R12 is selected from a group consisting of an unsubstituted alkyl, a substituted alkyl, an acyl, an unsubstituted aryl, a substituted aryl, and a halogen; and Z is selected from a group consisting of C, O, and N.
  • According to other embodiments of the present invention, pharmaceutical compositions are provided for the treatment of various disorders, diseases, and pathologies, such as cancer, the compositions comprising a compound having the general structure II, IIIA or IIIB, and a pharmaceutically acceptable carrier.
  • According to other embodiments of the present invention, methods for the treatment of various disorders, diseases, and pathologies, such as cancer, are provided, the methods comprising administering to a subject in need thereof a pharmacologically effective dose of a pharmaceutical composition comprising a compound having the general structure II, IIIA or IIIB.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 shows the data on inhibition of PC3 cell proliferation by some compounds of the present invention, according to one embodiment of the present invention.
  • FIG. 2 shows the data on inhibition of U87 spheroid cell growth by some compounds of the present invention, according to one embodiment of the present invention.
  • FIG. 3 shows the data on inhibition of target kinase activities in U87 spheroid cell by some compounds of the present invention, according to one embodiment of the present invention.
  • FIG. 4 shows the data on inhibition of PC3 cell proliferation by some compounds of the present invention, according to another embodiment of the present invention.
  • FIG. 5 shows the data on inhibition of U87 spheroid cell growth by some compounds of the present invention, according to another embodiment of the present invention.
  • FIG. 6 shows the data on inhibition of target kinase activities in U87 spheroid cell by some compounds of the present invention, according to another embodiment of the present invention.
  • FIG. 7 shows the PI3K assay data, including compound 1 of the invention.
    •  DETAILED DESCRIPTION OF THE INVENTION
  • The following definitions are used, unless otherwise described.
  • The terms “alkyl” and “substituted alkyl” refer to substituted and unsubstituted C1-C10 straight chain saturated aliphatic hydrocarbon groups, substituted and unsubstituted C2-C10 straight chain unsaturated aliphatic hydrocarbon groups, substituted and unsubstituted C4-C10 branched saturated aliphatic hydrocarbon groups, substituted and unsubstituted C4-C10 branched unsaturated aliphatic hydrocarbon groups, substituted and unsubstituted C3-C8 cyclic saturated aliphatic hydrocarbon groups, substituted and unsubstituted C5-C8 cyclic unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of “alkyl” shall include but is not limited to: methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, ethenyl, propenyl, butenyl, penentyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, isopropyl (i-Pr), isobutyl (i-Bu), tert-butyl (t-Bu), sec-butyl (s-Bu), isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, methylcyclopropyl, ethylcyclohexenyl, butenylcyclopentyl, adamantyl, norbornyl and the like. Alkyl substituents are independently selected from a group consisting of halogen, —OH, —SH, —NH2, —CN, —NO2, ═O, ═CH2, trihalomethyl, carbamoyl, arylC0-10alkyl, heteroarylC0-10alkyl, C1-10alkyloxy, arylC0-10alkyloxy, arylC1-10alkylthio, arylC0-10alkylthio, C1-10alkylamino, arylC0-10alkylamino, N-aryl-N—C0-10alkylamino, C1-10alkylcarbonyl, arylC0-10alkylcarbonyl, C1-10alkylcarboxy, arylC0-10alkylcarboxy, C1-10alkylcarbonylamino, arylC0-10alkylcarbonylamino, tetrahydrofuryl, morpholinyl, piperazinyl, hydroxypyronyl, —C0-10alkylCOORa and —C0-10alkylCONRbRc, wherein Ra, Rb and Rc are independently selected from hydrogen, alkyl, aryl, or Rb and Rc are taken together with the nitrogen to which they are attached forming a saturated cyclic or unsaturated cyclic system containing 3 to 8 carbon atoms, with at least one substituent.
  • The term “alkenyl” refers to straight-chained or branched hydrocarbyl groups having at least one carbon-carbon double bond, and having between about 2 and about 12 carbon atoms, and the term “substituted alkenyl” refers to alkenyl groups further bearing one or more substitutents described above. The term “alkynyl” refers to straight-chained or branched hydrocarbyl groups having at least one carbon-carbon triple bond, and having between about 2 and about 12 carbon atoms, and the term “substituted alkynyl” refers to alkynyl groups further bearing one or more substitutents described above.
  • The term “aryl” refers to an unsubstituted, monosubstituted, disubstituted or trisubstituted monocyclic, polycyclic, biaryl aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e.g., 3-phenyl, 4-naphtyl and the like). The aryl substituents are independently selected from a group consisting of halogen, —OH, —SH, —CN, —NO2, trihalomethyl, hydroxypyronyl, C1-10alkyl, arylC0-10alkyl, C0-10alkyloxyC0-10alkyl, arylC0-10alkyloxyC0-10alkyl, C0-10alkylthioC0-10alkyl, arylC0-10alkylthioC0-10alkyl, C0-10alkylaminoC0-10alkyl, arylC0-10alkylaminoC0-10alkyl, N-aryl-N—C0-10alkylaminoC0-10alkyl, C1-10alkylcarbonylC0-10alkyl, arylC0-10alkylcarbonylC0-10alkyl, C1-10alkylcarboxyC0-10alkyl, arylC0-10alkylcarboxyC0-10alkyl, C1-10alkylcarbonylaminoC0-10alkyl, arylC0-10alkylcarbonylaminoC0-10alkyl, —C0-10alkylCOORa, and —C0-10alkylCONRbRc, wherein Ra, Rb and Rc, are independently selected from hydrogen, alkyl, aryl or Rb and Rc, are taken together with the nitrogen to which they are attached forming a saturated cyclic or unsaturated cyclic system containing 3 to 8 carbon atoms with at least one substituent.
  • The definition of “aryl” includes, but is not limited to, such specific groups as phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl and the like.
  • The terms “heteroaryl”, “heterocycle” or “heterocyclic” refer to a monovalent unsaturated group having a single ring or multiple condensed (also known as “fused”) rings, from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring. The heteroaryl groups in this invention can be optionally substituted with 1 to 3 substituents selected from a group consisting of: halogen, —OH, —SH, —CN, —NO2, trihalomethyl, hydroxypyronyl, C1-10alkyl, arylC0-10alkyl, C0-10alkyloxyC0-10alkyl, arylC0-10alkyloxyC0-10alkyl, C0-10alkylthioC0-10alkyl, arylC0-10alkylaminoC0-10alkyl, C0-10alkylaminoC0-10alkyl, arylC0-10alkylaminoC0-10alkyl, N-aryl-N—C0-10alkylaminoC1-10alkyl, C1-10alkylcarbonylC0-10alkyl, arylC0-10alkylcarbonylC0-10alkyl, C1-10alkylcarboxyC0-10alkyl, arylC0-10alkylcarboxyC0-10alkyl, C1-10alkylcarbonylaminoC0-10alkyl, aryl-C0-10alkylcarbonylaminoC0-10alkyl, —C0-10alkylCOORa, and —C0-10alkylCONRbRc wherein Ra, Rb and Rc, are independently selected from hydrogen, alkyl, aryl, or Rb and Rc, are taken together with the nitrogen to which they are attached forming a saturated cyclic or unsaturated cyclic system containing 3 to 8 carbon atoms with at least one substituent.
  • The definition of “heteroaryl” includes, but is not limited to, such specific groups as thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl, pyrrolyl-2,5-dione, 3-pyrrolinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, indolizinyl, indazolyl, phthalimidyl (or isoindoly-1,3-dione), imidazolyl, 2H-imidazolinyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolidinyl-2,5-dione, imidazolidinyl-2,4-dione, 2-thioxo-imidazolidinyl-4-one, imidazolidinyl-2,4-dithione, thiazolidinyl-2,4-dione, 4-thioxo-thiazolidinyl-2-one, piperazinyl-2,5-dione, tetrahydro-pyridazinyl-3,6-dione, 1,2-dihydro-[1,2,4,5]tetrazinyl-3,6-dione, [1,2,4,5]tetrazinanyl-3,6-dione, dihydro-pyrimidinyl-2,4-dione, pyrimidinyl-2,4,6-trione and the like.
  • The term “acyl” refers to a radical —R—C(═O)—, i.e., to a radical derived from an organic acid by the removal of the carboxylic hydroxyl group. Typical examples of acyl groups include acetyl and benzoyl moieties.
  • The terms “halogen”, “halide” or “halo” refer to fluorine, chlorine, bromine, and iodine.
  • The term “kinase” refers to any enzyme that catalyzes the addition of phosphate groups to a protein residue; for example, serine and threonine kinases catalyze the addition of phosphate groups to serine and threonine residues.
  • The term “effective amount” of a compound refers a non-toxic but sufficient amount of the compound that provides a desired effect. This amount may vary from subject to subject, depending on the species, age, and physical condition of the subject, the severity of the disease that is being treated, the particular compound used, its mode of administration, and the like. Therefore, it is difficult to generalize an exact “effective amount,” yet, a suitable effective amount may be determined by one of ordinary skill in the art.
  • The term “pharmaceutically acceptable” refers to a compound, additive or composition that is not biologically or otherwise undesirable. For example, the additive or composition may be administered to a subject along with a compound of the invention without causing any undesirable biological effects or interacting in an undesirable manner with any of the other components of the pharmaceutical composition in which it is contained.
  • The term “pharmaceutically acceptable salts” includes hydrochloric salt, hydrobromic salt, hydroiodic salt, hydrofluoric salt, sulfuric salt, citric salt, maleic salt, acetic salt, lactic salt, nicotinic salt, succinic salt, oxalic salt, phosphoric salt, malonic salt, salicylic salt, phenylacetic salt, stearic salt, pyridine salt, ammonium salt, piperazine salt, diethylamine salt, nicotinamide salt, formic salt, urea salt, sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, lithium salt, cinnamic salt, methylamino salt, methanesulfonic salt, picric salt, tartaric salt, triethylamino salt, dimethylamino salt, tris(hydroxymethyl)aminomethane salt and the like. Additional pharmaceutically acceptable salts are known to those of skill in the art.
  • As used herein, the term “patient” refers to organisms to be treated by the methods of the present invention. Such organisms include, but are not limited to, humans. In the context of the invention, the term “subject” generally refers to an individual who will receive or who has received treatment for the treatment of a disease, disorder or pathology.
  • According to embodiments of the present invention, there are provided compounds having the general structure I, or pharmaceutically acceptable salts thereof:
  • Figure US20110212961A1-20110901-C00005
  • In the general structure I, X is a six-member ring selected from the group consisting of an unsubstituted phenyl, a substituted phenyl, an unsubstituted pyridine, a substituted pyridine, an unsubstituted pyrimidine and a substituted pyrimidine; Y is selected from the group consisting of H, an unsubstituted alkenyl, a substituted alkenyl, an unsubstituted alkynyl and a substituted alkynyl; and R is selected from the group consisting of H, an unsubstituted alkyl and a substituted alkyl.
  • In some embodiments, the compounds of the general structure I may be derivatives of indazole, which are described in more detail below. For these embodiments, accordingly, in the general structure I, X may be an unsubstituted or substituted phenyl having at least one substitutent independently selected from the group consisting of an amino group, a substituted amido group, nitro group, an ester group, carboxyl group, and morpholino group.
  • In other embodiments, the compounds of the general structure I may be derivatives of pyrazolopyridine, which are described in more detail below. For these embodiments, accordingly, in the general structure I, X may be an unsubstituted or substituted pyridine. In yet other embodiments, the compounds of the general structure I may be derivatives of pyrazolopyrimidine, which are described in more detail below. For these embodiments, accordingly, in the general structure I, X may be a substituted pyrimidine having at least one substitutent independently selected from the group consisting of a substituted amino group, morpholino group, piperazino group, and piperidino group.
  • Examples of some sub-genera that are within the purview of the present invention and are described by the general structure I include the structures where X is a moiety derived from substituted pyridine, such as compounds having the general structure II:
  • Figure US20110212961A1-20110901-C00006
  • In the general structure II, R1 is selected from a group consisting of a substituted alkenyl and a substituted alkynyl, wherein the substitutent(s) in each of the substituted alkenyl and the substituted alkynyl is(are) selected from the group consisting of an aryl, a substituted aryl, a heteroaryl, and a substituted heteroaryl; R2 is selected from a group consisting of a halogen, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted alkyl, a substituted alkyl, and (CH2)nOR6; R3 is selected from a group consisting of H, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted alkyl, and a substituted alkyl; R4 is selected from a group consisting of OH and OR7; each of R5, R6 and R7 is independently selected from a group consisting of an unsubstituted alkyl and a substituted alkyl; and n is an integer having the value of 1, 2, or 3.
  • Examples of some other sub-genera that are within the purview of the present invention and are described by the general structure I include the structures, where X is a moiety derived from substituted pyrimidine, such as compounds having the general IIIA or IIIB:
  • Figure US20110212961A1-20110901-C00007
  • In the general structures IIIA and IIIB, R8 is selected from a group consisting of an unsubstituted aryl and a substituted aryl; each of R9, R10, R11, and R12 is selected from a group consisting of an unsubstituted alkyl, a substituted alkyl, an acyl, an unsubstituted aryl, a substituted aryl, and a halogen; and Z is selected from a group consisting of C, O, and N.
  • Non-limiting examples of some specific compounds that are within the purview of the present invention include the compounds 1-37:
  • Figure US20110212961A1-20110901-C00008
    Figure US20110212961A1-20110901-C00009
    Figure US20110212961A1-20110901-C00010
    Figure US20110212961A1-20110901-C00011
    Figure US20110212961A1-20110901-C00012
    Figure US20110212961A1-20110901-C00013
    Figure US20110212961A1-20110901-C00014
    Figure US20110212961A1-20110901-C00015
    Figure US20110212961A1-20110901-C00016
    Figure US20110212961A1-20110901-C00017
  • The compounds of the present invention are capable of inhibiting kinase, for example, by selectively targeting at the kinases PI3 K-AKT-mTOR signal transduction pathway, for the treatment of various disorders, diseases, and pathologies, such as cancer. Accordingly, the compounds having the structure I, including sub-genera II, IIIA and IIIB, or pharmaceutically acceptable salts thereof can be used for preparing pharmaceutical compositions, e.g., by combining these compounds and pharmaceutically acceptable carriers. The pharmaceutical compositions can then be used in pharmacologically effective doses for the treatment of various disorders, diseases, and pathologies, such as cancer.
  • Various synthetic schemes can be designed for manufacturing the products having the structure I, including the sub-genera II, IIIA and IIIB. Two such schemes, as applicable to compounds of the sub-genera II and IIIA are shown below as reaction schemes A and B, respectively.
  • Figure US20110212961A1-20110901-C00018
  • Pharmaceutically acceptable salts of the compounds of the present invention may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • The above-described compounds I, including the sub-genera II, IIIA and IIIB can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.
  • The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders, for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Useful dosages of the compounds I, including the sub-genera II, IIIA and IIIB can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to those having ordinary skill in the art who can, for example, be guided by the procedures described in U.S. Pat. No. 4,938,949.
  • Generally, the concentration of the compound(s) I, including the sub-genera II, IIIA and IIIB in a liquid composition, such as a lotion, can be between about 0.1 and 25 mass %, such as between about 0.5 and 10 mass %. The concentration in a semi-solid or solid composition such as a gel or a powder can be between about 0.1 and 25 mass %, such as between about 0.5 and 2.5 mass %.
  • The amount of the compound(s) I, including the sub-genera II, IIIA and IIIB, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • In general, however, a suitable dose can be in the range of between about 0.5 and 100 mg/kg, e.g., between about 10 and 75 mg/kg of body weight per day, such as between about 15 and 60 mg/kg/day. The compound(s) I, including the sub-genera II, IIIA and IIIB can be conveniently administered in unit dosage form; for example, containing 5 to 1000 mg, such as 10 to 750 mg, for example, 50 to 500 mg of active ingredient per unit dosage form. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • FIGS. 1-7 further exemplify embodiments of the present invention, which are intended to further illustrate but not limit the invention. FIG. 1 illustrates inhibition of PC3 cell proliferation by pyrazolopyridines (the above shown compounds of the sub-genera II). FIG. 4 illustrates inhibition of PC3 cell proliferation by amininopyrimidines (the above shown compounds of the sub-genera IIIA). As can be seen from FIGS. 1 and 4, a substantial degree of inhibition has been achieved.
  • FIG. 2 illustrates inhibition of U87 spheroid cell growth by pyrazolopyridines (the above shown compounds of the sub-genera II). FIG. 5 illustrates inhibition of U87 spheroid cell growth by amininopyrimidines (the above shown compounds of the sub-genera IIIA).
  • Finally, FIG. 3 shows the data on inhibition of target kinase activities in U87 spheroid cell by pyrazolopyridines (the above shown compounds of the sub-genera II), while FIG. 6 shows the same for amininopyrimidines (the above shown compounds of the sub-genera IIIA). These figures provide additional information as to the effectiveness of inhibition using compounds of the present invention.
  • Table 1 below provides shows the data on inhibition of PI3K and mTOR kinases by some compounds of the invention.
  • TABLE 1
    Assay results on Inhibition PI3K and mTOR
    by Compounds of the Invention
    PI3 K
    (% at
    25 μM, mTOR
    or (Inhibition
    IC50), % at 50
    P110α, μM, or
    Structure μM IC50)
    Figure US20110212961A1-20110901-C00019
         		0.083  9%
    Figure US20110212961A1-20110901-C00020
         		 6%
    Figure US20110212961A1-20110901-C00021
         		 6%
    Figure US20110212961A1-20110901-C00022
         		0.075 34%
    Figure US20110212961A1-20110901-C00023
         		0.299 30% (IC50 > 100 uM)
    Figure US20110212961A1-20110901-C00024
         		0.062 46% (IC50 > 100 uM)
    Figure US20110212961A1-20110901-C00025
         		−1%
    Figure US20110212961A1-20110901-C00026
         		 5%
    Figure US20110212961A1-20110901-C00027
         		−3%
    Figure US20110212961A1-20110901-C00028
         		 7%
    Figure US20110212961A1-20110901-C00029
         		13%
    Figure US20110212961A1-20110901-C00030
         		 4%
    Figure US20110212961A1-20110901-C00031
         		24%
    Figure US20110212961A1-20110901-C00032
         		 1%
    Figure US20110212961A1-20110901-C00033
         		0.058  9%
    Figure US20110212961A1-20110901-C00034
         		 3%
    Figure US20110212961A1-20110901-C00035
         		 2%
    Figure US20110212961A1-20110901-C00036
         		 5%
    Figure US20110212961A1-20110901-C00037
         		0.082
    Figure US20110212961A1-20110901-C00038
         		 3%
    Figure US20110212961A1-20110901-C00039
         		−7%
    Figure US20110212961A1-20110901-C00040
         		−27%  
    Figure US20110212961A1-20110901-C00041
         		−14%  
    Figure US20110212961A1-20110901-C00042
         		−5%
    Figure US20110212961A1-20110901-C00043
         		−11%  
    Figure US20110212961A1-20110901-C00044
         		−17%  
    Figure US20110212961A1-20110901-C00045
         		31 μM
    Figure US20110212961A1-20110901-C00046
         		−6%
    Figure US20110212961A1-20110901-C00047
         		 3%
    Figure US20110212961A1-20110901-C00048
         		15%
    Figure US20110212961A1-20110901-C00049
         		 7%
  • Although the invention has been described with reference to the above example, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

Claims (4)

1. A compound having the general structure I or a pharmaceutically acceptable salt thereof:
Figure US20110212961A1-20110901-C00050
wherein:
X is a six-member ring selected from the group consisting of an unsubstituted phenyl, a substituted phenyl, an unsubstituted pyridine, a substituted pyridine, an unsubstituted pyrimidine and a substituted pyrimidine;
Y is selected from the group consisting of H, an unsubstituted alkenyl, a substituted alkenyl, an unsubstituted alkynyl and a substituted alkynyl;
and R is selected from the group consisting of H, an unsubstituted alkyl and a substituted alkyl.
2. A pharmaceutical composition comprising a compound claim 1 and a pharmaceutically acceptable carrier therefor.
3. A method of treatment of a disorder, disease, or pathology, comprising administering a pharmacologically effective dose of a pharmaceutical composition of claim 2 to a subject in need thereof, thereby treating the disorder, disease, or pathology.
4. The method of claim 3, wherein the disorder, disease, or pathology is cancer.
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