Patent Application
20050250829
The invention relates to compounds that may be used to inhibit kinases as well as compositions of matter and kits comprising these compounds. The present invention also relates to methods for inhibiting kinases as well as treatment methods using compounds according to the present invention.
The invention relates to inhibitors of enzymes that catalyze phosphoryl transfer and/or that bind ATP/GTP nucleotides, compositions comprising the inhibitors, and methods of using the inhibitors and inhibitor compositions. The inhibitors and compositions comprising them are useful for treating or modulating disease in which phosphoryl transferases, including kinases, may be involved, symptoms of such disease, or the effect of other physiological events mediated by phosphoryl transferases, including kinases. The invention also provides for methods of making the inhibitor compounds and methods for treating diseases in which one or more phosphoryl transferase, including kinase, activities is involved.
Phosphoryl transferases are a large family of enzymes that transfer phosphorous-containing groups from one substrate to another. By the conventions set forth by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (IUBMB) enzymes of this type have Enzyme Commission (EC) numbers starting with 2.7.-.- (See, Bairoch A., The ENZYME database in Nucleic Acids Res. 28:204-305 (2000)). Kinases are a class of enzymes that function in the catalysis of phosphoryl transfer. The protein kinases constitute the largest subfamily of structurally related phosphoryl transferases and are responsible for the control of a wide variety of signal transduction processes within the cell. (See, Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The protein kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, histidine, etc.). Protein kinase sequence motifs have been identified that generally correspond to each of these kinase families (See, for example, Hanks, S. K.; Hunter, T., FASEB J. 9:576-596 (1995); Kinghton et al., Science, 253:407-414 (1991); Hiles et al., Cell 70:419-429 (1992); Kunz et al., Cell, 73:585-596 (1993); Garcia-Bustos et al., EMBO J., 13:2352-2361 (1994)). Lipid kinases (e.g. PI3K) constitute a separate group of kinases with structural similarity to protein kinases.
Protein and lipid kinases regulate many different cell processes including, but not limited to, proliferation, growth, differentiation, metabolism, cell cycle events, apoptosis, motility, transcription, translation and other signaling processes, by adding phosphate groups to targets such as proteins or lipids. Phosphorylation events catalyzed by kinases act as molecular on/off switches that can modulate or regulate the biological function of the target protein. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc. Protein and lipid kinases can function in signaling pathways to activate or inactivate, or modulate the activity of (either directly or indirectly) the targets. These targets may include, for example, metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels or pumps, or transcription factors. Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in a number of diseases and disease conditions, including, for example, inflammation, cancer, allergy/asthma, diseases and conditions of the immune system, disease and conditions of the central nervous system (CNS), cardiovascular disease, dermatology, and angiogenesis.
Initial interest in protein kinases as pharmacological targets was stimulated by the findings that many viral oncogenes encode structurally modified cellular protein kinases with constitutive enzyme activity. These findings pointed to the potential involvement of oncogene related protein kinases in human proliferatives disorders. Subsequently, deregulated protein kinase activity, resulting from a variety of more subtle mechanisms, has been implicated in the pathophysiology of a number of important human disorders including, for example, cancer, CNS conditions, and immunologically related diseases. The development of selective protein kinase inhibitors that can block the disease pathologies and/or symptoms resulting from aberrant protein kinase activity has therefore generated much interest.
Cancer results from the deregulation of the normal processes that control cell division, differentiation and apoptotic cell death. Protein kinases play a critical role in this regulatory process. A partial non-limiting list of such kinases includes ab1, Aurora-A, Aurora-B, Aurora-C, ATK, bcr-abl, Blk, Brk, Btk, c-Kit, c-Met, c-Src, CDK1, CDK2, CDK4, CDK6, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Flt-1, Fps, Frk, Fyn, Hck, IGF-R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, Ros, Tie1, Tie2, Trk, Yes and Zap70. In mammalian biology, such protein kinases comprise mitogen activated protein kinase (MAPK) signaling pathways. MAPK signaling pathways are inappropriately activated by a variety of common disease-associated mechanisms such as mutation of ras genes and deregulation of growth factor receptors (Magnuson et al., Seminars in Cancer Biology 5:247-252 (1994)). Therefore the inhibition of protein kinases is an object of the present invention.
Aurora kinases (Aurora-A, Aurora-B, Aurora-C) are serine/threonine protein kinases that have been implicated in human cancer, such as colon, breast and other solid tumors. Aurora-A (also sometimes referred to as AIK) is believed to be involved in protein phosphorylation events that regulate the cell cycle. Specifically, Aurora-A may play a role in controlling the accurate segregation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities. In human colon cancer tissue, Aurora-A, Aurora-B, Aurora-C have been found to be overexpressed (See, Bischoff et al., EMBO J., 17:3052-3065 (1998); Schumacher et al., J. Cell Biol. 143:1635-1646 (1998); Kimura et al., J. Biol. Chem., 272:13766-13771 (1997)).
There is a continued need to find new therapeutic agents to treat human diseases. The protein kinases, specifically but not limited to Aurora-A, Aurora-B and Aurora-C are especially attractive targets for the discovery of new therapeutics due to their important role in cancer, diabetes, Alzheimer's disease and other diseases.
The present invention relates to compounds that have activity for inhibiting kinases. The present invention also provides compositions, articles of manufacture and kits comprising these compounds.
In one embodiment, a pharmaceutical composition is provided that comprises a kinase inhibitor according to the present invention as an active ingredient. Pharmaceutical compositions according to the invention may optionally comprise 0.001%-100% of one or more kinase inhibitors of this invention. These pharmaceutical compositions may be administered or coadministered by a wide variety of routes, including for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally. The compositions may also be administered or coadministered in slow release dosage forms.
The invention is also directed to kits and other articles of manufacture for treating disease states associated with kinases.
Also provided are methods for preparing compounds, compositions and kits according to the present invention. For example, several synthetic schemes are provided herein for synthesizing compounds according to the present invention.
Also provided are methods for using compounds, compositions, kits and articles of manufacture according to the present invention.
In one embodiment, the compounds, compositions, kits and articles of manufacture are used to inhibit kinases. In one variation, the compounds, compositions, kits and articles of manufacture are used to inhibit an Aurora kinase.
In another embodiment, the compounds, compositions, kits and articles of manufacture are used to treat a disease state for which kinases possesses activity that contributes to the pathology and/or symptomology of the disease state.
In another embodiment, a compound is administered to a subject wherein kinase activity within the subject is altered, preferably reduced.
In another embodiment, a prodrug of a compound is administered to a subject that is converted to the compound in vivo where it inhibits kinases.
In another embodiment, a method of inhibiting kinases is provided that comprises contacting kinases with a compound according to the present invention.
In another embodiment, a method of inhibiting kinases is provided that comprises causing a compound according to the present invention to be present in a subject in order to inhibit kinases in vivo.
In another embodiment, a method of inhibiting kinases is provided that comprises administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits kinases in vivo. It is noted that the compounds of the present invention may be the first or second compounds.
In another embodiment, a therapeutic method is provided that comprises administering a compound according to the present invention.
In another embodiment, a method of inhibiting cell proliferation is provided that comprises contacting a cell with an effective amount of a compound according to the present invention.
In another embodiment, a method of inhibiting cell proliferation in a patient is provided that comprises administering to the patient a therapeutically effective amount of a compound according to the present invention.
In another embodiment, a method of treating a condition in a patient which is known to be mediated by kinases, or which is known to be treated by kinase inhibitors, comprising administering to the patient a therapeutically effective amount of a compound according to the present invention.
In another embodiment, a method is provided for using a compound according to the present invention in order to manufacture a medicament for use in the treatment of disease state which is known to be mediated by kinases, or which is known to be treated by kinase inhibitors.
In another embodiment, a method is provided for treating a disease state for which kinases possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: causing a compound according to the present invention to be present in a subject in a therapeutically effective amount for the disease state.
In another embodiment, a method is provided for treating a disease state for which kinases possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a first compound to a subject that is converted in vivo to a second compound such that the second compound is present in the subject in a therapeutically effective amount for the disease state. It is noted that the compounds of the present invention may be the first or second compounds.
In another embodiment, a method is provided for treating a disease state for which kinases possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a compound according to the present invention to a subject such that the compound is present in the subject in a therapeutically effective amount for the disease state.
It is noted in regard to all of the above embodiments that the present invention is intended to encompass all pharmaceutically acceptable ionized forms (e.g., salts) and solvates (e.g., hydrates) of the compounds, regardless of whether such ionized forms and solvates are specified since it is well know in the art to administer pharmaceutical agents in an ionized or solvated form. It is also noted that unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all possible stereoisomers (e.g., enantiomers or diastereomers depending on the number of chiral centers), independent of whether the compound is present as an individual isomer or a mixture of isomers. Further, unless otherwise specified, recitation of a compound is intended to encompass all possible resonance forms and tautomers. With regard to the claims, the language “compound comprising the formula” is intended to encompass the compound and all pharmaceutically acceptable ionized forms and solvates, all possible stereoisomers, and all possible resonance forms and tautomers unless otherwise specifically specified in the particular claim.
It is further noted that prodrugs may also be administered which are altered in vivo and become a compound according to the present invention. The various methods of using the compounds of the present invention are intended, regardless of whether prodrug delivery is specified, to encompass the administration of a prodrug that is converted in vivo to a compound according to the present invention. It is also noted that certain compounds of the present invention may be altered in vivo prior to inhibiting kinases and thus may themselves be prodrugs for another compound. Such prodrugs of another compound may or may not themselves independently have kinase inhibitory activity.
Definitions
Unless otherwise stated, the following terms used in the specification and claims
“Alicyclic” means a moiety comprising a non-aromatic ring structure. Alicyclic moieties may be saturated or partially unsaturated with one, two or more double or triple bonds. Alicyclic moieties may also optionally comprise heteroatoms such as nitrogen, oxygen and sulfur. The nitrogen atoms can be optionally quaternerized or oxidized and the sulfur atoms can be optionally oxidized. Examples of alicyclic moieties include, but are not limited to moieties with C3-C8 rings such as cyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene.
“Aliphatic” means a moiety characterized by a straight or branched chain arrangement of constituent carbon atoms and may be saturated or partially unsaturated with one, two or more double or triple bonds.
“Alkoxy” means an oxygen moiety having a further alkyl substituent. The alkoxy groups of the present invention can be optionally substituted.
“Alkyl” represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having a chain of carbon atoms, optionally with oxygen (See “oxaalkyl”) or nitrogen atoms (See “aminoalkyl”) between the carbon atoms. CX alkyl and CX-Y alkyl are typically used where X and Y indicate the number of carbon atoms in the chain. For example, C1-6 alkyl includes alkyls that have a chain of between 1 and 6 carbons (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl represented along with another radical (e.g., as in arylalkyl, heteroarylalkyl) means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond (e.g., (C6-10)aryl(C1-3)alkyl includes, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-thienylmethyl, 2-pyridinylmethyl and the like).
“Alkylene”, unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical. CX alkylene and CX-Y alkylene are typically used where X and Y indicate the number of carbon atoms in the chain. For example, C1-6 alkylene includes methylene (—CH2—), ethylene (—CH2CH2—), trimethylene (—CH2CH2CH2—), tetramethylene (—CH2CH2CH2CH2—) 2-butenylene (—CH2CH═CHCH2—), 2-methyltetramethylene (—CH2CH(CH3)CH2CH2—), pentamethylene (—CH2CH2CH2CH2CH2—) and the like).
“Alkylidene” means a straight or branched saturated or unsaturated, aliphatic radical connected to the parent molecule by a double bond. CX alkylidene and CX-Y alkylidene are typically used where X and Y indicate the number of carbon atoms in the chain. For example, C1-6 alkylidene includes methylene (═CH2), ethylidene (═CHCH3), isopropylidene (═C(CH3)2), propylidene (═CHCH2CH3), allylidene (═CH—CH═CH2), and the like).
“Amino” means a nitrogen moiety having two further substituents where, for example, a hydrogen or carbon atom is attached to the nitrogen. For example, representative amino groups include —NH2, —NHCH3, —N(CH3)2, —NHC1-10-alkyl, —N(C1-10-alkyl)2, —NHaryl, —NHheteroaryl, —N(aryl)2, —N(heteroaryl)2, and the like. Optionally, the two substituents together with the nitrogen may also form a ring. Unless indicated otherwise, the compounds of the invention containing amino moieties may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
“Aminoalkyl” means an alkyl, as defined above, except where one or more substituted or unsubstituted nitrogen atoms (—N—) are positioned between carbon atoms of the alkyl. For example, an (C2-6) aminoalkyl refers to a chain comprising between 2 and 6 carbons and one or more nitrogen atoms positioned between the carbon atoms.
“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).
“Aromatic” means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4n+2. An aromatic ring may be such that the ring atoms are only carbon atoms or may include carbon and non-carbon atoms (see Heteroaryl).
“Aryl” means a monocyclic or polycyclic ring assembly wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring assembly. If one or more ring atoms is not carbon (e.g., N, S), the aryl is a heteroaryl. CX aryl and CX-Y aryl are typically used where X and Y indicate the number of atoms in the ring.
“Bicycloalkyl” means a saturated or partially unsaturated fused bicyclic or bridged polycyclic ring assembly.
“Bicycloaryl” means a bicyclic ring assembly wherein the rings are linked by a single bond or fused and at least one of the rings comprising the assembly is aromatic. CX bicycloaryl and CX-Y bicycloaryl are typically used where X and Y indicate the number of carbon atoms in the bicyclic ring assembly and directly attached to the ring.
“Bridging ring” as used herein refers to a ring that is bonded to another ring to form a compound having a bicyclic structure where two ring atoms that are common to both rings are not directly bound to each other. Non-exclusive examples of common compounds having a bridging ring include borneol, norbornane, 7-oxabicyclo[2.2.1]heptane, and the like. One or both rings of the bicyclic system may also comprise heteroatoms.
“Carbamoyl” means the radical —OC(O)NRaRb where Ra and Rb are each independently two further substituents where a hydrogen or carbon atom is attached to the nitrogen.
“Carbocycle” means a ring consisting of carbon atoms.
“Carbocyclic ketone derivative” means a carbocyclic derivative wherein the ring contains a —CO— moiety.
“Carbonyl” means the radical —CO—. It is noted that the carbonyl radical may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, aldehydes, amides, esters, and ketones.
“Carboxy” means the radical —CO2—. It is noted that compounds of the invention containing carboxy moieties may include protected derivatives thereof, i.e., where the oxygen is substituted with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.
“Cyano” means the radical —CN.
“Cycloalkyl” means a non-aromatic, saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly. CX cycloalkyl and CX-Y cycloalkyl are typically used where X and Y indicate the number of carbon atoms in the ring assembly. For example, C3-10 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, and the like.
“Cycloalkylene” means a divalent saturated or partially unsaturated, monocyclic or polycyclic ring assembly. CX cycloalkylene and CX-Y cycloalkylene are typically used where X and Y indicate the number of carbon atoms in the ring assembly.
“Disease” specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the “side effects” of such therapy.
“Fused ring” as used herein refers to a ring that is bonded to another ring to form a compound having a bicyclic structure when the ring atoms that are common to both rings are directly bound to each other. Non-exclusive examples of common fused rings include decalin, naphthalene, anthracene, phenanthrene, indole, furan, benzofuran, quinoline, and the like. Compounds having fused ring systems may be saturated, partially saturated, carbocyclics, heterocyclics, aromatics, heteroaromatics, and the like.
“Halo” means fluoro, chloro, bromo or iodo.
“Halo-substituted alkyl”, as an isolated group or part of a larger group, means “alkyl” substituted by one or more “halo” atoms, as such terms are defined in this Application. Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g. halo-substituted (C1-3)alkyl includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the like).
“Heteroatom” refers to an atom that is not a carbon atom. Particular examples of heteroatoms include, but are not limited to nitrogen, oxygen, and sulfur.
“Heteroatom moiety” includes a moiety where the atom by which the moiety is attached is not a carbon. Examples of heteroatom moieties include —N═, —NRc—, —N+(O−)═, —O—, —S— or —S(O)2—, wherein Rc is further substituent.
“Heterobicycloalkyl” means bicycloalkyl, as defined in this Application, provided that one or more of the atoms within the ring is a heteroatom. For example hetero(C9-12)bicycloalkyl as used in this application includes, but is not limited to, 3-aza-bicyclo[4.1.0]hept-3-yl, 2-aza-bicyclo[3.1.0]hex-2-yl, 3-aza-bicyclo[3.1.0]hex-3-yl, and the like.
“Heterocycloalkylene” means cycloalkylene, as defined in this Application, provided that one or more of the ring member carbon atoms is replaced by a heteroatom.
“Heteroaryl” means a cyclic aromatic group having five or six ring atoms, wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon. The nitrogen atoms can be optionally quaternerized and the sulfur atoms can be optionally oxidized. Heteroaryl groups of this invention include, but are not limited to, those derived from furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrroline, thiazole, 1,3,4-thiadiazole, triazole and tetrazole. “Heteroaryl” also includes, but is not limited to, bicyclic or tricyclic rings, wherein the heteroaryl ring is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroaryl or heterocycloalkyl ring. These bicyclic or tricyclic heteroaryls include, but are not limited to, those derived from benzo[b]furan, benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine, indolizine, imidazo[1,2a]pyridine, quinoline, isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine, imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyrazine, pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine, pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrimidine, pyrrolo[1,2-a]pyrazine, triazo[1,5-a]pyridine, pteridine, purine, carbazole, acridine, phenazine, phenothiazene, phenoxazine, 1,2-dihydropyrrolo[3,2,1-hi]indole, indolizine, pyrido[1,2-a]indole and 2 (1H)-pyridinone. The bicyclic or tricyclic heteroaryl rings can be attached to the parent molecule through either the heteroaryl group itself or the aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl group to which it is fused. The heteroaryl groups of this invention can be substituted or unsubstituted.
“Heterobicycloaryl” means bicycloaryl, as defined in this Application, provided that one or more of the atoms within the ring is a heteroatom. For example, hetero(C8-10)bicycloaryl as used in this Application includes, but is not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl, tetrahydroisoquinolinyl, and the like.
“Heterocycloalkyl” means cycloalkyl, as defined in this Application, provided that one or more of the atoms forming the ring is a heteroatom selected, independently from N, O, or S. Non-exclusive examples of heterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, 1,3-dioxanyl, 1,4-dioxanyl and the like.
“Hydroxy” means the radical —OH.
“Iminoketone derivative” means a derivative comprising the moiety —C(NR)—, wherein R comprises a hydrogen or carbon atom attached to the nitrogen.
“Isomers” mean any compound having an identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes “optical isomers.” A carbon atom bonded to four nonidentical substituents is termed a “chiral center.” A compound with one chiral center has two enantiomeric forms of opposite chirality. A mixture of the two enantiomeric forms is termed a “racemic mixture.” A compound that has more than one chiral center has 2n-1 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a “diastereomeric mixture.” When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see “Advanced Organic Chemistry.”, 4th edition, March, Jerry, John Wiley & Sons, New York, 1992).
“Nitro” means the radical —NO2.
“Oxaalkyl” means an alkyl, as defined above, except where one or more oxygen atoms (—O—) are positioned between carbon atoms of the alkyl. For example, an (C2-6)oxaalkyl refers to a chain comprising between 2 and 6 carbons and one or more oxygen atoms positioned between the carbon atoms.
“Oxoalkyl” means an alkyl, further substituted with a carbonyl group. The carbonyl group may be an aldehyde, ketone, ester, amide, acid or acid chloride.
“Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
“Pharmaceutically acceptable salts” means salts of inhibitors of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid; cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.
Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
“Prodrug” means a compound that is convertible in vivo metabolically into an inhibitor according to the present invention. The prodrug itself may or may not also have kinase inhibitory activity. For example, an inhibitor comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound. Suitable esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, esters of amino acids, and the like. Similarly, an inhibitor comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.
“Protected derivatives” means derivatives of inhibitors in which a reactive site or sites are blocked with protecting groups. Protected derivatives are useful in the preparation of inhibitors or in themselves may be active as inhibitors. A comprehensive list of suitable protecting groups can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.
“Substituted or unsubstituted” means that a given moiety may consist of only hydrogen substituents through available valencies (unsubstituted) or may further comprise one or more non-hydrogen substituents through available valencies (substituted) that are not otherwise specified by the name of the given moiety. For example, isopropyl is an example of an ethylene moiety that is substituted by —CH3. In general, a non-hydrogen substituent may be any substituent that may be bound to an atom of the given moiety that is specified to be substituted. Examples of substituents include, but are not limited to, aldehyde, alicyclic, aliphatic, (C1-10)alkyl, alkylene, alkylidene, amide, amino, aminoalkyl, aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl, carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo, heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl, heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl, and oxoalkyl moieties, each of which may optionally also be substituted or unsubstituted.
“Sulfinyl” means the radical —SO—. It is noted that the sulfinyl radical may be further substituted with a variety of substituents to form different sulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters, and sulfoxides.
“Sulfonyl” means the radical —SO2—. It is noted that the sulfonyl radical may be further substituted with a variety of substituents to form different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones.
“Therapeutically effective amount” means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
“Thiocarbonyl” means the radical —CS—. It is noted that the thiocarbonyl radical may be further substituted with a variety of substituents to form different thiocarbonyl groups including thioacids, thioamides, thioesters, and thioketones.
“Treatment” or “treating” means any administration of a compound of the present invention and includes:
It is noted in regard to all of the definitions provided herein that the definitions should be interpreted as being open ended in the sense that further substituents beyond those specified may be included. Hence, a C1 alkyl indicates that there is one carbon atom but does not indicate what are the substituents on the carbon atom. Hence, a C1 alkyl comprises methyl (i.e., —CH3) as well as —CRaRbRc where Ra, Rb, and Rc may each independently be hydrogen or any other substituent where the atom attached to the carbon is a heteroatom or cyano. Hence, CF3, CH2OH and CH2CN, for example, are all C1 alkyls.
Kinase Inhibitors
In one embodiment, kinase inhibitors of the present invention comprise a compound comprising Formula I:
In one variation, J, K, L, and M each comprises a carbon ring atom. In another variation, J, K and L each comprises a carbon ring atom and M is nitrogen. In another variation of the compound of the invention, at least one of X, Y and Z comprises a nitrogen ring atom.
In each of the above variations, the ring formed by X, Y and Z may comprise substituents that form a ring fused to the ring formed by X, Y, and Z.
Also in each of the above variations, the ring formed by J, K, L, and M may comprise substituents that form a ring fused to the ring formed by J, K, L, and M.
Also in each of the above variations, the ring formed by X, Y and Z comprises substituents that form a ring fused to the ring formed by X, Y, and Z, and the ring formed by J, K, L, and M comprises substituents that form a ring fused to the ring formed by J, K, L, and M.
The ring(s) fused to the ring formed by X, Y and Z and/or the ring formed by J, K, L, and M may be a substituted or unsubstituted alicyclic ring, aryl ring or heteroaryl ring. The fused ring is optionally a 5 or 6 membered ring.
It is noted that in one variation of the above, the fused ring is a substituted or unsubstituted heteroaryl selected from the group consisting of pyrazole, triazole, isoxazole, oxazole, thiazole, isothiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, imidazole, benzimidazole, indole, isoindole, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyridopyridine, quinoxaline and triazine.
In another embodiment, kinase inhibitors of the present invention may comprise one of Formula IIa, IIb, IIc, IId, IIe, or IIf:
In another embodiment, kinase inhibitors of the present invention may comprise one of Formula IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg or IIIh:
wherein:
In regard to compounds comprising Formula IIIa to IIIh, in one variation, at least one of V, W, X, Y and Z is N.
Also, in regard to compounds comprising the formula IIIa to IIIh, in another variation, W is N.
Further, in regard to compounds comprising the formulae IIa to IIf and IIIa to IIIh, the variables R11, R12, R13 and R14 each may be independently selected from the group consisting of hydrogen, F, Br, Cl, —OCH3, —SO2Me, —SO2NH2, —SO2NHMe, —SO2NHCH2CH2OH, —SO2NMe2, —NHSO2(3-fluorophenyl), perhalo(C1-10)alkyl, —OCF3, —CF3, (C1-10)alkyl, hydroxy-(C1-10)alkyl, aryl, aryl-(C1-10)alkyl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, hydroxy, aryloxy, heteroaryloxy, arylalkyl, heteroaryl(C1-10)alkyl, cycloalkyl, heterocycloalkyl, HS—, (C1-6)alkylS—, cyano, nitro, cycloalkoxy, (C1-12)alkoxy, —COOH, —CO2Me, carboxamide, (C1-12)alkylNHCO—, R9R10N—(C1-12)alkyl aminocarbonyl, R9R10N—((C1-12)alkoxycarbonyl, hetero-(C1-6)alkylaminocarbonyl, heterocycloalkyl-(C1-6)alkylCO—, heteroaryl-(C1-6)alkylCO—, heterocycloalkyl-(C1-6)alkylOCO—, heteroaryl-(C1-6)alkylOCO—, (C1-6)alkylOCO—, diethoxyphosphorylmethyl, imino group, R9R10N—(C1-6)alkylsulfonyl, —NH2, —NHCH3, —N(CH3)2, —NH(C1-3)alkyl, —N(C1-3-alkyl)2, R9R10N—(C1-12)alkyl aminocarbonylamino, R9R10N—(C1-6)alkyl alkoxycarbonylamino, heterocycloalkyl-(C1-6)alkyl aminocarbonylamino, heteroaryl-(C1-6)alkyl aminocarbonyl amino, (C3-12)heterocycloalkyl-(C1-6)alkoxycarbonylamino, heteroaryl-(C1-6)alkoxycarbonylamino, (C1-6)alkyl carbonylamino, ((C1-6)alkyl carbonyl)(C1-6 alkyl)amino, R9R10N—(C1-6)alkyl carbonylamino, [R9R10N—(C1-6)alkylcarbonyl][(C1-6)alkyl]amino, R9R10N—(C1-6)alkyl sulfonylamino, [R9R10N—(C1-6)alkylsulfonyl][(C1-6)alkyl]amino, and —NR9R10 where R9 and R10 are independently selected from the group consisting of hydrogen, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R9 and R10 together are —(CH2)4-5— optionally interrupted by one O, S, NH or —N(C1-3)alkyl group, or where R9 and R10 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-1-yl, each unsubstituted or substituted.
Also, in regard to the above variations, each R11, R12 and R13 may be independently selected from the group consisting of hydrogen, (C1-6)alkyl, hydroxy, hydroxy-(C1-6)alkyl, carboxamide, mono-(C1-6)alkyl aminocarbonyl, substituted aryl-(C1-6)alkyl, heteroaryl, heterocyclo, heteroaryl-(C1-6)alkyl, (C1-6)alkoxy, aryloxy, heteroaryloxy, amino, mono- or di- (C1-6)alkyl-amino, (C1-6)alkyl aminocarbonyl, mono- or di-(C1-6)alkyl-amino (C1-6)alkoxycarbonyl, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl aminocarbonylamino, mono- or di-(C1-6)alkyl-amino (C1-6)alkoxycarbonylamino, (C1-6)alkyl carbonylamino, ((C1-6)alkyl carbonyl)((C1-6)alkyl)amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl carbonylamino, [mono- or di-(C1-6)alkyl-amino (C1-6)alkyl carbonyl][(C1-6)alkyl]amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonylamino, [mono- or di-(C1-6)alkyl-amino(C1-6)alkylsulfonyl][(C1-6)alkyl]amino, mono- or di-(C1-6)alkyl-amino(C1-6)alkylsulfonyl, heteroaryl(C1-6)alkyl aminocarbonyl, heterocyclyl(C1-6)alkyl aminocarbonyl, heteroaryl(C1-6)alkyl aminocarbonylamino, heterocyclyl(C1-6)alkyl aminocarbonylamino, heteroaryl(C1-6)alkoxycarbonylamino, heterocyclyl(C1-6)alkoxycarbonylamino, heteroaryl(C1-6)alkylcarbonyl, heterocyclyl(C1-6)alkyl carbonyl, heteroaryl(C1-6)alkoxycarbonyl, heterocyclyl(C1-6)alkoxycarbonyl, (C1-6)alkyl sulfonyl (C1-6)alkylaminoalkyl, (C1-6)alkyl sulfonyl-(C1-6)alkyl-aminoalkyl-heteroaryl-, (C1-6)alkoxycarbonyl, halo, cyano, diethoxyphosphorylmethyl, trifluoromethyl and trifluoromethoxy, each substituted or unsubstituted.
According to each of the above variations, each R11, R12 and R13 may be independently selected from the group consisting of hydrogen, (C1-6)alkyl, hydroxy, hydroxy-(C1-6)alkyl, carboxamide, mono-(C1-6)alkyl aminocarbonyl, substituted aryl-(C1-6)alkyl, heteroaryl, heterocyclo, heteroaryl-(C1-6)alkyl, heterocyclyl-(C1-6)alkyl, heteroaryloxy, heterocyclyloxy, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl aminocarbonyl, mono- or di- (C1-6)alkyl-amino (C1-6)alkoxycarbonyl, mono- or di-(C1-6)alkyl-amino(C1-6)alkyl aminocarbonylamino, mono- or di-(C1-6)alkyl-amino (C1-6)alkoxycarbonylamino, (C1-6)alkyl carbonylamino, ((C1-6)alkyl carbonyl)((C1-6)alkyl)amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl carbonylamino, [mono- or di-(C1-6)alkyl-amino (C1-6)alkyl carbonyl][(C1-6)alkyl]amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonylamino, [mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonyl][(C1-6)alkyl]amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonyl, heteroaryl(C1-6)alkyl aminocarbonyl, heteroaryl(C1-6)alkyl carbonyl, (C1-6)alkyl sulfonyl (C1-6)alkyl aminoalkyl, (C1-6)alkyl sulfonyl-(C1-6)alkyl-aminoalkyl- heteroaryl-, halo, cyano and trifluoromethyl, each substituted or unsubstituted.
Further, according to each of the above embodiments, each R11, R12 and R13 is independently selected from the group consisting of hydrogen, hydroxymethyl, hydroxyethyl, 4-pyridylmethyl, morpholin-4-yl, acetamido, N-methylacetamido, carboxamide, diethylaminoethylsulfonyl, 5-methyl-3-pyrazolon-1-yl and 3-ethyl-piperidine-2,6-dion-3-yl, each substituted or unsubstituted. Also, for each of the above embodiments, R11 may optionally be selected from the group consisting of hydrogen, 2-(2-pyridyl)ethenyl, 2-(4-hydroxyphenyl)ethenyl, 3-(methoxycarbonyl)phenoxy, 3-ethyl-piperidine-2,6-dion-3-yl, 4-(methoxycarbonyl)phenoxy, 4-morpholino, 4-pyridylmethyl, 5-methyl-3-pyrazolon-1-yl, 5-oxazolyl, benzoyl, Br, —C(OH)(CF3)2, CF3, CH2CH2OH, —CH2PO(OEt)2, CH3, CN, CO2Me, —CONH2, F, H, I, —NHAc, —NMeAc, NO2, —OCH2Ph, OH, OMe, OCF3, OPh, SMe, and —SO2CH2CH2NEt2, each substituted or unsubstituted.
In yet another variation of the above, the invention provides the above compounds wherein R12 and R13 are each independently selected from the group consisting of hydrogen, halogen and methyl.
In accordance to the above embodiments, the invention further provides compounds wherein Q is C—R15, where R15 is selected from the group consisting of hydrogen, F, Br, Cl, —OCH3, —SO2Me, —SO2NH2, —SO2NHMe, —SO2NHCH2CH2OH, —SO2NMe2, —NHSO2(3-fluorophenyl), perhalo(C1-10)alkyl, —OCF3, —CF3, (C1-10)alkyl, hydroxy-(C1-10)alkyl, aryl, aryl-(C1-10)alkyl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, hydroxy, aryloxy, heteroaryloxy, arylalkyl, heteroaryl(C1-10)alkyl, cycloalkyl, heterocycloalkyl, HS—, (C1-6)alkylS—, cyano, nitro, cycloalkoxy, (C1-12)alkoxy, —COOH, —CO2Me, carboxamide, (C1-12)alkylNHCO—, R9R10N—(C1-12)alkyl aminocarbonyl, R9R10N—(C1-12)alkoxycarbonyl, hetero-(C1-6)alkylaminocarbonyl, heterocycloalkyl-(C1-6)alkylCO—, heteroaryl-(C1-6)alkylCO—, heterocycloalkyl-(C1-6)alkylOCO—, heteroaryl-(C1-6)alkylOCO—, (C1-6)alkylOCO—, diethoxyphosphorylmethyl, imino group, R9R10N—(C1-6)alkylsulfonyl, —NH2, —NHCH3, —N(CH3)2, —NH(C1-3)alkyl, —N(C1-3-alkyl)2, R9R10N—(C1-12)alkyl aminocarbonylamino, R9R10N—(C1-6)alkyl alkoxycarbonyl amino, heterocycloalkyl-(C1-6)alkyl aminocarbonyl amino, heteroaryl-(C1-6)alkyl aminocarbonylamino, (C3-12)heterocycloalkyl-(C1-6)alkoxycarbonylamino, heteroaryl-(C1-6)alkoxycarbonylamino, (C1-6)alkyl carbonylamino, ((C1-6)alkyl carbonyl)(C1-6)alkyl)amino, R9R10N—(C1-6)alkyl carbonylamino, [R9R10N—(C1-6)alkylcarbonyl][(C1-6)alkyl]amino, R9R10N—(C1-6)alkyl sulfonylamino, [R9R10N—(C1-6)alkylsulfonyl][(C1-6)alkyl]amino, and —NR9R10 where R9 and R10 are independently selected from the group consisting of hydrogen, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R9 and R10 together are —(CH2)4-5— optionally interrupted by one O, S, NH or —N(C1-3)alkyl group, or where R9 and R10 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-1-yl, each unsubstituted or substituted.
Further, according to the above variations, R15 may be selected from the group consisting of hydrogen, (C1-12)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-12)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted;
Also, according to the above variations, R14 may be selected from the group consisting of (C1-6)alkyl, hydroxy, hydroxy-(C1-6)alkyl, carboxamide, mono-(C1-6)alkyl aminocarbonyl, substituted aryl-(C1-6)alkyl, heteroaryl, heterocyclo, heteroaryl-(C1-6)alkyl, heterocyclyl-(C1-6)alkyl, heteroaryloxy, heterocyclyloxy, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl aminocarbonyl, mono- or di-(C1-6)alkyl-amino (C1-6)alkoxycarbonyl, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl aminocarbonylamino, mono- or di-(C1-6)alkyl-amino (C1-6)alkoxycarbonylamino, (C1-6)alkyl carbonylamino, ((C1-6)alkyl carbonyl)((C1-6)alkyl)amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl carbonylamino, [mono- or di-(C1-6)alkyl-amino (C1-6)alkyl carbonyl][(C1-6)alkyl]amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonylamino, [mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonyl][(C1-6)alkyl]amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonyl, heteroaryl(C1-6)alkyl aminocarbonyl, heteroaryl (C1-6)alkyl carbonyl, (C1-6)alkyl sulfonyl (C1-6)alkyl aminoalkyl, (C1-6)alkyl sulfonyl-(C1-6)alkyl- aminoalkyl-heteroaryl-, halo, cyano and trifluoromethyl.
Also, according to each of the above variations, R14 may also be selected from the group consisting of hydroxymethyl, hydroxyethyl, 4-pyridylmethyl, 4-morpholino, acetamido, N-methylacetamido, carboxamide, diethylaminoethylsulfonyl, 5-methyl-3-pyrazolon-1-yl and 3-ethyl-piperidine-2,6-dion-3-yl.
In another embodiment, the invention provides kinase inhibitors of Formula IV or V:
wherein:
In each of the above variations, the invention further provides kinase inhibitors wherein R11, R12 and R13 are each independently selected from the group consisting of F, Br, Cl, —OCH3, —SO2Me, —SO2NH2, —SO2NHMe, —SO2NHCH2CH2OH, —SO2NMe2, —NHSO2(3-fluorophenyl), perhalo(C1-10)alkyl, —OCF3, —CF3, (C1-10)alkyl, hydroxy-(C1-10)alkyl, aryl, aryl-(C1-10)alkyl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, hydroxy, aryloxy, heteroaryloxy, arylalkyl, heteroaryl(C1-10)alkyl, cycloalkyl, heterocycloalkyl, HS—, (C1-6)alkylS—, cyano, nitro, cycloalkoxy, (C1-12)alkoxy, —COOH, —CO2Me, carboxamide, (C1-12)alkylNHCO—, R9R10N—(C1-12)alkyl aminocarbonyl, R9R10N—(C1-12)alkoxycarbonyl, hetero-(C1-6)alkylaminocarbonyl, heterocycloalkyl-(C1-6)alkylCO—, heteroaryl-(C1-6)alkylCO—, heterocycloalkyl-(C1-6)alkylOCO—, heteroaryl-(C1-6)alkylOCO—, (C1-6)alkylOCO—, diethoxyphosphorylmethyl, imino group, R9R10N—(C1-6)alkylsulfonyl, —NH2, —NHCH3, —N(CH3)2, —NH(C1-3)alkyl, —N(C1-3-alkyl)2, R9R10N—(C1-12)alkyl aminocarbonylamino, R9R10N—(C1-6)alkyl alkoxycarbonylamino, heterocycloalkyl-(C1-6)alkyl aminocarbonylamino, heteroaryl-(C1-6)alkyl aminocarbonylamino, (C3-12)heterocycloalkyl-(C1-6)alkoxycarbonylamino, heteroaryl-(C1-6)alkoxycarbonyl amino, (C1-6)alkyl carbonylamino, ((C1-6)alkyl carbonyl)(C1-6 alkyl)amino, R9R10N—(C1-6)alkyl carbonylamino, [R9R10N—(C1-6)alkylcarbonyl][(C1-6)alkyl]amino, R9R10N—(C1-6)alkyl sulfonylamino, [R9R10N—(C1-6)alkylsulfonyl][(C1-6)alkyl]amino, and —NR9R10 where R9 and R10 are independently selected from the group consisting of hydrogen, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R9 and R10 together are —(CH2)4-5— optionally interrupted by one O, S, NH or —N(C1-3)alkyl group, or where R9 and R10 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-1-yl, each unsubstituted or substituted.
Also, in regard to the above variations, there is provided compounds wherein R11 is selected from the group consisting of (C1-6)alkyl, hydroxy, hydroxy-(C1-6)alkyl, carboxamide, mono-(C1-6)alkyl aminocarbonyl, substituted aryl-(C1-6)alkyl, heteroaryl, heteroaryl-(C1-6)alkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkyl-(C1-6)alkyl, heterocycloalkoxy, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl aminocarbonyl, mono- or di-(C1-6)alkyl-amino (C1-6)alkoxycarbonyl, mono- or di-(C1-6)alkyl-amino(C1-6)alkyl aminocarbonylamino, mono- or di-(C1-6)alkyl-amino (C1-6)alkoxycarbonylamino, (C1-6)alkyl carbonylamino, ((C1-6)alkyl carbonyl)((C1-6)alkyl)amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl carbonylamino, [mono- or di-(C1-6)alkyl-amino (C1-6)alkyl carbonyl][(C1-6)alkyl]amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonylamino, [mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonyl][(C1-6)alkyl]amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonyl, heteroaryl (C1-6)alkyl aminocarbonyl, heteroaryl(C1-6)alkyl carbonyl, heterocycloalkyl(C1-6)alkyl aminocarbonyl, heterocycloalkyl(C1-6)alkyl carbonyl, (C1-6)alkyl sulfonyl, (C1-6)alkyl aminoalkyl, (C1-6)alkyl sulfonyl-(C1-6)alkyl-aminoalkyl-heteroaryl-, (C1-6)alkyl sulfonyl- (C1-6)alkyl-aminoalkyl-heterocycloalkyl-, halo, cyano and trifluoromethyl, each substituted or unsubstituted.
In yet another variation, the kinase inhibitors comprise compounds wherein W is CH and R11 is selected from the group consisting of Cl, Br, NH2, NO2, NH(C1-6)alkyl, N[(C1-6)alkyl]2, NH(C1-6)alkyl-N[(C1-6)alkyl]2, NH(C1-6)alkylphenyl, NH[(C1-6)alkyl]-4-hydroxyphenyl, NH(C1-6)alkyl-4-morpholino, NH(C1-6)alkyl-piperazinyl, N[(C1-6)alkyl]-4-pyridinyl, NH(3-pyridinyl), NHphenyl, NH(3-fluorophenyl), pyrrolidin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, S-phenyl, and S-4-acetamidophenyl, each substituted or unsubstituted.
Furthermore, in each of the above variation, R11 may be selected from the group consisting of hydroxymethyl, hydroxyethyl, 4-pyridylmethyl, 4-morpholino, acetamido, N-methylacetamido, carboxamide, diethylaminoethylsulfonyl, 5-methyl-3-pyrazolon-1-yl and 3-ethyl-piperidine-2,6-dion-3-yl, each substituted or unsubstituted. Also, in regard to the above variations, R11 is selected from the group consisting of H, CF3, F, Cl, CN, CONH2, and OMe. In the above variations, R11 is selected from the group consisting of hydrogen, CH2OH, CH3, and OMe. In another variation of the above compounds, R13 may be hydrogen.
In another embodiment, the invention provides kinase inhibitors of Formula VIa, VIb, VIc, VId, VIe, VIf, or VIg:
wherein:
The invention further provides the compound of Formulae VIa to VIh, wherein W is N and R11 is selected from the group consisting of (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-12)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted.
In one variation, R12 is selected from the group consisting of hydrogen, (C1-6)alkyl, hydroxy, hydroxy-(C1-6)alkyl, carboxamide, mono-(C1-6)alkyl aminocarbonyl, substituted aryl-(C1-6)alkyl, heteroaryl, heterocyclo, heteroaryl-(C1-6)alkyl, (C1-6)alkoxy, aryloxy, heteroaryloxy, amino, mono- or di-(C1-6)alkyl-amino, (C1-6)alkyl aminocarbonyl, mono- or di-(C1-6)alkyl-amino (C1-6)alkoxycarbonyl, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl aminocarbonylamino, mono- or di-(C1-6)alkyl-amino (C1-6)alkoxycarbonylamino, (C1-6)alkyl carbonylamino, ((C1-6)alkyl carbonyl)((C1-6)alkyl)amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl carbonylamino, [mono- or di-(C1-6)alkyl-amino (C1-6)alkyl carbonyl][(C1-6)alkyl]amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonylamino, [mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonyl][(C1-6)alkyl]amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonyl, heteroaryl (C1-6)alkyl aminocarbonyl, heterocyclyl(C1-6)alkyl aminocarbonyl, heteroaryl(C1-6)alkyl aminocarbonylamino, heterocyclyl(C1-6)alkyl aminocarbonylamino, heteroaryl(C1-6)alkoxycarbonylamino, heterocyclyl(C1-6)alkoxycarbonylamino, heteroaryl (C1-6)alkyl carbonyl, heterocyclyl(C1-6)alkyl carbonyl, heteroaryl(C1-6)alkoxycarbonyl, heterocyclyl(C1-6)alkoxycarbonyl, (C1-6)alkyl sulfonyl (C1-6)alkyl aminoalkyl, (C1-6)alkyl sulfonyl-(C1-6)alkyl-aminoalkyl-heteroaryl-, (C1-6)alkoxycarbonyl, halo, cyano, diethoxyphosphorylmethyl, trifluoromethyl and trifluoromethoxy, each substituted or unsubstituted.
In another variation of the above compounds, R12 may be selected from the group consisting of 2-(2-pyridyl)ethenyl, 2-(4-hydroxyphenyl)ethenyl, 3-(methoxycarbonyl)phenoxy, 3-ethyl-piperidine-2,6-dion-3-yl, 4-(methoxycarbonyl)phenoxy, 4-morpholino, 4-pyridylmethyl, 5-methyl-3-pyrazolon-1-yl, 5-oxazolyl, benzoyl, Br, —C(OH)(CF3)2, CF3, CH2CH2OH, —CH2PO(OEt)2, CH2, CN, CO2Me, —CONH2, F, H, I, —NHAc, —NMeAc, NO2, —OCH2Ph, OH, OMe, OCF3, OPh, SMe, and —SO2CH2CH2NEt2, each substituted or unsubstituted. Also, in yet another variation, R12 is selected from the group consisting of hydrogen, halogen and methyl and R13 selected from the group consisting of halogen and methyl.
In another variation of the above compounds, R12 may be selected from the group consisting of 2-(2-pyridyl)ethenyl, 2-(4-hydroxyphenyl)ethenyl, 3-(methoxycarbonyl)phenoxy, 3-ethyl-piperidine-2,6-dion-3-yl, 4-(methoxycarbonyl)phenoxy, 4-morpholino, 4-pyridylmethyl, 5-methyl-3-pyrazolon-1-yl, 5-oxazolyl, benzoyl, Br, —C(OH)(CF3)2, CF3, CH2CH2OH, —CH2PO(OEt)2, CH2, CN, CO2Me, —CONH2, F, H, I, —NHAc, —NMeAc, —OCH2Ph, and —SO2CH2CH2NEt2, each substituted or unsubstituted. Also, in yet another variation, R12 is selected from the group consisting of hydrogen, halogen and methyl and R13 selected from the group consisting of halogen and methyl. In each of the above specific embodiments, the invention provides kinase inhibitors wherein R11 and R12 or R12 and R13 are taken together to form a substituted or unsubstituted fused ring, and the fused ring may be a substituted or unsubstituted 5 or 6 membered aryl or heteroaryl ring. In another variation, the substituted or unsubstituted aryl or heteroaryl ring may be selected from the group consisting of substituted or unsubstituted benzene, naphthylene, furan, benzofuran, thiophene, benzothiophene, pyrazole, triazole, isoxazole, oxazole, thiazole, isothiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, imidazole, benzimidazole, indole, isoindole, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyridopyridine, quinoxaline and triazine, each substituted or unsubstituted.
In the above specific embodiments, R4 may be selected from the group consisting of hydrogen, (C1-6)alkyl, (C1-6)alkoxy, hydroxy-(C1-6)alkyl, (C1-10)alkoxycarbonyl, aryl, heterocyclyl, heteroaryl, aminocarbonyl, (C1-6)alkyl aminocarbonyl, halogen and hydroxy, each substituted or unsubstituted, and R11 is selected from the group consisting of hydroxymethyl, hydroxyethyl, 4-pyridylmethyl, 4-morpholino, acetamido, N-methylacetamido, carboxamide, diethylaminoethylsulfonyl, 5-methyl-3-pyrazolon-1-yl and 3-ethyl-piperidine-2,6-dion-3-yl, each substituted or unsubstituted.
According to each of the above embodiments, the invention provides kinase inhibitors wherein R3 is selected from the group consisting of hydrogen, fluoro, bromo, iodo, (C1-6)alkyl, cyano and nitro. Also, according to each of the above embodiments, R3 may be selected from the group consisting of hydrogen and methyl.
In yet another variation of the above, R4 may be selected from the group consisting of hydroxy and (C1-6)alkyl, or the compounds wherein R4 may be selected from the group consisting of 2-furanyl, 3-thienyl, Br, CO2Et, hydrogen, and phenyl.
According to each of the above embodiments, the invention provides kinase inhibitors wherein R4 is selected from the group consisting of hydrogen, (C1-6)alkyl, (C1-6)alkoxy, hydroxy(C1-6)alkyl, (C1-10)alkoxycarbonyl, aryl, heterocyclyl, heteroaryl, aminocarbonyl, (C1-6)alkyl aminocarbonyl, halogen and hydroxy.
In yet another embodiment, the invention provides kinase inhibitors wherein R3 and R4 are joined together to form a fused ring structure selected from the group consisting of thiazole, imidazole, triazole and pyridine. In the above embodiment, the fused ring may be substituted by one to five substituents selected from the group consisting of halo, amino, (C1-6)alkyl amino, (C1-6)alkyl and (C1-6)alkyl carbonyl. In a further variation, the ring is pyridine substituted by 1 or 2 halogen or 1 or 2 methyl groups.
In each of the above embodiments, the invention provides compounds wherein R3 and R4 are joined together to form a fused ring structure and are together selected from the group consisting of —NH—CH═N—, —NH—N═N—, —S—CH═N—, and —CH═CH—CH═N—.
Furthermore, according to any one of the above variations, R3 and R4 may be independently selected from the group consisting of methyl and OH.
Also, in regard to any of the above variations, R5 may be selected from the group consisting of hydrogen, (C1-6)alkyl, (C1-6)alkenyl, halo, phenyl, heteroaryl, heterocycloalkyl and (C1-6)alkoxy, each substituted or unsubstituted. According to each of the above variations, R5 may be selected from the group consisting of hydrogen, halo, ethyl and methyl.
Furthermore, in regard to any of the above variations, R5 is selected from the group consisting of Cl, methyl, 2-furanyl, 2-thienyl, Br, CH═CH2, hydrogen and phenyl.
In yet another embodiment, the invention provides kinase inhibitors of Formula VII:
wherein:
In one variation, J, K, L, and M are each carbon. In another variation, J, K and L are each carbon and M is nitrogen. In still another variation, at least one of Q, U, and V is nitrogen.
In each of the above embodiments, R11 and R12 or R12 and R13 can be taken together to form a further ring that is fused to the ring comprising Q, U, and V.
Also, in each of the above embodiments, two of R3, R4, R5 and R6 can be taken together to form a ring that is fused to the ring comprising J, K, L, and M.
Further, in each of the above embodiments, the ring formed by Q, U, and V can comprise substituents that form a ring fused to the ring formed by Q, U, and V, and the ring formed by J, K, L, and M can comprise substituents that form a ring fused to the ring formed by J, K, L, and M.
In particular embodiments where R11 and R12, R12 and R13, and/or two of R3, R4, R5 and R6 are taken together to form a fused ring, the fused ring can be a substituted or unsubstituted 5 or 6 membered aryl or heteroaryl ring. Specifically, the fused ring can be an alicyclic ring.
In another embodiment, the invention provides kinase inhibitors of Formula VIIIa, VIIIb, and VIIIc:
wherein:
In another embodiment, the invention provides kinase inhibitors of Formula IXa, IXb, and IXc:
wherein:
In another embodiment, the invention provides kinase inhibitors of Formula Xa, Xb, and Xc:
wherein:
In another embodiment, the invention provides kinase inhibitors of Formula XIa, XIb, XIc, and XId:
wherein:
In another embodiment, the invention provides kinase inhibitors of Formula XIIa, XIIb, XIIc, and XIId:
wherein:
In another embodiment, the invention provides kinase inhibitors of Formula XIIIa, XIIIb, XIIIc, and XIIId:
wherein:
In particular embodiments of compounds comprising Formulae VIIIa, VIIIb, VIIIc, IXa, XIb, IXc, Xa, Xb, Xc, XIa, XIb, XIc, XId, XIIa, XIIb, XIIc, XIId, XIIIa, XIIIb, XIIIc, and XIIId, W is N.
In another embodiment, the invention provides kinase inhibitors of Formula XIV:
wherein:
In one variation, at least one of V, W, X, Y and Z is N.
In another embodiment, the invention provides kinase inhibitors of Formula XVa and XVb:
wherein:
In another embodiment, the invention provides kinase inhibitors of Formula XVIa, XVIb, XVIc, XVId, XVIe, XVIf, XVIg, and XVIh:
wherein:
In regard to compounds comprising Formulae VIIIa, VIIIb, VIIIc, IXa, IXb, IXc, Xa, Xb, Xc, XIa, XIb, XIc, XId, XIIa, XIIb, XIIc, XIId, XIIIa, XIIIb, XIIIc, XIIId, XIV, XVa, XVb, XVIa, XVIb, XVIc, XVId, XVIe, XVIf, XVIg, and XVIh, R3 and R4 can be taken together to form a substituted or unsubstituted fused ring. In particular embodiments, the fused ring is a substituted or unsubstituted 5 or 6 membered aryl or heteroaryl ring; or a substituted or unsubstituted alicyclic ring.
In regard to compounds comprising Formulae VIIIa, VIIIb, VIIIc, IXa, IXb, IXc, Xa, Xb, Xc, XIa, XIb, XIc, XId, XIIa, XIIb, XIIc, XIId, XIIIa, XIIIb, XIIIc, XIIId, XIV, XVa, XVb, XVIa, XVIb, XVIc, XVId, XVIe, XVIf, XVIg, and XVIh, R3 and R4 can be joined together to form a fused ring structure selected from the group consisting of thiazole, imidazole, triazole and pyridine. In particular embodiments, the ring is substituted by one to five substituents selected from the group consisting of halo, amino, (C1-6)alkyl amino, (C1-6)alkyl and (C1-6)alkyl carbonyl. Specifically, the ring can be pyridine substituted by 1 or 2 halogen, or 1 or 2 methyl.
Further in regard to compounds comprising Formulae VIIIa, VIIIb, VIIIc, IXa, IXb, IXc, Xa, Xb, Xc, XIa, XIb, XIc, XId, XIIa, XIIb, XIIc, XIId, XIIIa, XIIIb, XIIIc, XIIId, XIV, XVa, XVb, XVIa, XVIb, XVIc, XVId, XVIe, XVIf, XVIg, and XVIh, R3 and R4 can be taken together to form a fused ring structure and are together selected from the group consisting of —NH—CH═N—, —NH—N═N—, —S—CH═N—, and —CH═CH—CH═N—.
In another embodiment, the invention provides kinase inhibitors of Formula XVIIa, XVIIb, XVIIc, and XVIId:
wherein:
In another embodiment, the invention provides kinase inhibitors of Formula XVIII:
wherein:
In another embodiment, the invention provides kinase inhibitors of Formula XIX:
wherein:
In another embodiment, the invention provides kinase inhibitors of Formula XX:
wherein:
In another embodiment, the invention provides kinase inhibitors of Formula XXI:
wherein:
In another embodiment, the invention provides kinase inhibitors of Formula XXII:
wherein:
In each of the above embodiments, R4 can be selected from the group consisting of NHSO2R18, SO2NHR18, SO2R18, C(NH2)═N(OH), CN, and F; and R18 is selected from the group consisting of (C1-10)alkyl, (C4-12)aryl, and (C4-12)heteroaryl, each substituted or unsubstituted.
In each of the above embodiments, R15 and/or R16 can be (T)a—N(R19)2; wherein each T is independently selected from the group consisting of NH, O, (CH2)n where n is 1, 2, 3, or 4, CO, and S; a is 0, 1, 2, or 3; and each R19 is independently selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-12)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted, or the R19 groups are joined together to form a ring structure selected from the group consisting of hetero (C3-12)cycloalkyl, heteroaryl, hetero (C8-12)bicycloaryl, heteroaryloxy, and hetero (C3-12)cycloalkoxy, each substituted or unsubstituted.
In one particular variation, R16 is selected from the group consisting of H and (C1-6)alkyl.
In another embodiment, the present invention relates to a compound selected from the group consisting of:
An example of a particular compound according to the present invention is 3-(1-Methyl-1H-benzoimidazol-2-yl)-1H-indol-2-ol whose structure is
It is noted that the compounds of the present invention may be in the form of a pharmaceutically acceptable salt, biohydrolyzable ester, biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate or prodrug thereof. For example, where the compound comprises a substituent that is convertible in vivo to a different substituent such as a hydrogen.
It is further noted that the compounds of the present invention may optionally be solely or predominantly in the enol tautomer in its active state. It is further noted that the compound may be present in a mixture of stereoisomers, or the compound comprises a single stereoisomer.
The invention also provides pharmaceutical compositions comprising, as an active ingredient, a compound according to any one of the above embodiments and variations. In addition, the composition may be a solid or liquid formulation adapted for oral administration. In a further variation, the pharmaceutical composition may be a tablet. In yet another variation, the pharmaceutical composition may be a liquid formulation adapted for parenteral administration.
In one embodiment, there is provided the pharmaceutical composition comprising a compound according to each of the above variations wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, and intrathecally.
In one embodiment, a kit is provided that comprises a composition comprising at least one kinase inhibitor of the present invention in combination with instructions. The instructions may indicate the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition. The kit may also comprise packaging materials. The packaging material may comprise a container for housing the composition. The kit may also optionally comprise additional components, such as syringes for administration of the composition. The kit may comprise the composition in single or multiple dose forms.
In another embodiment, an article of manufacture is provided that comprises a composition comprising at least one kinase inhibitor of the present invention in combination with packaging materials. The packaging material may comprise a container for housing the composition. The container may optionally comprise a label indicating the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition. The kit may also optionally comprise additional components, such as syringes for administration of the composition. The article of manufacture may comprise the composition in single or multiple dose forms.
In another embodiment, there is provided a method for treating cancer comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a composition of the present invention. In one embodiment, the cancer is selected from the group consisting of squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, non small-cell lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, glioma, colorectal cancer, genitourinary cancer and gastrointestinal cancer.
In another embodiment, there is provided a method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: causing a compound or composition according to the present invention to be present in a subject in a therapeutically effective amount for the disease state.
In yet another embodiment, there is provided a method for treating inflammation, inflammatory bowel disease, psoriasis, or transplant rejection, comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a compound or composition according to the present invention.
In yet another embodiment, the present invention provides a method of preventing or treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a first compound to a subject that is converted in vivo to a second compound according to any one of the compounds or compositions of the present invention wherein the second compound is present in a subject in a therapeutically effective amount for the disease state.
In yet another embodiment, there is provided a method of preventing or treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a compound or composition of the present invention, wherein the compound is present in the subject in a therapeutically effective amount for the disease state.
In a further embodiment, there is provided a method for preventing or treating dementia related diseases and Alzheimer's Disease, comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a compound or composition according to any one of the above embodiments. In one particular variation, the dementia related diseases are selected from the group consisting of Frontotemporal dementia Parkinson's Type, Parkinson dementia complex of Guam, HIV dementia, diseases with associated neurofibrillar tangle pathologies, predemented states, vascular dementia, dementia with Lewy bodies, Frontotemporal dementia and dementia pugilistica.
In another embodiment, there is provided a method for preventing or treating amyotrophic lateral sclerosis, corticobasal degeneration, Down syndrome, Huntington's Disease, Parkinson's Disease, postencephelatic parkinsonism, progressive supranuclear palsy, Pick's Disease, Niemann-Pick's Disease, stroke, head trauma and other chronic neurodegenerative diseases, Bipolar Disease, affective disorders, depression, schizophrenia, cognitive disorders, hair loss and contraceptive medication, comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a compound or composition according to any one of the above embodiments.
In yet another embodiment, there is provided a method for preventing or treating mild Cognitive Impairment, Age-Associated Memory Impairment, Age-Related Cognitive Decline, Cognitive Impairment No Dementia, mild cognitive decline, mild neurocognitive decline, Late-Life Forgetfulness, memory impairment and cognitive impairment and androgenetic alopecia, comprising administering to a mammal, including man in need of such prevention and/or treatment, a therapeutically effective amount of a compound or composition according to any one of the above embodiments.
In another embodiment, there is provided a method for preventing or treating dementia related diseases, Alzheimer's Disease and conditions associated with kinases, comprising administering to a mammal, including man in need of such prevention and/or treatment, a therapeutically effective amount of a compound or composition according to the above embodiments.
In another embodiment, there is provided a method for treating arthritis comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a compound or composition according to any one of the above embodiment.
In another embodiment, there is provided a method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a first compound to a subject that is converted in vivo to a second compound or composition according to any one of the embodiments of the present invention, wherein the second compound is present in a subject in a therapeutically effective amount for the disease state.
In another embodiment, there is provided a method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a compound or composition according to any one of the above embodiments, wherein the compound is present in the subject in a therapeutically effective amount for the pathology and/or symptomology.
In another embodiment, there is provided a method of inhibiting kinase, the method comprising: contacting kinase with a compound or composition according to any one of the above embodiments. In one variation, the inhibition arises from a favorable conformation adopted by the compound in its enol form, and the conformation arises from an intramolecular hydrogen bonding of the enol hydrogen and an adjacent nitrogen atom of the compound. In another variation, the inhibition arises from a favorable conformation adopted by the compound in its enol form, and the inhibition arises from a hydrogen bonding interaction between the enol tautomer and an active site residue of the kinase.
In another embodiment, there is provided a method of inhibiting kinase, the method comprising: causing a compound or composition according to any one of the above embodiments to be present in a subject in order to inhibit kinase in vivo.
In another embodiment, there is provided a method of inhibiting kinase, the method comprising: administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits kinase in vivo and the second compound is a compound or composition according to any one of the above embodiments.
In still another embodiment, there is provided a therapeutic method, the method comprising: administering a compound or composition according to any one of the above embodiments to a subject.
In another variation of each of the above embodiments and variations, the kinase comprises Aurora kinase.
It is noted that the compounds of the present invention may be in the form of a pharmaceutically acceptable salt, biohydrolyzable ester, biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate or a prodrug thereof (e.g., where the compound comprises a substituent that is convertible in vivo to a different substituent such as hydrogen).
Salts, Hydrates, and Prodrugs of Kinase Inhibitors
It should be recognized that the compounds of the present invention may be present and optionally administered in the form of salts, hydrates and prodrugs that are converted in vivo into the compounds of the present invention. For example, it is within the scope of the present invention to convert the compounds of the present invention into and use them in the form of their pharmaceutically acceptable salts derived from various organic and inorganic acids and bases in accordance with procedures well known in the art.
When the compounds of the present invention possess a free base form, the compounds can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding salts such as sulfate, nitrate, phosphate, etc.; and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate. Further acid addition salts of the present invention include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptaoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate, lactobionate, malate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate and phthalate. It should be recognized that the free base forms will typically differ from their respective salt forms somewhat in physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base forms for the purposes of the present invention.
When the compounds of the present invention possess a free acid form, a pharmaceutically acceptable base addition salt can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Examples of such bases are alkali metal hydroxides including potassium, sodium and lithium hydroxides; alkaline earth metal hydroxides such as barium and calcium hydroxides; alkali metal alkoxides, e.g. potassium ethanolate and sodium propanolate; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N-methylglutamine. Also included are the aluminum salts of the compounds of the present invention. Further base salts of the present invention include, but are not limited to: copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium and zinc salts. Organic base salts include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g., arginine, betaine, caffeine, chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris-(hydroxymethyl)-methylamine (tromethamine). It should be recognized that the free acid forms will typically differ from their respective salt forms somewhat in physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid forms for the purposes of the present invention.
Compounds of the present invention that comprise basic nitrogen-containing groups may be quaternized with such agents as (C1-4)alkyl halides, e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides, bromides and iodides; di(C1-4)alkyl sulfates, e.g., dimethyl, diethyl and diamyl sulfates; (C10-18)alkyl halides, e.g., decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (C1-4)alkyl halides, e.g., benzyl chloride and phenethyl bromide. Such salts permit the preparation of both water-soluble and oil-soluble compounds of the present invention.
N-oxides of compounds according to the present invention can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0° C. Alternatively, the N-oxides of the compounds can be prepared from the N-oxide of an appropriate starting material.
Prodrug derivatives of compounds according to the present invention can be prepared by modifying substituents of compounds of the present invention that are then converted in vivo to a different substituent. It is noted that in many instances, the prodrugs themselves also fall within the scope of the range of compounds according to the present invention. For example, prodrugs can be prepared by reacting a compound with a carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, or the like) or an acylating agent. Further examples of methods of making prodrugs are described in Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.
Protected derivatives of compounds of the present invention can also be made. Examples of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.
Compounds of the present invention may also be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
A “pharmaceutically acceptable salt”, as used herein, is intended to encompass any compound according to the present invention that is utilized in the form of a salt thereof, especially where the salt confers on the compound improved pharmacokinetic properties as compared to the free form of compound or a different salt form of the compound. The pharmaceutically acceptable salt form may also initially confer desirable pharmacokinetic properties on the compound that it did not previously possess, and may even positively affect the pharmacodynamics of the compound with respect to its therapeutic activity in the body. An example of a pharmacokinetic property that may be favorably affected is the manner in which the compound is transported across cell membranes, which in turn may directly and positively affect the absorption, distribution, biotransformation and excretion of the compound. While the route of administration of the pharmaceutical composition is important, and various anatomical, physiological and pathological factors can critically affect bioavailability, the solubility of the compound is usually dependent upon the character of the particular salt form thereof, which it utilized. One of skill in the art will appreciate that an aqueous solution of the compound will provide the most rapid absorption of the compound into the body of a subject being treated, while lipid solutions and suspensions, as well as solid dosage forms, will result in less rapid absorption of the compound.
Preparation of Kinase Inhibitors
Various methods may be developed for synthesizing compounds according to the present invention. Representative methods for synthesizing these compounds are provided in the Examples. It is noted, however, that the compounds of the present invention may also be synthesized by other synthetic routes that others may devise.
It will be readily recognized that certain compounds according to the present invention have atoms with linkages to other atoms that confer a particular stereochemistry to the compound (e.g., chiral centers). It is recognized that synthesis of compounds according to the present invention may result in the creation of mixtures of different stereoisomers (enantiomers, diastereomers). Unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all of the different possible stereoisomers.
Various methods for separating mixtures of different stereoisomers are known in the art. For example, a racemic mixture of a compound may be reacted with an optically active resolving agent to form a pair of diastereoisomeric compounds. The diastereomers may then be separated in order to recover the optically pure enantiomers. Dissociable complexes may also be used to resolve enantiomers (e.g., crystalline diastereoisomeric salts). Diastereomers typically have sufficiently distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) that they can be readily separated by taking advantage of these dissimilarities. For example, diastereomers can typically be separated by chromatography or by separation/resolution techniques based upon differences in solubility. A more detailed description of techniques that can be used to resolve stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
Composition Comprising Kinase Inhibitors
A wide variety of compositions and administration methods may be used in conjunction with the kinase inhibitors of the present invention. Such compositions may include, in addition to the kinase inhibitors of the present invention, conventional pharmaceutical excipients, and other conventional, pharmaceutically inactive agents. Additionally, the compositions may include active agents in addition to the kinase inhibitors of the present invention. These additional active agents may include additional compounds according to the invention, and/or one or more other pharmaceutically active agents.
The compositions may be in gaseous, liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration to be used. For oral administration, capsules and tablets are typically used. For parenteral administration, reconstitution of a lyophilized powder, prepared as described herein, is typically used.
Compositions comprising kinase inhibitors of the present invention may be administered or coadministered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally. The compounds and/or compositions according to the invention may also be administered or coadministered in slow release dosage forms.
The kinase inhibitors and compositions comprising them may be administered or coadministered in any conventional dosage form. Co-administration in the context of this invention is intended to mean the administration of more than one therapeutic agent, one of which includes a kinase inhibitor, in the course of a coordinated treatment to achieve an improved clinical outcome. Such co-administration may also be coextensive, that is, occurring during overlapping periods of time.
Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may optionally include one or more of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; agents for the adjustment of tonicity such as sodium chloride or dextrose, and agents for adjusting the acidity or alkalinity of the composition, such as alkaline or acidifying agents or buffers like carbonates, bicarbonates, phosphates, hydrochloric acid, and organic acids like acetic and citric acid. Parenteral preparations may optionally be enclosed in ampules, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material.
When kinase inhibitors according to the present invention exhibit insufficient solubility, methods for solubilizing the compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN, or dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.
Upon mixing or adding kinase inhibitors according to the present invention to a composition, a solution, suspension, emulsion or the like may be formed. The form of the resulting composition will depend upon a number of factors, including the intended mode of administration, and the solubility of the compound in the selected carrier or vehicle. The effective concentration needed to ameliorate the disease being treated may be empirically determined.
Compositions according to the present invention are optionally provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, dry powders for inhalers, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds, particularly the pharmaceutically acceptable salts, preferably the sodium salts, thereof. The pharmaceutically therapeutically active compounds and derivatives thereof are typically formulated and administered in unit-dosage forms or multiple-dosage forms. Unit-dose forms, as used herein, refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit-dose forms include ampoules and syringes individually packaged tablet or capsule. Unit-dose forms may be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pint or gallons. Hence, multiple dose form is a multiple of unit-doses that are not segregated in packaging.
In addition to one or more kinase inhibitors according to the present invention, the composition may comprise: a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose; a lubricant, such as magnesium stearate, calcium stearate and talc; and a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polyinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and other such binders known to those of skill in the art. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents. Actual methods of preparing such dosage forms are known in the art, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975. The composition or formulation to be administered will, in any event, contain a sufficient quantity of a kinase inhibitor of the present invention to reduce kinases activity in vivo, thereby treating the disease state of the subject.
Dosage forms or compositions may optionally comprise one or more kinase inhibitors according to the present invention in the range of 0.005% to 100% (weight/weight) with the balance comprising additional substances such as those described herein. For oral administration, a pharmaceutically acceptable composition may optionally comprise any one or more commonly employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate, sodium saccharin, talcum. Such compositions include solutions, suspensions, tablets, capsules, powders, dry powders for inhalers and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparing these formulations are known to those skilled in the art. The compositions may optionally contain 0.01%-100% (weight/weight) of one or more kinase inhibitors, optionally 0.1-95%; and optionally 1-95%.
Salts, preferably sodium salts, of the kinase inhibitors may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings. The formulations may further include other active compounds to obtain desired combinations of properties.
Formulations for Oral Administration
Oral pharmaceutical dosage forms may be as a solid, gel or liquid. Examples of solid dosage forms include, but are not limited to tablets, capsules, granules, and bulk powders. More specific examples of oral tablets include compressed, chewable lozenges and tablets that may be enteric-coated, sugar-coated or film-coated. Examples of capsules include hard or soft gelatin capsules. Granules and powders may be provided in non-effervescent or effervescent forms. Each may be combined with other ingredients known to those skilled in the art.
In certain embodiments, kinase inhibitors according to the present invention are provided as solid dosage forms, preferably capsules or tablets. The tablets, pills, capsules, troches and the like may optionally contain one or more of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent.
Examples of binders that may be used include, but are not limited to, microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste.
Examples of lubricants that may be used include, but are not limited to, talc, starch, magnesium or calcium stearate, lycopodium and stearic acid.
Examples of diluents that may be used include, but are not limited to, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.
Examples of glidants that may be used include, but are not limited to, colloidal silicon dioxide.
Examples of disintegrating agents that may be used include, but are not limited to, crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose.
Examples of coloring agents that may be used include, but are not limited to, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate.
Examples of sweetening agents that may be used include, but are not limited to, sucrose, lactose, mannitol and artificial sweetening agents such as sodium cyclamate and saccharin, and any number of spray-dried flavors.
Examples of flavoring agents that may be used include, but are not limited to, natural flavors extracted from plants such as fruits and synthetic blends of compounds that produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate.
Examples of wetting agents that may be used include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
Examples of anti-emetic coatings that may be used include, but are not limited to, fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates.
Examples of film coatings that may be used include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.
If oral administration is desired, the salt of the compound may optionally be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.
When the dosage unit form is a capsule, it may optionally additionally comprise a liquid carrier such as a fatty oil. In addition, dosage unit forms may optionally additionally comprise various other materials that modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
Compounds according to the present invention may also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may optionally comprise, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
The kinase inhibitors of the present invention may also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. For example, if a compound is used for treating asthma or hypertension, it may be used with other bronchodilators and antihypertensive agents, respectively.
Examples of pharmaceutically acceptable carriers that may be included in tablets comprising kinase inhibitors of the present invention include, but are not limited to binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents. Enteric-coated tablets, because of the enteric-coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines. Sugar-coated tablets may be compressed tablets to which different layers of pharmaceutically acceptable substances are applied. Film-coated tablets may be compressed tablets that have been coated with polymers or other suitable coating. Multiple compressed tablets may be compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned. Coloring agents may also be used in tablets. Flavoring and sweetening agents may be used in tablets, and are especially useful in the formation of chewable tablets and lozenges.
Examples of liquid oral dosage forms that may be used include, but are not limited to, aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
Examples of aqueous solutions that may be used include, but are not limited to, elixirs and syrups. As used herein, elixirs refer to clear, sweetened, hydroalcoholic preparations. Examples of pharmaceutically acceptable carriers that may be used in elixirs include, but are not limited to solvents. Particular examples of solvents that may be used include glycerin, sorbitol, ethyl alcohol and syrup. As used herein, syrups refer to concentrated aqueous solutions of a sugar, for example, sucrose. Syrups may optionally further comprise a preservative.
Emulsions refer to two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid. Emulsions may optionally be oil-in-water or water-in-oil emulsions. Examples of pharmaceutically acceptable carriers that may be used in emulsions include, but are not limited to non-aqueous liquids, emulsifying agents and preservatives.
Examples of pharmaceutically acceptable substances that may be used in non-effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents.
Examples of pharmaceutically acceptable substances that may be used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide.
Coloring and flavoring agents may optionally be used in all of the above dosage forms.
Particular examples of preservatives that may be used include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
Particular examples of non-aqueous liquids that may be used in emulsions include mineral oil and cottonseed oil.
Particular examples of emulsifying agents that may be used include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.
Particular examples of suspending agents that may be used include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as sodium cyclamate and saccharin.
Particular examples of wetting agents that may be used include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
Particular examples of organic acids that may be used include citric and tartaric acid.
Sources of carbon dioxide that may be used in effervescent compositions include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof.
Particular examples of flavoring agents that may be used include natural flavors extracted from plants such fruits, and synthetic blends of compounds that produce a pleasant taste sensation.
For a solid dosage form, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule. Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. water, to be easily measured for administration.
Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include those set forth in U.S. Pat. Nos. Re 28,819 and 4,358,603.
Injectables, Solutions, and Emulsions
The present invention is also directed to compositions designed to administer the kinase inhibitors of the present invention by parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectables may be prepared in any conventional form, for example as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
Examples of excipients that may be used in conjunction with injectables according to the present invention include, but are not limited to water, saline, dextrose, glycerol or ethanol. The injectable compositions may also optionally comprise minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplated herein. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.
Parenteral administration of the formulations includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as the lyophilized powders described herein, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous.
When administered intravenously, examples of suitable carriers include, but are not limited to physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
Examples of pharmaceutically acceptable carriers that may optionally be used in parenteral preparations include, but are not limited to aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
Examples of aqueous vehicles that may optionally be used include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection.
Examples of nonaqueous parenteral vehicles that may optionally be used include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil.
Antimicrobial agents in bacteriostatic or fungistatic concentrations may be added to parenteral preparations, particularly when the preparations are packaged in multiple-dose containers and thus designed to be stored and multiple aliquots to be removed. Examples of antimicrobial agents that may be used include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride.
Examples of isotonic agents that may be used include sodium chloride and dextrose. Examples of buffers that may be used include phosphate and citrate. Examples of antioxidants that may be used include sodium bisulfate. Examples of local anesthetics that may be used include procaine hydrochloride. Examples of suspending and dispersing agents that may be used include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Examples of emulsifying agents that may be used include Polysorbate 80 (TWEEN 80). A sequestering or chelating agent of metal ions include EDTA.
Pharmaceutical carriers may also optionally include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
The concentration of a kinase inhibitor in the parenteral formulation may be adjusted so that an injection administers a pharmaceutically effective amount sufficient to produce the desired pharmacological effect. The exact concentration of a kinase inhibitor and/or dosage to be used will ultimately depend on the age, weight and condition of the patient or animal as is known in the art.
Unit-dose parenteral preparations may be packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration should be sterile, as is know and practiced in the art.
Injectables may be designed for local and systemic administration. Typically a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1% w/w up to about 90% w/w or more, preferably more than 1% w/w of the kinase inhibitor to the treated tissue(s). The kinase inhibitor may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment will be a function of the location of where the composition is parenterally administered, the carrier and other variables that may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens may need to be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations. Hence, the concentration ranges set forth herein are intended to be exemplary and are not intended to limit the scope or practice of the claimed formulations.
The kinase inhibitor may optionally be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease state and may be empirically determined.
Lyophilized Powders
The kinase inhibitors of the present invention may also be prepared as lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. The lyophilized powders may also be formulated as solids or gels.
Sterile, lyophilized powder may be prepared by dissolving the compound in a sodium phosphate buffer solution containing dextrose or other suitable excipient. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. Briefly, the lyophilized powder may optionally be prepared by dissolving dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent, about 1-20%, preferably about 5 to 15%, in a suitable buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH. Then, a kinase inhibitor is added to the resulting mixture, preferably above room temperature, more preferably at about 30-35° C., and stirred until it dissolves. The resulting mixture is diluted by adding more buffer to a desired concentration. The resulting mixture is sterile filtered or treated to remove particulates and to insure sterility, and apportioned into vials for lyophilization. Each vial may contain a single dosage or multiple dosages of the kinase inhibitor.
Topical Administration
The kinase inhibitors of the present invention may also be administered as topical mixtures. Topical mixtures may be used for local and systemic administration. The resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration.
The kinase inhibitors may be formulated as aerosols for topical application, such as by inhalation (see, U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will typically have diameters of less than 50 microns, preferably less than 10 microns.
The kinase inhibitors may also be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the kinase inhibitor alone or in combination with other pharmaceutically acceptable excipients can also be administered.
Formulations for Other Routes of Administrations
Depending upon the disease state being treated, other routes of administration, such as topical application, transdermal patches, and rectal administration, may also be used. For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories are used herein mean solid bodies for insertion into the rectum that melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The typical weight of a rectal suppository is about 2 to 3 gm. Tablets and capsules for rectal administration may be manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.
Examples of Formulations
The following are particular examples of oral, intravenous and tablet formulations that may optionally be used with compounds of the present invention. It is noted that these formulations may be varied depending on the particular compound being used and the indication for which the formulation is going to be used.
Kits Comprising Kinase Inhibitors
The invention is also directed to kits and other articles of manufacture for treating diseases associated with kinases. It is noted that diseases are intended to cover all conditions for which the kinases possesses activity that contributes to the pathology and/or symptomology of the condition.
In one embodiment, a kit is provided that comprises a composition comprising at least one kinase inhibitor of the present invention in combination with instructions. The instructions may indicate the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition. The kit may also comprise packaging materials. The packaging material may comprise a container for housing the composition. The kit may also optionally comprise additional components, such as syringes for administration of the composition. The kit may comprise the composition in single or multiple dose forms.
In another embodiment, an article of manufacture is provided that comprises a composition comprising at least one kinase inhibitor of the present invention in combination with packaging materials. The packaging material may comprise a container for housing the composition. The container may optionally comprise a label indicating the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition. The kit may also optionally comprise additional components, such as syringes for administration of the composition. The kit may comprise the composition in single or multiple dose forms.
It is noted that the packaging material used in kits and articles of manufacture according to the present invention may form a plurality of divided containers such as a divided bottle or a divided foil packet. The container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a “refill” of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. The container that is employed will depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle that is in turn contained within a box. Typically the kit includes directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral, topical, transdermal and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
One particular example of a kit according to the present invention is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
Another specific embodiment of a kit is a dispenser designed to dispense the daily doses one at a time in the order of their intended use. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter that indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
1. Preparation of Kinase Inhibitors
Various methods may be developed for synthesizing compounds according to the present invention. Representative methods for synthesizing these compounds are provided in the Examples. It is noted, however, that the compounds of the present invention may also be synthesized by other synthetic routes that others may devise.
It will be readily recognized that certain compounds according to the present invention have atoms with linkages to other atoms that confer a particular stereochemistry to the compound (e.g., chiral centers). It is recognized that synthesis of compounds according to the present invention may result in the creation of mixtures of different stereoisomers (enantiomers, diastereomers). Unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all of the different possible stereoisomers.
Various methods for separating mixtures of different stereoisomers are known in the art. For example, a racemic mixture of a compound may be reacted with an optically active resolving agent to form a pair of diastereoisomeric compounds. The diastereomers may then be separated in order to recover the optically pure enantiomers. Dissociable complexes may also be used to resolve enantiomers (e.g., crystalline diastereoisomeric salts). Diastereomers typically have sufficiently distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) that they can be readily separated by taking advantage of these dissimilarities. For example, diastereomers can typically be separated by chromatography or by separation/resolution techniques based upon differences in solubility. A more detailed description of techniques that can be used to resolve stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
Compounds according to the present invention can also be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds are set forth in the definitions section of this Application. Alternatively, the salt forms of the compounds can be prepared using salts of the starting materials or intermediates.
The free acid or free base forms of the compounds can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
The N-oxides of compounds according to the present invention can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0° C. Alternatively, the N-oxides of the compounds can be prepared from the N-oxide of an appropriate starting material.
Compounds in an unoxidized form can be prepared from N-oxides of compounds by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80° C.
Prodrug derivatives of the compounds can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, or the like).
Protected derivatives of the compounds can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.
Compounds according to the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
Compounds according to the present invention can also be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of compounds, dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or thee-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:
All references to ether or Et2O are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in ° C. (degrees Centigrade). All reactions conducted under an inert atmosphere at RT unless otherwise noted.
1H NMR spectra were recorded on a Bruker Avance 400. Chemical shifts are expressed in parts per million (ppm). Coupling constants are in units of Hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).
Low-resolution mass spectra (MS) and compound purity data were acquired on a Waters ZQ LC/MS single quadrupole system equipped with electrospray ionization (ESI) source, UV detector (220 and 254 nm), and evaporative light scattering detector (ELSD). Thin-layer chromatography was performed on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid, Ninhydrin or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (230-400 mesh, Merck).
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as the Aldrich Chemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis, Mo.), or may be prepared by methods well known to a person of ordinary skill in the art, following procedures described in such standard references as Fieser and Fieser's Reagents for Organic Synthesis, vols. 1-17, John Wiley and Sons, New York, N.Y., 1991; Rodd's Chemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier Science Publishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons, New York, N.Y., 1991; March J.: Advanced Organic Chemistry, 4th ed., John Wiley and Sons, New York, N.Y.; and Larock: Comprehensive Organic Transformations, VCH Publishers, New York, 1989.
The entire disclosure of all documents cited throughout this application are incorporated herein by reference.
2. Synthetic Schemes for Kinase Inhibitors of the Present Invention
Kinase inhibitors according to the present invention may be synthesized according to the reaction schemes shown below. Other reaction schemes could be readily devised by those skilled in the art. It should also be appreciated that a variety of different solvents, temperatures and other reaction conditions can be varied to optimize the yields of the reactions.
In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Greene and P. G. M. Wuts in “Protective Groups in Organic Chemistry” John Wiley and Sons, 1991.
Step 1: Alkylation of Isatin
The heteroaromatic compound (2.5 mmol) in THF (5 mL) was cooled to 0° C. under N2 and nBuLi (2.5 mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h, then isatin (147 mg, 1 mmol) in THF (5 mL) was added via syringe. The reaction was allowed to warm to 23° C. and was stirred overnight. The reaction was quenched with water, diluted with Et2O, washed with water and brine, and the organic layer was dried (MgSO4) and concentrated in vacuo. The crude product was carried forward.
Step 2: Reduction of 3-Hydroxy-3-Substituted Oxindoles
The alcohol (0.6 mmol) was placed in AcOH/HCl (1:1, 4 mL) and stirred at 23° C. for 5 min, followed by addition of SnCl2 (1.2 mmol). If complete conversion is not observed after 1 h, the reaction was warmed to 50° C. for 18 h. Once conversion is complete, the crude reaction mixture is poured over ice and neutralized with NaHCO3. The aqueous layer is extracted with Et2O, washed with water and brine, dried (MgSO4) and conc in vacuo. The crude product is purified by flash chromatography using a gradient of EtOAc in hexanes to give the final product.
The alkylation of 1,2-diketoamides, such as isatin, or its derivatives, may be performed by the metalation of various aromatic or heteroaromatic compounds and their substituted derivatives using metals or organometal compounds. The 1,2-diketoamides may be subsequently treated with the metalated aromatic or heteroaromatic compound to form the alkoxide intermediate, which may be quenched to form the corresponding alcohol. The reaction may be performed in an aprotic organic solvent, such as THF and the like, and the reaction may be performed between about −78° C. and 25° C., more preferably between about −50° C. and 15° C., and most preferably between about −25° C. and 5° C.
The reaction may be stirred for about 5 minutes to about 24 hours, or until the reaction is deemed complete. In a particular embodiment, the reaction may be stirred at about 0° C. for about one hour and then allowed to warm to about 23° C. overnight. Once the reaction is deemed to be complete, the reaction mixture may be quenched with water, diluted with an organic solvent such as diethyl ether, and then further washed with water and brine. The solvent may be dried and the product may be purified and isolated, if desired, using standard methods known in the art. In some processes, the crude product may be used as is in the subsequent reaction without further purification.
The direct reduction of the alcohol to the hydrocarbon compound may be performed using various metals known in the art. In one embodiment, the reduction of the tertiary alcohol may be accomplished with a metal halide in acidic an acidic condition. For example, the above alcohol may be placed in a solution of acetic acid and hydrochloric acid and the mixture may be stirred at about 23° C. for about 5 minutes and a metal, such as SnCl2 may be added. The reaction may be stirred at about room temperature or may be heated to about 50° C. for about 1 hour to about 3 days, preferably about 18 to 20 hours until conversion is complete. The reaction may be worked up, and the product may be purified and isolated using standard methods known in the art.
Step 1:
Under ice cooling, 60% NaH (96 mg, 2.4 mmol) is added to a THF (10 mL) solution of (1H-Benzoimidazol-2-yl)-acetic acid methyl ester (456 mg, 2.4 mmol) and 1-Fluoro-2-nitrobenzene (282 mg, 2.0 mmol), and the mixture stirred at 23° C. for 2 hours. The reaction is diluted with EtOAc and washed with water and brine, then dried (MgSO4) and concentrated in vacuo. If necessary, the product is purified by recrystallization or chromatography.
Step 2:
A DMF (50 mL) solution of (1H-Benzoimidazol-2-yl)-(2-nitro-phenyl)-acetic acid methyl ester (1.0 g, 3.2 mmol) is mixed with 10% Pd/C (100 mg) and the mixture stirred under hydrogen at atmospheric pressure at 23° C. for 18 hours. The reaction is filtered through celite and the filtrate mixed with saturated brine and extracted with EtOAc. The organic layer is washed with water and brine, then dried (MgSO4) and concentrated in vacuo. If necessary, the product is purified by recrystallization or chromatography.
For example, Reaction Scheme 2 and variations thereof can be used to prepare the following:
Step 1:
Ethyl 3-oxobutyrate (130 mg, 1.0 mmol) is added to an acetic anhydride (10 mL) solution of 2-chloro-[1,2,4]triazolo[1,5-a]pyridine (153 mg, 1.0 mmol) and sodium acetate (82 mg, 1.0 mmol) and stirred at 60° C. The reaction solution is alkalized and then extracted with EtOAc. The residue, after evaporation of the solvent, is mixed with 4 M HCl and stirred, and the alkalized reaction solution extracted with EtOAc. If necessary, the product is purified by recrystallization or chromatography.
Step 2:
Under ice cooling, 60% NaH (96 mg, 2.4 mmol) is added to a THF (10 mL) solution of [1,2,4]Triazolo[1,5-a]pyridin-2-yl-acetic acid methyl ester (458 mg, 2.4 mmol) and 1-Fluoro-2-nitro-benzene (282 mg, 2.0 mmol), and the mixture stirred at 23° C. for 2 hours. The reaction product is diluted with EtOAc and washed with water and brine, then dried (MgSO4) and concentrated in vacuo. If necessary, the product is purified by recrystallization or chromatography.
Step 3:
A DMF (50 mL) solution of (2-Nitro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-acetic acid methyl ester (1.0 g, 3.2 mmol) is mixed with 10% Pd/C (100 mg) and the mixture stirred under hydrogen at atmospheric pressure at 23° C. for 18 hours. The reaction product is filtered through celite and the filtrate mixed with saturated brine and extracted with EtOAc. The organic layer is washed with water and brine, then dried (MgSO4) and concentrated in vacuo. If necessary, the product is purified by recrystallization or chromatography.
For example, Reaction Scheme 3, and variations thereof, can be used to prepare the following:
In each of the above reaction procedures or schemes, the various substituents may be selected from among the various substituents otherwise taught herein.
Descriptions of the syntheses of particular compounds according to the present invention based on the above reaction schemes are set forth herein.
3. Example of Kinase Inhibitor
The present invention is further exemplified, but not limited by, the following example that describes a particular compound according to the invention that was prepared according to Reaction Scheme 1:
3-(1-Methyl-1H-benzoimidazol-2-yl)-1H-indol-2-ol: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.93 (s, 3H), 6.99 (d, 2H), 7.11 (d, 2H), 7.44 (d, 2H), 7.62 (d, 2H), 10.29 (s, 1H), 11.01 (s, 1H). ESI-MS: m/z 264.0 (M+H)+.
4. Biological Testing
The activity of compounds as protein kinase inhibitors may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of the activated protein kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/protein kinase complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with the protein kinase bound to known radioligands.
A. Determination of Inhibition of AIK
The inhibitory properties of compounds relative to AIK may be determined by the Direct Fluorescence Polarization detection method (FP) using a Greiner small volume black 384-well-plate format under the following reaction conditions: 50 mM Hepes pH 7.3, 10 mM MgCl2, 10 mM NaCl, 1 mM DTT, 0.01% Brij35, 100 nM Fluorescein-LRRASLG peptide (provided by SYNPEP), 5% DMSO, 2.5 uM ATP. Detection of the reaction product is performed by addition of IMAP binding reagent (Molecular Devices). Reaction product may be determined quantitatively by FP using an Analyst HT plate reader (Molecular Devices) with an excitation wavelength at 485 nm and emission at 530 nm and using a Fluorescein 505 dichroic mirror.
The assay reaction may be initiated as follows: 2 ul of (3×) 300 nM Fl-Peptide/7.5 uM ATP was added to each well of the plate, followed by the addition of 2 ul of (3×) inhibitor (2.5 fold serial dilutions for 11 data points for each inhibitor) containing 15% DMSO. 2 ul of (3×) 7.5 nM AIK solution may be added to initiate the reaction (final enzyme concentration was 2.5 nM for AIK). The reaction mixture may then be incubated at room temperature for 45 min, and quenched and developed by addition of 20 ul of 1 to 400 diluted IMAP binding reagent in 1× proprietary IMAP binding buffer. Fluorescence polarization readings of the resulting reaction mixtures may be measured after a 60-minute incubation at room temperature.
IC50 values may be calculated by non-linear curve fitting of the compound concentrations and fluorescent polarization values to the standard IC50 equation. As a reference point for this assay, Staurosporin showed an IC50 of <10 nM.
B. Determination of Inhibition of c-KIT
The inhibitory properties of compounds relative to c-Kit may be determined by the Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) method using a small volume black 384-well-plate (Greiner) format under the following reaction conditions: 50 mM Hepes pH 7.3, 10 mM MgCl2, 10 mM NaCl, 1 mM DTT, 0.01% Brij35, 250 nM Biotin-EGPWLEEEEEAYGWMDF peptide (provided by SYNPEP), 5% DMSO, 100 uM ATP. Detection of the reaction product may be performed by addition of Streptavidin-APC (Prozyme) and Eu-Anti-phosphotyrosine antibody (Perkin Elmer). Reaction product may be determined quantitatively by TR-FRET reading using an Analyst HT plate reader (Molecular Devices) with an excitation wavelength at 330 nm and emission at 615 nm (Europium) compared to 330 nm excitation (Europium) and emission 665 nm (APC) and using an Europium 400 dichroic mirror.
The assay reaction may be initiated as follows: 4 ul of (2.5×) 625 nM Biotin-Peptide/250 uM ATP was added to each well of the plate, followed by the addition of 2 ul of (5×) inhibitor (2.5 fold serial dilutions for 11 data points for each inhibitor) containing 25% DMSO. 4 ul of (2.5×) c-Kit solution may be added to initiate the reaction (final enzyme concentration was 0.13 nM for c-Kit). The reaction mixture may then be incubated at room temperature for 30 min, and quenched and developed by addition of 10 ul of (2×) 3.2 nM Eu-Antibody and 25 nM Streptavidin-APC in 50 μM Hepes pH 7.3, 30 mM EDTA, 0.1% Triton X-100 buffer. TR-FRET readings of the resulting reaction mixtures may be measured after a 60-minute incubation at room temperature on the Analyst HT.
IC50 values may be calculated by non-linear curve fitting of the compound concentrations and ratio metric Eu:APC values to the standard IC50 equation. As a reference point for this assay, Staurosporin showed an IC50 of <5 nM.
The following abbreviations have been used:
The kinase inhibitor provided herein was found to have IC50 values less than 100,000 nM.
It will be apparent to those skilled in the art that various modifications and variations can be made in the compounds, compositions, kits, and methods of the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of the invention provided they come within the scope of the appended claims and their equivalents.
This application claims the benefit of U.S. Provisional Application No. 60/565,236, filed Apr. 23, 2004, which is incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 60565236 | Apr 2004 | US |
