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WO2003031405A2 - Methodes de synthese de purines substituees - Google Patents

Methodes de synthese de purines substituees Download PDF

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Publication number
WO2003031405A2
WO2003031405A2 PCT/US2002/032679 US0232679W WO03031405A2 WO 2003031405 A2 WO2003031405 A2 WO 2003031405A2 US 0232679 W US0232679 W US 0232679W WO 03031405 A2 WO03031405 A2 WO 03031405A2
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formula
compound
resin
bound
substituted
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WO2003031405A3 (fr
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Sheng Ding
Qiang Ding
Nathanael S. Gray
Peter G. Schultz
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IRM LLC
Scripps Research Institute
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IRM LLC
Scripps Research Institute
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Priority to CA002463507A priority Critical patent/CA2463507A1/fr
Priority to JP2003534389A priority patent/JP2005509612A/ja
Priority to AU2002334992A priority patent/AU2002334992B2/en
Priority to EP02801053A priority patent/EP1529048A4/fr
Publication of WO2003031405A2 publication Critical patent/WO2003031405A2/fr
Anticipated expiration legal-status Critical
Publication of WO2003031405A3 publication Critical patent/WO2003031405A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6

Definitions

  • This invention pertains to the field of methods for preparing libraries of purine compounds.
  • the invention relates to methods of preparing 2, 6, 9- substituted purine compounds on solid phase supports by employing sulfenylpurine intermediates.
  • the purine ring system is a key structural element of the substrates and ligands of many biosynthetic, regulatory and signal transduction proteins including cellular kinases, G proteins and polymerases.
  • inhibitors of protein kinases have proven to be invaluable tools in the elucidation of signal transduction networks as well as promising clinical candidates in a multitude of disease such as cancer, cardiovascular disease, inflammatory disease and neurological disease.
  • various purine analogs have been found to be highly potent therapeutic agents for disease.
  • the purine ring system has been a good starting point in the search for inhibitors of kinases, G proteins and many biomedically significant processes.
  • the design of synthetic schemes for generating a multitude of structurally diverse compounds typically involves creating the libraries in situ in solution phase or on solid support, i.e., solid phase.
  • solid phase synthesis the desired compounds are generated while attached to the solid support via a linker prepared on a polymeric solid support material, e.g., polystyrene.
  • the present invention is directed to methods of preparing diverse 2,6-, 2,9, 2,6,9-, O 6 -alkyl- and O 6 -aryl-substituted purine compounds on solid support phase.
  • the methods involve using a novel intermediate compound, a 2-halo-6- sulfenyl purine.
  • the invention also encompasses these sulfenylpurine intermediates and methods for their preparation.
  • the present invention provides a method of preparing a 2,6,9-substituted purine compounds having the Formula I:
  • Ri and R 2 are independently selected and are functional groups including, but not limited to, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl and heterocyclyl;
  • R 3 is hydrogen; and
  • j is a functional group including, but not limited to, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl and heterocyclyl; or, R 3 and Rj when taken together with the nitrogen and carbon atoms to which they are respectively attached form an optionally substituted saturated heterocyclic ring.
  • R 1 and R are as defined above and n is 0 or 1.
  • R 3 and R are as defined above.
  • Ri, R 2 , R 3 and Ri are as defined above.
  • the compound is a compound of Formula
  • X in Formula VI, is fluoro, chloro or bromo, and n is as defined above.
  • R in Formula VI, is fluoro, chloro or bromo, and n is as defined above.
  • n is as defined above.
  • the compound of Formula II can be prepared using a method comprising: a) capturing a compound of Formula VI
  • the compound of Formula NI is prepared by reacting 2-halo-6-halo-purine with a compound of Formula IX:
  • the halo groups of the 2-halo-6-halo-purine compound are fluoro, chloro, bromo or iodo and, preferably chloro.
  • step (a) is carried out with m-chloroperbenzoic acid in a buffered solution.
  • step (c) is carried out in the presence of trifluoroacetic acid.
  • alkylation of the compound of Formula NI is carried out in the presence of an inert solvent and a phosphine (e.g., triphenylphosphine, tricyclohexylphosphine, etc.).
  • the resin is 4-formyl-3,5-dimethyloxyphenoxymethyl functional polystyrene resin.
  • the present invention also provides a combinatorial library or array comprising a plurality of 2, 6, 9-substituted purine compounds prepared by the above method.
  • the present invention provides a compound of Formula NI:
  • the present invention provides a method of preparing 2, 9-substituted purine compounds having the Formula X:
  • Ri and R 2 are independently selected and are functional groups including, but not limited to, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl and heterocyclyl; and n is 0 or 1.
  • the resin- bound compound of Formula II is prepared using one of the methods set forth above for preparing such compound.
  • the present invention also provides a combinatorial library or array comprising a plurality of 2,9-substituted purine compounds prepared by the above method.
  • the present invention provides a method for preparing O 6 -alkyl-purine compounds of Formula XI:
  • Ri and R are independently selected and are functional groups including, but not limited to, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl and heterocyclyl;
  • R 3 is a functional group including, but not limited to, alkyl and substituted alkyl; and
  • n is 0 or 1.
  • the resin-bound compound of Formula II is prepared using one of the methods set forth above for preparing such compound.
  • the present invention also provides a combinatorial library or array comprising a plurality of O 6 -alkyl-purine compounds prepared by the above method.
  • the present invention provides a method for preparing O 6 -aryl purine compounds of Formula XIII:
  • Ri and R are independently selected and are functional groups including, but not limited to, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl and heterocyclyl; R 3 is a functional group including, but not limited to, aryl or substituted aryl; and n is 0 or 1.
  • the resin-bound compound of Formula II is prepared using one of the methods set forth above for preparing such compound.
  • the present invention also provides a combinatorial library or array comprising a plurality of O 6 -aryl-purine compounds prepared by the above method.
  • the present invention provides a method for preparing a compound of Formula NI:
  • X is fluoro, chloro or bromo; and n is 0 or 1.
  • the present invention provides a method for the for synthesis of a C2-substituted purine, the method comprising reacting a C6- sulfenylpurine with a nucleophile, wherein X is halogen, and the nucleophile is substituted at the C2 position of the purine.
  • the nucleophile is an amine.
  • the C6-sulfenyl ⁇ urine comprises a solid support, Formula XIN:
  • the method further comprises oxidizing a thioether linkage between the purine and the sulfenyl moiety to a sulfone of Formula XN:
  • R 1 is a functional group including, but not limited to, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl and heterocyclyl, and substituting a different group at the C6 position of the purine.
  • the C6 sulfenylpurine is a 2-fluoro-6-phenylsulfenyl or a 2-fluoro-6-benzylsulfenyl.
  • Figure 1 shows examples of substituents that have been introduced at the C2 position of purines using the methods of the invention as shown in Scheme 6. These substituents were introduced by palladium catalyzed cross-coupling reactions using Pd 2 (dba) 3 , carbene or phosphine ligand, corresponding boronic acid and Cs 2 CO 3 for C-C bond formation, anilme and KO'Bu for C-N bond formation, phenol and K 3 PO 4 for C-O bond formation. These substituents can also be introduced by reacting with corresponding aniline/phenol and KO l Bu in THF at 70 °C.
  • Figure 2 shows validated substituents at the C2 position of purine introduced by nucleophilic aromatic substitution with primary and secondary amines as shown in Scheme 11.
  • Figure 3 shows validated substituents at the C6 position of purine introduced by nucleophilic aromatic substitution with primary and secondary amines as shown in Scheme 11.
  • the term "leaving group” refers to a portion of a substrate that is cleaved from the substrate in a reaction.
  • Protecting group refers to a portion of a substrate that is substantially stable under a particular reaction condition, but which is cleaved from the substrate under a different reaction condition.
  • a protecting group can also be selected such that it participates in the direct oxidation of the aromatic ring component of the compounds of the invention.
  • useful protecting groups see, for example, Greene et al, Protective Groups In Organic Synthesis, John Wiley & Sons, New York (1991).
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C ⁇ - do means one to ten carbons).
  • saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • alkyl groups examples include vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-pro ⁇ ynyl, 3-butynyl, and the higher homologs and isomers.
  • alkyl unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below as “heteroalkyl.” Alkyl groups which are limited to hydrocarbon groups are termed "homoalkyl".
  • alkoxy alkylamino and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized.
  • the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group.
  • the heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule.
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH 2 -CH 2 -S-CH 2 CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include 1 -(1,2,5,6-tetrahydropyridyl), 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2- piperazinyl, and the like.
  • haloalkyl are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(C ⁇ -C 4 )alkyl is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • aryl means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (up to three rings), which are fused together or linked covalently.
  • heteroaryl refers to aryl groups (or rings) that contain from zero to four heteroatoms selected from N, O, and S, wherein the mtrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-is
  • aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l- naphthyloxy)propyl, and the like).
  • alkyl group e.g., benzyl, phenethyl, pyridylmethyl and the like
  • an oxygen atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l- naphthyloxy
  • R', R", R'" and R" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present.
  • R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.
  • -NR'R is meant to include, but not be limited to, 1-pyrrolidinyl and 4- morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like).
  • each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present.
  • the term "independently selected” is used herein to indicate that the R groups, e.g., RI and R2, can be identical or different (e.g., R.1 and R2 may all be substituted alkyls or RI may be a substituted alkyl and R2 may be an aryl, etc.).
  • a named R group will generally have the structure which is recognized in the art as corresponding to R groups having that name. For the purposes of illustration, representative R groups as enumerated above are defined herein. These definitions are intended to supplement and illustrate, not preclude, the definitions known to those of skill in the art.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CRR') q -U-, wherein T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH ) r -B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'- or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X-(CR"R'") -, where s and d are independently integers of from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR'-.
  • the substituents R, R', R" and R'" are preferably independently selected from hydrogen or substituted or unsubstituted (C ⁇ -C 6 )alkyl.
  • the term "heterocycle,” refers to both heterocycloalkyl and heteroaryl groups.
  • heteroatom is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
  • salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al, Journal of Pharmaceutical Science, 66, 1-19 (1977)).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the present invention provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention. [0064] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the present invention.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • the present invention provides solid phase methods of preparing diverse purine compounds.
  • the present invention provides methods for producing 2,6-, 2,6,9-, 2,9-, O -alkyl-, and O aryl-substituted purine compounds as well as novel substituted purine compounds.
  • the methods use novel C-6 sulfenylpurine compounds as intermediates. Methods of preparing the intermediates are also encompassed by the present invention.
  • the methods of the present invention overcome limitations described above in preparing 2,6 and 2,6,9-substituted purines by, for example, employing 1) an arylsulfenyl group as a "protective" group at the C6 position of the purine ring which when subsequently oxidized to an arylsulfonyl group allows the quantitative and selective substitution by an amine to the C2 position prior to substitution at the C6 position; and 2) in preferred embodiments, a "traceless" amine linkage to solid support, wherein the amine linker is incorporated into the final purine compound.
  • the methods described herein are useful not only for substitution of purines, but also of other heterocycles.
  • the methods are suitable for use with a combinatorial scaffold approach towards heterocycle libraries, as described in U.S. Provisional Patent Application No. 60/331,835, which is entitled “Kinase Inhibitor Scaffolds,” and which was filed on November 20, 2001, in U.S. Provisional Patent Application No. 60/346,480, which is entitled “Kinase Inhibitor Scaffolds,” and which was filed on January 7, 2002, and in U.S. Provisional Patent Application No. 60/348,089, which is entitled “Kinase Inhibitor Scaffolds,” and which was filed on January 10, 2002.
  • the methods are also suitable for use in conjunction with the methods described in U.S. Provisional Patent Application No. 60/328,763, which is entitled “Expanding the Diversity of Purine Libraries,” and which was filed on October 12, 2001.
  • the present invention provides a method of preparing a 2,6,9-substituted purine compounds having the Formula I
  • Ri and R 2 are independently selected and are functional groups including, but not limited to, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl and heterocyclyl; R 3 is hydrogen; and j is a functional group including, but not limited to, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl and heterocyclyl; or, R 3 and j when taken together with the nitrogen and carbon atoms to which they are respectively attached form an optionally substituted saturated heterocyclic ring.
  • Ri and R 2 are as defined above and n is 0 or 1.
  • R 3 and Ri are as defined above.
  • R ls R 2 , R 3 and R 4 are as defined above.
  • the resin utilized to bind the compound of Formula II in step (a) refers to a polymeric resin, including, but not limited to, polystyrene, polypropylene, polyethylene glycol, polyacrylamide, cellulose and the like which has been chemically modified by an amino group as is described in more detail below.
  • the amino group is eventually incorporated into the purine compound as described in more detail below.
  • Oxidation of the resin-bound compound of Formula II is generally carried out at room temperature utilizing a suitable oxidizing reagent and a solvent.
  • suitable oxidizing agents include, but not limited to, perbenzoic acid, m-chloroperbenzoic acid, performic acid, peracetic acid, perphthalic acid, and the like.
  • the oxidizing agent is m-chloroperbenzoic acid.
  • Suitable solvents include, but are not limited to, water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, or any other organic solvent which does not adversely affect the reaction.
  • the reaction is also carried out in the presence of a base to neutralize the oxidizing agent, thereby providing a buffered solution.
  • Suitable bases include, but are not limited to, inorganic bases such as alkali metal hydroxides, e.g., sodium hydroxide, potassium hydroxide, etc., and alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide.
  • inorganic bases such as alkali metal hydroxides, e.g., sodium hydroxide, potassium hydroxide, etc.
  • alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide.
  • the amine employed in step (b) to displace the sulfone group of the compound of Formula III includes, but is not limited to, primary amines, cyclic secondary amines (such as piperazines) and electron-rich anilines (see, e.g., Table l-"C6-substituent" column).
  • the reaction is conveniently effected by suspending the compound of Formula III in an inert solvent, such as 1,4-dioxane, followed by the addition of the amine.
  • the resin- bound compound is then washed in a solvent such as methanol and dichloromethane, and dried under vacuum to provide the resin-bound compound of Formula V.
  • Cleavage of the resin-bound compound of Formula V and liberation of the desired compound of Formula I from the resin as described in step (c) of the method is typically carried in the presence of an acid.
  • Suitable acids include, but are not limited to, an organic acid such as formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid and the like, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, etc., or the like.
  • the reaction is usually carried out in a solvent such as water, an alcohol such as methanol, ethanol, 1,4, dioxane, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a solvent such as water, an alcohol such as methanol, ethanol, 1,4, dioxane, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • the desired purine compound is freed from the resin by cleavage, it can be isolated by simply removing the solvent, e.g., by filtration.
  • the compound is a compound of Formula II, and can be prepared using a method comprising:
  • X in Formula NI, is fluoro, chloro or bromo, and n is as defined above.
  • R 2 , X and n are as defined above.
  • Alkylation of the ⁇ 9 position of the compound of Formula NI as described in step (a) of preparing the compound of Formula II can be effected under known conditions, e.g., Mitsunobu conditions as described, e.g., in Tsunoda et al, Tetrahedron Letters, 34, 1639 (1993).
  • the compound of Formula NI is mixed with an alcohol, e.g., a primary, secondary or tertiary alcohol, in approximately equimolar amounts or with an excess of either compound, in an inert solvent, such as tetrahydrofuran, chloroform or dichloromethane.
  • a slight molar excess of an azodicarboxylate, e.g., diisopropyl azodicarboxylate, and a phosphine, e.g., triphenylphosphine or tributylphosphine, are added, and the reaction is stirred at a temperature, e.g., room temperature, for a sufficient amount of time to obtain the compound of Formula Nil.
  • the compound of Formula II can be prepared using a method comprising: a) capturing a compound of Formula NI
  • the C6 position can be substituted following oxidation of the thioether to the sulfone, as demonstrated in the synthesis of 2,4-diaminopyridine (Gayo et al, Tetrahedron Lett, 38, 211 (1997)).
  • the 2-fluoro-6-thiophenylpurine can be prepared by reacting excess thiophenol with 2-fluoro-6-chloropurine in methanol at 0 °C and purified by recrystallization.
  • PAL 4-formyl-3,5- dimethoxyphenoxymethyl functionalized polystyrene resin
  • the purine ring can then, for example, be captured at the C2- position by reacting the PAL-amine resin with 1.5 equivalents of the crude N9-alkylated 2- fluoro-6-phenylsulfenylpurine and 3 equivalents of di-isopropylethylamine in n-butanol at 80 °C.
  • the C6 position can then be substituted following oxidation-activation of the thioether to the sulfone (see, Scheme 2).
  • This combinatorial scheme of the present invention has the following merits: (1) the difficulty of C2 substitution is overcome by "directing" the first substitution to C2 by using phenylsulfenyl group as a "protective” group at the C6 position; (2) N9 modification is accomplished in solution and purified by resin-capture; (3) the PAL linker allows traceless cleavage; and (4) construction of focused C6 purine libraries can readily be accomplished because this is the last step in the combinatorial synthesis scheme.
  • the method of the present invention has numerous advantages over any previously used method.
  • C2 substituents are preferably limited to primary amines (e.g., Table 1) due to the need for a reaction site to attach the purine to solid support. In some embodiments, it has been found that immobilized anilines only result in partial capture of the purine from solution. Because m-chloroperbenzoic acid is used in preferred embodiments to convert the C6 thioether to a sulfone in the final activation step, substituents having functional groups prone to oxidation cannot be readily used in the first two derivatization steps. C6 displacement of the sulfone works for primary amines, cyclic secondary amines (such as piperazines) and electron-rich anilines (see, Table 1).
  • Resin-bound amines are used to capture a C6- phenylmecapto-9-alkylated purine directly from the crude Mitsunobu alkylation reaction mixture.
  • the C6 position is then substituted following oxidation-activation of the thioether to the sulfone.
  • This strategy overcomes the difficulty of C2 substitution by "directing" the first substitution to C2 by using a phenylsulfenyl group to protect the C6 position.
  • a thousand compound combinatorial purine library has been synthesized using this approach in 96-well format. Detailed procedures, and results showing the validation of the methods for synthesis of substituted purines having a wide variety of different substituents are shown in Example 1.
  • (P) suitable protecting group a. R r NH 2 , NaBH(OAc) 3l 1% HOAc, THF; b. R 2 OH, PPh 3 , DiAD, THF; c.1, DiEA, BuOH, 80 °C; d. CH 2 CI 2 :TFA: e 2 S:H 2 0/45:45:5:5 Scheme 5. 2,9-Disubstituted guanines from protected 2-bromohypoxanthine
  • N9 Modification of N9 was achieved by regioselective alkylation of 2,6-dichloropurine under Mitsunobu conditions as previously reported.
  • the purified N9-alkylpurine could be captured onto Wang resin by treatment with 1.2 equivalents of potassium t-butoxide in THF for 8 hours.
  • the quantitative C2 amination was accomplished with non-hindered primary and secondary amines at 100 °C in DMSO for 12 hours.
  • palladium-catalyzed cross- coupling conditions were required to drive the reaction to completion.
  • the typical conditions involved reaction of the 2-chloropurine substrate with 5 equivalents of aniline in the presence of Pd 2 (dba) 3 (7 mol%), carbene ligand 1 (14 mol%), and 6 equivalents of KO t Bu in anhydrous 1,4-dioxane under argon.
  • the reactions are typically complete after stirring at 80 °C for 12 hours.
  • the 2- chloro can be reacted with arylboronic acids to form direct C-C bond connections and with phenols to form C-O connections.
  • the present invention provides an alternative method in which a 6-phenylmercaptopurine is alkylated at N9, followed by capture at C2 with a resin- bound amine and subsequently converted to the guanine derivative by oxidation of the sulfenyl group to sulfonyl group and its subsequent hydrolysis (Scheme 7).
  • This scheme has also been developed to prepare 2,6,9-trisubstituted purines.
  • the Wang resin capture strategy allows focused diversity at the C2 position with versatile reactions such as palladium catalyzed cross-coupling reactions, but requires purification of the Mitsunobu product in the first step and high temperatures for chloride displacement conditions.
  • the second approach offers the opportunity of focusing diversity at the N9 position without the need for purification of the Mitsunobu product and effects the C2 functionalization under mild conditions, but limits the C2 substituents to primary amines.
  • the present invention provides methods to synthesize O -aryl- and O -alkyl- purines, which are closely related to guanine analogs and have exhibited interesting biological activities.
  • O6-cyclohexylmethylguanine has been shown to be a competitive inhibitor of cyclin-dependent kinase 1 and 2 (CDK1 and 2) and exhibits an unique binding mode to the ATP-binding site (see, Arris et. al, J. Med. Chem., 43, 2797 (2000)).
  • Resin-bound guanine 3 offers direct access to O 6 - alkyl- purines by Mitsunobu alkylation.
  • resin-bound 6-benzenesolfonylpurine 2 could serve as a versatile intermediate to O 6 -aryl-, O 6 -alkyl- purines through DABCO/DBU mediated SNA ⁇ displacement reaction (Scheme 8). As shown in Table 2, a variety of phenols were validated using the methods of the present invention and all of them gave satisfactory results.
  • the methods of the present invention provide general and versatile solid phase strategies for the synthesis of combinatorial guanine and O°-aryl- and O 6 -alkyl- purine libraries.
  • 2,9-Disubstituted guanine analogs and O 6 -aryl/alkyl purine analogs can be constructed from commercially available purine or hypoxanthine in a traceless fashion, thus allowing ease access to compound libraries.
  • the present invention provides a resin-capture- release strategy for making combinatorial 2,6,9-trisubstituted purine libraries by capturing N9 derivatized purines at the C6 position with a thio-modified polymer.
  • the C2 halo (e.g., fluoro) group is subsequently substituted with primary and secondary amines, followed by thioether oxidation and release by C6 substitution with amines and anilines.
  • This approach complements the strategy discussed above in which a 6-phenylsulfenylpurine scaffold was captured at the C2 position with a resin-bound amine (see also, Sheng and Gray, US Provisional Patent Appl. No.
  • the starting scaffold 2-thiophenyl-6-chloropurine
  • the starting scaffold can be obtained by thiophenol displacement of commercially available 2-bromohypoxanthine followed by chlorination with POCl 3 in 90% overall yield.
  • Mitsunobu reaction can first be used to carry out alkylation reactions at the N9 position.
  • Resin-bound amine 1 which is obtained by reductive animation of a 4-formyl-3,5-dimethoxyphenoxymethyl functionalized polystyrene resin (PAL), is used to capture the N9 alkylated purine from the crude Mitsunobu reaction mixture by nucleophilic substitution at C6.
  • PAL 4-formyl-3,5-dimethoxyphenoxymethyl functionalized polystyrene resin
  • the present invention provides a method in which the purine is first linked to solid support at the C6 via a thioether.
  • the thioether linked purine is obtained by resin-capture of the crude N9 Mitsunobu alkylation product at C6 using a methylmercapto resin.
  • the C2 position is subsequently derivatized by a nucleophilic substitution reaction with amines.
  • the C6 substituent is then introduced by displacement of the sulfonyl group with amines after oxidative activation of thioether linkage and the final product is released into the reaction solution (Scheme 11).
  • This approach offers, inter alia, the following advantages: (1) secondary amines can be introduced at the C2 position; (2) only the activated polymer-bound purine intermediate can be released; (3) the activated sulfone linker allows traceless cleavage; and (4) construction of focused C2 purine libraries can readily be accomplished by coupling different amines at the C2, and using a single amine for the final displacement.
  • this method of the present invention provides an advantage relative to scheme 4 due to the technical difficulty in preparing Pal-amine resins by reductive animation in an array format.
  • the C2 position can be substituted with variety of primary amines, such and cyclic/acyclic secondary amines (see, Figure 2). Normally five equivalents of amines are used at a concentration of 2M in butanol to ensure quantitative substitution of 2-chloro-purine. Finally, the C6 displacement of the sulfonyl group can be carried out with diverse primary and secondary amines and electron-rich anilines (see, Figure 3). Rather than use excess amine to quantitatively release resin-bound purine, which requires follow-up purification by solid supported liquid extraction (SLE) (Johnson et al, Tetrahedron Lett. 54: 4097 (1998)), a limited amount of amine (0.8 equivalent) can be used.
  • SLE solid supported liquid extraction
  • this aspect of the invention provides an alternative approach or method for making combinatorial 2,6,9-trisubstituted purine libraries by capturing an N9 substituted 2-fluoro-6-chloropurine at the C6 position via a thioether linkage and subsequently modifying the polymer-bound purine intermediate at the C2 position, followed by substitution at the C6 position with concomitant release.
  • the present invention provides a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • the compounds described herein, or pharmaceutically acceptable addition salts or hydrates thereof can be delivered to a patient using a wide variety of routes or modes of administration. Suitable routes of administration include, but are not limited to, inhalation, transdermal, oral, rectal, transmucosal, intestinal and parenteral administration, including intramuscular, subcutaneous and intravenous injections.
  • the compounds described herein, or pharmaceutically acceptable salts and/or hydrates thereof may be administered singly, in combination with other compounds of the invention, and/or in cocktails combined with other therapeutic agents.
  • the choice of therapeutic agents that can be co-administered with the compounds of the invention will depend, in part, on the condition being treated.
  • the compounds when administered to a patient undergoing cancer treatment, the compounds may be administered in cocktails containing anti-cancer agents and/or supplementary potentiating agents.
  • the compounds may also be administered in cocktails containing agents that treat the side-effects of radiation therapy, such as anti-emetics, radiation protectants, etc.
  • Supplementary potentiating agents that can be co-administered with the compounds of the invention include, e.g., tricyclic anti-depressant drugs (e.g., imipramine, desipramine, amitriptyline, clomipramine, trimipramine, doxepin, nortriptyline, protriptyline, amoxapine and maprotiline); non-tricyclic and anti-depressant drugs (e.g., sertraline, trazodone and citalopram); Ca +2 antagonists (e.g., verapamil, nifedipine, nitrendipine and caroverine); amphotericin; triparanol analogues (e.g., tamoxifen); antiarrhythmic drugs (e.g., quinidine); antihypertensive drugs (e.g., reserpine); thiol depleters (e.g., buthion
  • the active compound(s) of the invention are administered er se or in the form of a pharmaceutical composition wherein the active compound(s) is in admixture with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • compositions for use in accordance with the present invention are typically formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxyniethylcellulose, and/or polyvinylpyrrolidone (PNP).
  • disintegrating agents maybe added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds may be formulated for parenteral administration by injection, e.g. , by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • formulatory agents such as suspending, stabilizing and/or dispersing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly, concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or transcutaneous delivery (e.g., subcutaneously or intramuscularly), intramuscular injection or a transdermal patch.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • N9 Mitsunobu alkylation reactions and C6 sulfone displacement reactions are carried out under anhydrous conditions under argon atmosphere.
  • C2 resin capture reactions are carried out in 4 mL scintillation glass vials unless otherwise noted.
  • Anhydrous tetrahydrofuran, and 1,4-dioxane are obtained by passing them through commercially available alumina columns. All other reagents, resins, and solvents are purchased at highest commercial quality and used without further purification. Purity of compounds are assessed by reverse-phase liquid chromatography / mass spectrometer
  • PAL 4-formyl-3,5-dimethoxyphenoxymethyl functionalized polystyrene resin
  • DMF 350 mL
  • a primary amine 56.5 mmol
  • sodium triacetoxyborohydride 7J8 g, 33.9 mmol
  • acetic acid 6.52 mL, 113 mmol
  • the mixture is shaken gently at room temperature for 12 hours and then washed with methanol (300 mL x 4) and dichloromethane (300 mL x 4) and dried under vacuum.
  • methanol 300 mL x 4
  • dichloromethane 300 mL x 4
  • LC elution methods using a Phenomenex Luna 50*2.00mm 5 ⁇ C18 column: (1) 10 minutes method: starting from 5% solvent A (acetonitrile) in solvent B (water with 0.5% acetic acid) and running the gradient to 95% A in 8 minutes, followed by 2 minutes elution with 95% A. (2) 6 minutes method: starting from 5% solvent A (acetonitrile) in solvent B (water with 0.5% acetic acid) and running the gradient to 95% A in 5 minutes, followed by 1 minutes elution with 95% A.
  • the resin 7 (0.05 mmol) was suspended in anhydrous 1,4-dioxane (0.6 mL), followed by addition of an amine (0J mmol). After overnight shaking at 80 °C, the resin was filtered using a polypropylene cartridge (45 ⁇ PTFE frit) and the flow-through solution was collected. The resin was subsequently washed by dichloromethane (0.5 mL x 3) and flow-through was combined and solvent was removed under reduced pressure to afford desired product 8 (in average >85% HPLC purity, 80% purified yield).
  • Table 8 shows the retention times, as well as calculated and observed molecular weights for purines having various substituents at the C6 and C2 positions that were made using the methods of the invention. These results demonstrate that the methods are applicable to attachment of a wide variety of substituents to purine scaffolds.

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Abstract

Cette invention concerne des méthodes générales de préparation de purines substituées par 2,9-, 2,6,9-, O6-aryle- et O6-alkyle- selon un mode combinatoire et sans trace. Ces méthodes font intervenir, dans certains modes de réalisation, une alkylation Mitsunobu de 2-fluoro-6-phénylsulfenylpurine à N9 avec des alcools en solution, suivie d'une capture C2 du noyau purique avec une amine liée à une résine, après quoi on procède à l'oxydation et au déplacement du groupe sulfonyle C6 avec des amines et des anilines.
PCT/US2002/032679 2001-10-12 2002-10-12 Methodes de synthese de purines substituees Ceased WO2003031405A2 (fr)

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Cited By (5)

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JP2007534687A (ja) * 2004-04-23 2007-11-29 エグゼリクシス， インコーポレイテッド キナーゼ調節因子および使用方法
US7829715B2 (en) 2004-04-28 2010-11-09 Astellas Pharma Inc. Method for producing solifenacin or salts thereof
CN102089308A (zh) * 2008-07-07 2011-06-08 艾科睿控股公司 Pi3k亚型选择性抑制剂
US9096542B2 (en) 2005-12-15 2015-08-04 Rigel Pharmaceuticals, Inc. Kinase inhibitors and their uses
US12441744B2 (en) 2022-12-16 2025-10-14 Astrazeneca Ab 2,6,9-trisubstituted purines

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BRPI0610824A8 (pt) * 2005-05-16 2017-04-04 Prometic Pharma Smt Ltd Compostos derivados de purina, uso dos mesmos e composição contendo os referidos compostos
JP6736253B2 (ja) * 2014-12-22 2020-08-05 ザ チャイニーズ ユニバーシティ オブ ホンコン 体細胞から多能性幹細胞を作製するための機械的操作とプログラミンの併用

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WO1999007705A1 (fr) * 1997-08-07 1999-02-18 The Regents Of The University Of California Purines inhibant des proteine kinases, des proteines g et des polymerases
EP1578722A4 (fr) * 2001-10-12 2006-09-06 Irm Llc Squelettes d'inhibiteurs de kinase et leurs methodes de preparation

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007534687A (ja) * 2004-04-23 2007-11-29 エグゼリクシス， インコーポレイテッド キナーゼ調節因子および使用方法
US8076338B2 (en) 2004-04-23 2011-12-13 Exelixis, Inc. Kinase modulators and methods of use
US7829715B2 (en) 2004-04-28 2010-11-09 Astellas Pharma Inc. Method for producing solifenacin or salts thereof
US9096542B2 (en) 2005-12-15 2015-08-04 Rigel Pharmaceuticals, Inc. Kinase inhibitors and their uses
US9834568B2 (en) 2005-12-15 2017-12-05 Rigel Pharmaceuticals, Inc. Kinase inhibitors and their uses
CN102089308A (zh) * 2008-07-07 2011-06-08 艾科睿控股公司 Pi3k亚型选择性抑制剂
EP2307414A4 (fr) * 2008-07-07 2011-10-26 Xcovery Holding Co Llc Inhibiteurs sélectifs des isoformes de la pi3 kinase
US8513221B2 (en) 2008-07-07 2013-08-20 Xcovery Holding, LLC PI3K isoform selective inhibitors
US12441744B2 (en) 2022-12-16 2025-10-14 Astrazeneca Ab 2,6,9-trisubstituted purines

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