[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

US20080125446A1 - Purine analogs having HSP90-inhibiting activity - Google Patents

Purine analogs having HSP90-inhibiting activity Download PDF

Info

Publication number
US20080125446A1
US20080125446A1 US11/772,496 US77249607A US2008125446A1 US 20080125446 A1 US20080125446 A1 US 20080125446A1 US 77249607 A US77249607 A US 77249607A US 2008125446 A1 US2008125446 A1 US 2008125446A1
Authority
US
United States
Prior art keywords
optionally substituted
canceled
methoxy
iodo
pent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/772,496
Inventor
Srinivas Rao Kasibhatla
Kevin Hong
Lin Zhang
Marco Antonio Biamonte
Marcus F. Boehm
Jiandong Shi
Junhua Fan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Conforma Therapeutics Corp
Original Assignee
Conforma Therapeutics Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Conforma Therapeutics Corp filed Critical Conforma Therapeutics Corp
Priority to US11/772,496 priority Critical patent/US20080125446A1/en
Publication of US20080125446A1 publication Critical patent/US20080125446A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • C07D473/02Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • C07D473/02Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/24Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one nitrogen and one sulfur atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • C07D473/26Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32Nitrogen atom
    • C07D473/34Nitrogen atom attached in position 6, e.g. adenine
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • C07D473/40Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6

Definitions

  • the invention relates in general to purine analogs and their use in inhibiting heat shock protein 90's (HSP90's) to thereby treat or prevent HSP90-dependent diseases, e.g., proliferative disorders such as breast cancer.
  • HSP90's heat shock protein 90's
  • HSP90s are ubiquitous chaperone proteins that are involved in folding, activation and assembly of a wide range of proteins, including key proteins involved in signal transduction, cell cycle control and transcriptional regulation.
  • HSP90 chaperone proteins are associated with important signaling proteins, such as steroid hormone receptors and protein kinases, including, e.g., Raf-1, EGFR, v-Src family kinases, Cdk4, and ErbB-2 (Buchner J., 1999, TIBS, 24:136-141; Stepanova, L. et al., 1996, Genes Dev. 10:1491-502; Dai, K. et al., 1996, J. Biol. Chem. 271:22030-4).
  • Hsp70 e.g., Hsp70, p60/Hop/Sti1, Hip, Bag1, HSP40/Hdj2/Hsj1, immunophilins, p23, and p50
  • HSP90 may assist HSP90 in its function (see, e.g., Caplan, A., Trends in Cell Biol., 9: 262-68 (1999).
  • Ansamycin antibiotics e.g., herbimycin A (HA), geldanamycin (GM), and 17-AAG are thought to exert their anticancerous effects by tight binding of the N-terminus pocket of HSP90, thereby destabilizing substrates that normally interact with HSP90 (Stebbins, C. et al., 1997, Cell, 89:239-250).
  • This pocket is highly conserved and has weak homology to the ATP-binding site of DNA gyrase (Stebbins, C. et al., supra; Grenert, J. P. et al., 1997, J. Biol. Chem., 272:23843-50).
  • ATP and ADP have both been shown to bind this pocket with low affinity and to have weal ATPase activity (Proromou, C. et al., 1997, Cell, 90: 65-75; Panaretou, B. et al., 1998, EMBO J., 17: 4829-36).
  • occupancy of this N-terminal pocket by ansamycins and other HSP90 inhibitors alters HSP90 function and inhibits protein folding.
  • ansamycins and other HSP90 inhibitors have been shown to prevent binding of protein substrates to HSP90 (Scheibel, T., H. et al., 1999, Proc. Natl. Acad. Sci.
  • the substrates are degraded by a ubiquitin-dependent process in the proteasome (Schneider, C., L., supra; Sepp-Lorenzino, L., et al., 1995, J. Biol. Chem., 270:16580-16587; Whitesell, L. et al., 1994, Proc. Natl. Acad. Sci. USA, 91: 8324-8328).
  • HSP90 substrate destabilization occurs in tumor and non-transformed cells a like and has been shown to be especially effective on a subset of signaling regulators, e.g., Raf (Schulte, T. W. et al., 1997, Biochem. Biophys. Res. Commun. 239:655-9; Schulte, T. W., et al., 1995, J. Biol. Chem. 270:24585-8), nuclear steroid receptors (Segnitz, B., and U. Gehring. 1997, J. Biol. Chem. 272:18694-18701; Smith, D. F. et al., 1995, Mol. Cell. Biol.
  • Raf Schote, T. W. et al., 1997, Biochem. Biophys. Res. Commun. 239:655-9
  • HSP90 inhibitors have also been implicated in a wide variety of other utilities, including use as anti-inflammation agents, anti-infectious disease agents, agents for treating autoimmunity, agents for treating ischemia, and agents useful in promoting nerve regeneration (See, e.g., Rosen et al., WO 02/09696; PCT/US01/23640; Degranco et al., WO 99/51223; PCT/US99/07242; Gold, U.S. Pat. No. 6,210,974 B1).
  • fibrogenetic disorders including but not limited to scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis, and pulmonary fibrosis may be treatable. (Strehlow, WO 02/02123; PCT/US01/20578).
  • Ansamycins and other HSP90 inhibitors thus hold great promise for the treatment and/or prevention of many types of disorders.
  • their relative insolubility makes them difficult to formulate and administer, and they are not easily synthesized and currently must, at least in part, be generated through fermentation.
  • the dose limiting toxicity of ansamyins is hepatic.
  • alternative HSP90 inhibitors are therefore needed.
  • Chiosis et al. described the design and synthesis of purine analogs that mimic geldanamycin and other ansamycins in their ability to bind the ATP binding pocket of, and thus inhibit, HSP90, See International Patent Application PCT/US01/46303 (WO 02/36075; Chemistry & Biology 8:289-299 (2001).
  • the specific compounds that Chiosis et al. described included a trimethoxybenzyl entity substituted at positions 3, 4, and 5. Using gel-binding assays, these were shown to bind HSP90 approximately 20-fold less avidly than the benzoquinone ansamycin, 17-AAG.
  • Applicants herein describe a set of purine-based compounds that have utility in inhibiting HSP90 and diseases that are HSP90-dependent, e.g., a variety of carcinomas, such as melanoma, breast cancer, etc.
  • the purine or purine analog has structure I, II, III, or IV:
  • A is selected from NR 1 2 , NHSO 2 R 2 , NR 1 NR 1 2 , NR 1 OR 4 , OR 3 , SR 3 , optionally substituted lower alkyl, C(O)N(R 4 ) 2 , guanidine, amidine, U, halogen, CN, N 3 and perhaloalkyl;
  • X is a 1 carbon, 2 carbon, or 3 carbon optionally substituted structure (C1-C3), or else NR 1 , S, S(O), S(O) 2 , O, or C(O).
  • carbon linkers having more than 1 carbon these may have single, double, or triple bonds between them.
  • Y is selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alicyclic, optionally substituted araalkyl, optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl, alkylaminoalkyl, alkylcarbonylaminoalkyl (—(CH 2 ) n —C(O)—NR—(CH 2 ) n ), alkylcarbonyoxylalkyl (—(CH 2 ) n —C(O)—O—(CH 2 ) n ), optionally substituted heterocyclic, hydroxyalkyl, haloalkyl, perhaloalkyl, C(O)R 2 , S(O) 2 R 2 , C(O)NHR 2 , and C(O)OR 2 ;
  • Z is selected from the group consisting of H, halogen, CN, OR 3 , SR 3 , perhaloalkyl, optionally substituted allyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alicyclic, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl, optionally substituted heterocyclic, C(O)R 2 , —S(O) 2 R 2 , NHOR 4 , and C(O)NR 4 2 ;
  • Q is selected from the group consisting of alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl, and heterocyclic, all optionally substituted; e.g.,
  • R 1 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclic, C(O)R 2 , —C(O)OR 2 , C(O)NR 4 2 , C(S)OR 2 , C(S)NR 4 2 , PO 3 R 4 , and SO 2 R 2 ;
  • R 2 is selected from alkyl, heteroalkyl, cycloalkyl, heterocyclic, heteroaryl, and aryl, all optionally substituted;
  • R 3 is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclic and C(O)NR 4 2 ; and
  • R 4 is selected from either H or from alkyl, cycloalkyl, heteroalkyl, aryl, and heterocyclic, all optionally substituted;
  • R 5 is selected from H, OH, and optionally substituted allyl
  • R 6 is independently selected from H, optionally substituted alkyl, OR 3 , SR 3 , NHR 3 , C(O)R 5 , NO 2 , CN, halogen, and S(O) 2 R 2 .
  • the alkyl, alkenyl, and alkynyl substituent are 1 to 8 carbon atoms in length, more preferably 1 to 6 carbon atoms in length, and optionally substituted.
  • the subscript “n” can be 1 to 10 inclusive, with 3 or less being preferred.
  • Table 1 Particularly preferred in Table 1 are compounds 1, 4, 31, 55, 58, 85, 113, 137, 140, 167, 191, 194, 221, 224, 226, 228, 232, 234, 235, 236, 239, 245, 248, 251, 259, 452, 453, 454, 455, 456, 457, 463, 469, 470, 471, 571 and 572, with the most preferred compounds being 1, 85, 113, 137, 140, 167, 191, 194, 221, 228, 239, 251, 259, 452, 453, 455, 571 and 572.
  • structure II is a tautomeric form of structure I when A is OH (OR 3 where R 3 is H)
  • structure III is another tautomeric form of structure I (when Z is OH)
  • structure IV is yet another tautomeric form of structure I in the event that both A and Z are OH. All four tautomeric possibilities can be represented essentially as shown in structure I, except that dashed lines appear between atoms 1 and 6 and 2 and 3, and between A and 6 and Z and 2, e.g., as shown:
  • the foregoing aspects and embodiments can also include varying levels and types of substitution on one or more of entities A, B, Q, W, X, Y and Z, above, where that entity is not already solely hydrogen but rather is a multi-atom substituent that contains one or more hydrogens that can be substituted for, e.g., with a halogen or combination of other atoms or chemical group(s).
  • substitutions may be made or included at any point in the synthesis of the final compounds, as appropriate, including, e.g., in the starting reagents or intermediates of the reaction scheme(s) used, or following the synthesis of one final product to convert it into another.
  • the following embodiments are illustrative:
  • the invention features pharmaceutical compositions containing one or more of the compounds or pharmaceutically acceptable salts thereof described for the preceding aspects. These additionally include one or more pharmaceutically acceptable carriers and/or excipients.
  • Another aspect of the invention features methods of making the compounds of the preceding aspects. These are described in greater detail in the next section and the examples to follow. Related aspects of the invention embrace intermediates of/in these synthetic methods to the extent they are novel, either alone or standing in the context of the specific synthesis objective.
  • the invention features methods of inhibiting an HSP90 molecule with a compound according to any of the previous aspects and embodiments.
  • HSP90 proteins are highly conserved in nature (see, e.g., NCBI accession it's P07900 and XM 004515 (human ⁇ and ⁇ HSP90, respectively), P11499 (mouse), AAB2369 (rat), P46633 (chinese hamster), JC1468 (chicken), AAF69019 (flesh fly), AAC21566 (zebrafish), AAD30275 (salmon), O02075 (pig), NP 015084 (yeast), and CAC29071 (frog).
  • the HSP90 inhibitors of the invention may be specifically directed against an HSP90 of the specific host patient or may be identified based on reactivity against an HSP90 homolog from a different species, or an HSP90 variant.
  • the methods feature contacting a cell having an HSP90 with a pharmaceutically effective amount of a compound or pharmaceutical composition according to any one of the preceding aspects.
  • the cell is preferably a mammalian cell, and more preferably a human cell, although any cell-type from any life-form that contains an HSP90, including non-mammalian lines, is contemplated for the invention.
  • the method can be “in vitro”, e.g., contacting a cell line in culture, or else can be “in vivo”, e.g., contacting a cell inside a live organism.
  • in vivo administration is made “in situ”, or directly to a specific cell or group of cells within an organism, e.g., intratumorally.
  • Ex vivo procedures are also envisioned wherein the cells are first removed from a patient, treated by contacting them with the compounds or compositions of the invention, and then administered back to a patient or “the” patient.
  • the compounds and compositions can be administered in a variety of ways, e.g., intravenously, parenterally, orally, bucally, intramuscularly, sublingually, topically, by aerosol, subcutaneously, intramuscularly, intraperitoneally, rectally, vaginally, intratumorally, or peritumorally.
  • the compounds or compositions are administered to treat or prevent a cancer, e.g., a breast cancer, melanoma, lung cancer, etc.
  • these compounds may be used in combination with or as an adjuvant/sensitizer for any chemotherapy regimen.
  • Such regimens may include the use of other anti-cancer compounds, e.g., taxol, Herceptin, Gleevac, etc.
  • the additions may be made simultaneously or sequentially and, if the latter, in any order.
  • the compounds or compositions are used for non-oncology applications, e.g., treating inflammation, infectious disease, autoimmune disease, and ischemia.
  • FIG. 1 shows IC 50 values for compounds of Table 3, Example 3, as measured using Her-2 degradation studies.
  • a “pharmaceutically acceptable salt” may be prepared for any compound of the invention having a functionality capable of forming a salt, for example an acid or base functionality.
  • Pharmaceutically acceptable salts may be derived from organic or inorganic acids and bases.
  • Compounds of the invention that contain one or more basic functional groups, e.g., amino or alkylamino, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable organic and inorganic acids.
  • These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • acids examples include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, gluconic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, 1,2 ethanesulfonic acid (edisylate), galactosyl-d-gluconic acid, and the like.
  • compositions of the present invention that contain one or more acidic functional groups are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases.
  • pharmaceutically-acceptable salts in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Illustrative examples of some of the bases that can be used include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. See, for example, Berge et al., supra.
  • Prodrugs are derivative compounds derivatized by the addition of a group that endows greater solubility to the compound desired to be delivered. Once in the body, the prodrug is typically acted upon by an enzyme, e.g., an esterase, amidase, or phosphatase, to generate the active compound. Suitable positions for derivatization of the compounds of the invention to create “prodrugs” include but are not limited to the Y group, the phenyl ring of the purines, and the Q group. Those of ordinary skill in the art have the knowledge and means to accomplish this without undue experimentation.
  • Tautomers are compounds whose structures differ in arrangements of atoms, but which exist in equilibrium.
  • T is in equilibrium with a second tautomeric form designated T.
  • the predominance of one tautomer versus another is controlled by factors which include but are not limited to the nature of the solvent, temperature, pressure, the presence or absence of other molecules, and the nature of substituents on the molecule having tautomeric forms.
  • alkyl refers to an optionally substituted straight-chain, optionally substituted branched-chain, or optionally substituted cyclic alkyl radical having from 1 to about 30 carbons, more preferably 1 to 12 carbons.
  • alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like.
  • cycloalkyl embraces cyclic configurations, is subsumed within the definition of alkyl and specifically refers to a monocyclic, bicyclic, tricyclic, and higher multicyclic alkyl radicals wherein each cyclic moiety has from 3 to about 8 carbon atoms.
  • cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • a “lower alkyl” is a shorter alkyl, e.g., one containing from 1 to about 6 carbon atoms.
  • alkenyl refers to an optionally substituted straight-chain, optionally substituted branched-chain, or optionally substituted cyclic alkenyl hydrocarbon radical having one or more carbon-carbon double-bonds and having from 2 to about 30 carbon atoms, more preferably 2 to about 18 carbons.
  • alkenyl radicals include ethenyl, propenyl, butenyl, 1,4-butadienyl and the like.
  • the term can also embrace cyclic alkenyl structures.
  • a “lower alkenyl” refers to an alkenyl having from 2 to about 6 carbons.
  • alkynyl refers to an optionally substituted straight-chain, optionally substituted branched-chain, or cyclic alkynyl hydrocarbon radical having one or more carbon-carbon triple-bonds and having from 2 to about 30 carbon atoms, more preferably 2 to about 12 carbon atoms.
  • the term also includes optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon radicals having one or more carbon-carbon triple bonds and having from 2 to about 6 carbon atoms as well as those having from 2 to about 4 carbon atoms.
  • alkynyl radicals include ethynyl, propynyl, butynyl and the like.
  • heteroalkyl, heteroalkenyl and heteroalkynyl include optionally substituted alkyl, alkenyl and alkynyl structures, as described above, and which have one or more skeletal chain atoms selected from an atom other that carbon, e.g., oxygen, nitrogen, sulfur, phosphorous or combinations thereof.
  • carbon chain may embrace any alkyl, alkenyl, alkynyl, or heteroalkyl, heteroalkenyl, or heteroalkynyl group, and may be linear, cyclic, or any combination thereof. If part of a linker and that linker comprises one or more rings as part of the core backbone, for purposes of calculating chain length, the “chain” only includes those carbon atoms that compose the bottom or top of a given ring and not both, and where the top and bottom of the ring(s) are not equivalent in length, the shorter distance shall be used in determining chain length. If the chain contains heteroatoms as part of the backbone, those atoms are not calculated as part of the carbon chain length.
  • alkoxy refers to an alkyl ether radical, alkyl-O—, wherein the term alkyl is defined as above.
  • alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
  • aryloxy refers to an aryl ether radical wherein the term aryl is defined as below.
  • aryloxy radicals include phenoxy, benzyloxy and the like.
  • alkylthio refers to an alkyl thio radical, alkyl-S—, wherein the term alkyl is defined as above.
  • arylthio refers to an aryl thio radical, aryl-S—, wherein the term aryl is defined as below.
  • aryl refers to an optionally substituted aromatic ring system.
  • aryl includes monocyclic aromatic rings, polyaromatic rings and polycyclic aromatic ring systems containing from six to about twenty carbon atoms.
  • aryl also includes monocyclic aromatic rings, polyaromatic rings and polycyclic ring systems containing from 6 to about 12 carbon atoms, as well as those containing from 6 to about 10 carbon atoms.
  • the polyaromatic and polycyclic aromatic rings systems may contain from two to four rings. Examples of aryl groups include, without limitation, phenyl, biphenyl, naphthyl and anthryl ring systems.
  • heteroaryl refers to optionally substituted aromatic ring systems containing from about five to about 20 skeletal ring atoms and having one or more heteroatoms such as, for example, oxygen, nitrogen, sulfur, and phosphorus.
  • heteroaryl also includes optionally substituted aromatic ring systems having from 5 to about 12 skeletal ring atoms, as well as those having from 5 to about 10 skeletal ring atoms.
  • heteroaryl may include five- or six-membered heterocyclic rings, polycyclic heteroaromatic ring systems and polyheteroaromatic ring systems where the ring system has two, three or four rings.
  • heterocyclic, polycyclic heteroaromatic and polyheteroaromatic include ring systems containing optionally substituted heteroaromatic rings having more than one heteroatom as described above (e.g., a six membered ring with two nitrogens), including polyheterocyclic ring systems of from two to four rings.
  • heteroaryl includes ring systems such as, for example, furanyl, benzofuranyl, chromenyl, pyridyl, pyrrolyl, indolyl, quinolinyl, N-alkyl pyrrolyl, pyridyl-N-oxide, pyrimidoyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, benzothiophenyl, purinyl, indolizinyl, thienyl and the like.
  • ring systems such as, for example, furanyl, benzofuranyl, chromenyl, pyridyl, pyrrolyl, indolyl, quinolinyl, N-alkyl pyrrolyl, pyridyl-N-oxide, pyrimidoyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, benzothiophenyl
  • heteroarylalkyl refers to a C1-C4 alkyl group containing a heteroaryl group, each of which may be optionally substituted.
  • heteroarylthio refers to the group —S-heteroaryl.
  • acyloxy refers to the ester group —OC(O)—R, where R is H, alkyl, alkenyl, alkynyl, aryl, or arylalkyl, wherein the alkyl, alkenyl, alkynyl and arylalkyl groups may be optionally substituted.
  • carboxy esters refers to —C(O)OR where R is alkyl, aryl or arylalkyl, wherein the alkyl, aryl and arylalkyl groups may be optionally substituted.
  • R and R′ are independently selected from the group consisting of H, alkyl, aryl and arylalkyl, wherein the alkyl, aryl and arylalkyl groups may be optionally substituted.
  • arylalkyl refers to an alkyl radical as defined above in which one H atom is replaced by an aryl radical as defined above, such as, for example, benzyl, 2-phenylethyl and the like.
  • alklaryl refers to an aryl radical as defined above in which one H atom is replaced by an alkyl radical as defined above, such as, for example, tolyl, xylyl and the like.
  • haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy include alkyl, alkenyl, alkynyl and alkoxy structures, as described above, that are substituted with one or more fluorines, chlorines, bromines or iodines, or with combinations thereof.
  • cycloalkyl, aryl, arylalkyl, heteroaryl, alkyl, alkynyl, alkenyl, haloalkyl and heteroalkyl include optionally substituted cycloalkyl, aryl, arylalkyl, heteroaryl, alkyl, alkynyl, alkenyl, haloalkyl and heteroalkyl groups.
  • carrier includes optionally substituted, saturated or unsaturated, three- to eight-membered cyclic structures in which all of the skeletal atoms are carbon.
  • heterocycle includes optionally substituted, saturated or unsaturated, three- to eight-membered cyclic structures in which one or more skeletal atoms is oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
  • Illustrative examples include pyridine, pyran, thiophan, pyrrole, furan, thiophen, pentatonic and hexatomic lactam rings, and the like.
  • membered ring can embrace any cyclic structure, including carbocycles and heterocycles as described above.
  • membered is meant to denote the number of skeletal atoms that constitute the ring.
  • pyridine, pyran, and thiophan are 6 membered rings and pyrrole, furan, and thiophen are 5 membered rings.
  • acyl includes alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl substituents attached to a compound via a carbonyl functionality (e.g., —CO-alkyl, —CO-aryl, —CO-arylalkyl or —CO-heteroarylalkyl, etc.).
  • “Optionally substituted” groups may be substituted or unsubstituted.
  • the substituents of an “optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or designated subsets thereof: alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxy, aryloxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylthio, arylthio, heteroarylthio, oxo, carboxyesters, carboxamido, acyloxy, halogens, CN, NO 2 , NH 2 , N 3 , NHCH 3 , N(CH 3 ) 2 , SH, SCH 3 , OH, OCH 3 , O
  • An optionally substituted group may be unsubstituted (e.g., —CH 2 CH 3 ), fully substituted (e.g., —CF 2 CF 3 ), monosubstituted (e.g., —CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., —CH 2 CF 3 ).
  • halogen includes F, Cl, Br and I.
  • sulfide refers to a sulfur atom covalently linked to two atoms; the formal oxidation state of said sulfur is (II).
  • thioether may used interchangeably with the term “sulfide”.
  • sulfoxide refers to a sulfur atom covalently linked to three atoms, at least one of which is an oxygen atom; the formal oxidation state of said sulfur atom is (IV).
  • sulfurone refers to a sulfur atom covalently linked to four atoms, at least two of which are oxygen atoms; the formal oxidation state of said sulfur atom is (VI).
  • Some of the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms.
  • the scope of the present invention is intended to cover all isomers per se, as well as mixtures of cis and trans isomers, mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers) as well. Further, it is possible using well known techniques to separate the various forms, and some embodiments of the invention may feature purified or enriched species of a given enantiomer or diasteriomer.
  • a “pharmacological composition” refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof with other chemical components, such as pharmaceutically acceptable carriers and/or excipients.
  • the purpose of a pharmacological composition is to facilitate administration of a compound to an organism.
  • pharmaceutically acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • excipient refers to an inert substance added to a pharmacological composition to further facilitate administration of a compound.
  • excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • a “pharmaceutically effective amount” means an amount which is capable of providing a therapeutic and/or prophylactic effect.
  • the specific dose of compound administered according to this invention to obtain therapeutic and/or prophylactic effect will, of course, be determined by the particular circumstances surrounding the case, including, for example the specific compound administered, the route of administration, the condition being treated, and the individual being treated.
  • a typical daily dose (administered in single or divided doses) will contain a dosage level of from about 0.01 mg/kg to about 50-100 mg/kg of body weight of an active compound of the invention.
  • Preferred daily doses generally will be from about 0.05 mg/kg to about 20 mg/kg and ideally from about 0.1 mg/kg to about 10 mg/kg.
  • Factors such as clearance rate and half-life and maximum tolerated dose (MTD) have yet to be determined but one of ordinary skill in the art can determine these using standard procedures.
  • the preferred therapeutic effect is the inhibition, to some extent, of the growth of cells characteristic of a proliferative disorder, e.g., breast cancer.
  • a therapeutic effect will also normally, but need not, relieve to some extent one or more of the symptoms other than cell growth or size of cell mass.
  • a therapeutic effect may include, for example, one or more of 1) a reduction in the number of cells; 2) a reduction in cell size; 3) inhibition (i.e., slowing to some extent, preferably stopping) of cell infiltration into peripheral organs, e.g., in the instance of cancer metastasis; 3) inhibition (i.e., slowing to some extent, preferably stopping) of tumor metastasis; 4) inhibition, to some extent, of cell growth; and/or 5) relieving to some extent one or more of the symptoms associated with the disorder.
  • the “IC 50 ” value of a compound of the invention can be greater for normal cells than for cells exhibiting a proliferative disorder, e.g., breast cancer cells. The value depends on the assay used.
  • a “standard” is meant a positive or negative control.
  • a negative control in the context of HER-2 expression levels is, e.g., a sample possessing an amount of HER-2 protein that correlates with a normal cell.
  • a negative control may also include a sample that contains no HER-2 protein.
  • a positive control does contain HER-2 protein, preferably of an amount that correlates with overexpression as found in proliferative disorders, e.g., breast cancers.
  • the controls may be from cell or tissue samples, or else contain purified ligand (or absent ligand), immobilized or otherwise. In some embodiments, one or more of the controls may be in the form of a diagnostic “dipstick.”
  • selective targeting is meant affecting one type of cell to a greater extent than another, e.g., in the case of cells with high as opposed to relatively low or normal Her-2 levels.
  • Synthesis of compounds of formula 1 (when X ⁇ C) in scheme 1 may include some or all of the following general steps.
  • the 8-substituted purine analogs of formula 5 or 2 can be prepared from 4,5-diaminopyrimidines and the carboxylates or their derivatives, such as amides, esters, nitriles, orthoesters, imidates etc (see, e.g., Townsend Chemistry of Nucleosides and Nucleotides, Vol. 1; Plenum Press, New York and London, page 148-158; Tetrahedron Lett. 36, 4249, 1995).
  • Substituted 4,5-diaminopyrimidines can be obtained commercially or from substituted 2-chloro-3-amino pyrimidine or 2-chloro-3-nitropyrimidines as known in the art. See, e.g., Tetrahedron, 40, 1433 (1984); J. Am, Chem. Soc., 118, 135 (1975); Synthesis 135 (1975); J. Med. Chem. 39, 4099 (1996).
  • Compounds of formula 5 can be converted to compounds of formula 2 by simple alkylation with alkylhalides, alkyltosylates, mesolates or triflates in polar solvents like THF, DMF or DMSO using bases like NaH, Cs 2 CO 3 or K 2 CO 3 , or by the well-known Mitsunobu alkylation method.
  • Compounds of formula 2 can be further modified to give compounds of formula 1 or the intermediates to prepare compounds of formula 1, e.g., substitution of 6-chloropurine by ammonia or alkylamines.
  • C-2 substitution of purines, e.g., halogenation with F, Cl or Br can be introduced via 2-aminopurines as described by Eaton et al., J. Org. Chem. 34(3), 747-8 (1969) or by nucleophilic substitution as described, e.g., in, J. Med. Chem. 36, 2938 (1993) and Heterocycles, 30, 435, (1990).
  • These C-2 substitutions also can be introduced via metalation as described, e.g., in J. Org. Chem. 62(20), 6833 (1997), followed by addition of desired electrophile.
  • General purine substitution can be accomplished as described in J. Med. Chem. 42, 2064 (1999).
  • intermediates of formula 2 can be prepared from chloroaminopyrimidines such as formula 6 by the following two steps: (1) treatment of the compounds of formula 6 with corresponding amine (Y—NH2), e.g., butylamine, in presence of base such as triethyl amine or N,N-diisopropyl amine in polar solvents such as n-BuOH to give the substituted diamine compounds of formula 4; (2) treatment of the compounds of formula 4 using the same methods as described earlier going from formula 7 to formula 5. Similar methods as described earlier can be used to introduce the C-2 substitution (point at which Z or G moiety attaches).
  • Compounds of formula 1 where A is other than NH 2 can be prepared starting with the corresponding substituent in place (if it can withstand the transformations), or, for halogen or substituted amines, these can be prepared from the 6-amine.
  • the compounds of formula 1 can also be prepared from formula 3, where L is halogen, using Negishi-type couplings (e.g., as described in J. Org. Chem. 2001, 66, 7522; J. Org. Chem. 1991, 56, 1445).
  • Compounds of formula 1 wherein X is a heteroatom such as S, O or N can be prepared by the following scheme 2. In general, these compounds are linked via their C-8 to one of the heteroatoms X ⁇ S, O, or N and can be prepared from the corresponding 8-halo (e.g., bromo, iodo or chloro) compounds such as formula 10 using nucleophiles such as sulfides, alkyl or arylthiols, amines, azides, and alcohols.
  • 8-halo e.g., bromo, iodo or chloro
  • substituted adenines or purines of formula 8 can be treated with halogenating agents such as bromine or iodine, followed by alkylation at N-9 to give compounds of formula 10, wherein M is halogen such as bromine or iodine sang et. al. PCT, WO 98/39344).
  • Compounds of formula 16 can be prepared from trihalopyrimidines such as those of formula 12 by nitration to give compounds of formula 13. Subsequent displacement of the halogen with amine (YNH 2 ) and reduction of the nitrogroup gives the diamines of formula 15. Alternatively, reduction of the nitrogroup may precede halogen displacement.
  • Diamines of formula 15 can be readily cyclized to the imidazole ring of the compounds of formula 16, wherein L is H, SH, OH or NH 2 (Org. Syn. Collective Vol. 2, 65; Org. Syn. Collective Vol. 4, 569).
  • the compounds of formula 1 can also be synthesized from the compounds of formula 16, wherein L is SH, OH, or NH 2 , by reacting with aromatic halides, boronic acids, triflates, or their equivalents in presence of a catalyst such as palladium or copper (Buchwald, S. L. et. al. J. Am. Chem. Soc., 1998, 120, 213-214; Buchwald, S. L. et. al. Ace. Chem. Res. 1998, 31, 805; Buchwald, S. L. et. al Org. Lett., 2002, 4, 3517-3520).
  • a catalyst such as palladium or copper
  • compounds of formulae 1 and 11 (wherein X ⁇ S or O) can be synthesized by coupling of the diazonium salts of the compounds of formulae 10 or 16 (wherein M or L is N 2 .BF 4 , N 2 .HCl, N 2 .H 2 SO 4 etc.) with HXE or HXQ (wherein X ⁇ S or O) in the presence of base such as t-BuOK, NaH, etc. in solvents such as DMF, MeOH, etc.
  • Z-groups of formula 1 can be introduced by modifying existing 2-substituents such as G.
  • Other substitutions such as S-alkyl or aryl, O-alkyl can be made from nucleophilic substitution reactions; metal-catalysed reactions, etc. (see, e.g., Aerschot et. al., J. Med. Chem. 36:2938 (1993); Buchwald, S. L. et. al., Heterocycles, 30: 435 (1990).
  • the E component (aromatic or heteroaromatic or alkyl) of the compounds of formula 11 can be further modified as needed using well known procedures including, e.g., nucleophilic additions, electrophilic additions, halogenations, etc. to give Q (see, e.g., Advanced Organic Chemistry, March. J. Wiley Interscience).
  • Compounds of formula 1, wherein X is S(O) or S(O) 2 can be prepared by the oxidation of the compounds of formula 1, wherein X ⁇ S, using reagents such as MCPBA, H 2 O 2 , NaIO 4 , Oxone, etc. in solvents such as CHCl 3 , CH 2 Cl 2 etc.
  • these sulfone compounds can be made by coupling of sulfonyl salts such as Li, Na, K (ArS(O) 2 Li) and compounds of formulae 10 or 16 (wherein M or L is halogen such as Br or D in polar solvents such as DMF. (Chem. Abstr. 1952, 4549). With controlled reduction of these sulfones, one can make compounds of formula 1 where X is S(O) and S(O) 2 .
  • the compounds utilized in the methods of the instant invention may be administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • the therapeutic or pharmaceutical compositions of the invention can be administered locally to the area in need of treatment.
  • This may be achieved by, for example, but not limited to, local infusion during surgery, topical application, e.g., cream, ointment, injection, catheter, or implant, said implant made, e.g., out of a porous, non-porous, or gelatinous material, including membranes, such as silastic membranes, or fibers.
  • the administration can also be by direct injection at the site (or former site) of a tumor or neoplastic or pre-neoplastic tissue.
  • the compounds or compositions of the invention can be delivered in a vesicle, e.g., a liposome (see, for example, Langer, 1990, Science, 249:1527-1533; Treat et al., 1989, Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Bernstein and Fidler (eds.), Liss, N.Y., pp. 353-365).
  • a liposome see, for example, Langer, 1990, Science, 249:1527-1533; Treat et al., 1989, Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Bernstein and Fidler (eds.), Liss, N.Y., pp. 353-365).
  • the compounds and pharmaceutical compositions used in the methods of the present invention can also be delivered in a controlled release system.
  • a pump may be used (see, Sefton, 1987, CRC Crit. Ref Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery, 88:507; Saudek et al., 1989, N. Engl. J. Med., 321:574).
  • a controlled release system can be placed in proximity of the therapeutic target. (see, Goodson, 1984, Medical Applications of Controlled Release, Vol. 2, pp. 115-138).
  • compositions used in the methods of the instant invention can also contain the active ingredient in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be un-coated or coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, or cellulose acetate butyrate may be employed as appropriate.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan mono
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending a gent and one or more preservatives.
  • a dispersing or wetting agent suspending a gent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the compounds and pharmaceutical compositions used in the methods of the instant invention may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • compositions may be in the form of a sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase.
  • the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.
  • the injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions can be prepared by mixing the inhibitors with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • creams, ointments, jellies, solutions or suspensions, etc., containing an compound or composition of the invention can be used.
  • topical application can include mouth washes and gargles.
  • the compounds used in the methods of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the methods, compounds and compositions of the instant invention may also be used in conjunction with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents.
  • the instant methods and compounds may also be useful in combination with other inhibitors of parts of the signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
  • the methods of the present invention may also be useful with other agents that inhibit angiogenesis and thereby inhibit the growth and invasiveness of tumor cells, including, but not limited to VEGF receptor inhibitors, including ribozymes and antisense targeted to VEGF receptors, angiostatin and endostatin.
  • VEGF receptor inhibitors including ribozymes and antisense targeted to VEGF receptors, angiostatin and endostatin.
  • antineoplastic agents examples include, in general, and as appropriate, alkylating agents, anti-metabolites; epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes; biological response modifiers and growth inhibitors; hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors.
  • antineoplastics include the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the epothilones, discodermolide, the pteridine family of drugs, diynenes and the podophyllotoxins.
  • Particularly useful members of those classes include, for example, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leuosine, paclitaxel and the like.
  • antineoplastic agents include estramustine, carboplatin, cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • a suitable amount of compound is administered to a mammal undergoing treatment for cancer, for example, breast cancer.
  • Administration typically occurs in an amount of between about 0.01 mg/kg of body weight to about 100 mg/kg of body weight per day (administered in single or divided doses), more preferably at least about 0.1 mg/kg of body weight per day.
  • a particular therapeutic dosage can include, e.g., from about 0.01 mg to about 1000 mg of compound, and preferably includes, e.g., from about 1 mg to about 1000 mg.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, preferably from about 1 mg to 300 mg, more preferably 10 mg to 200 mg, according to the particular application.
  • the amount administered will vary depending on the particular IC50 value of the compound used and the judgment of the attending clinician taking into consideration factors such as health, weight, and age. In combinational applications in which the compound is not the sole active ingredient, it may be possible to administer lesser amounts of compound and still have therapeutic or prophylactic effect.
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • the amount and frequency of administration of the compounds and compositions of the present invention used in the methods of the present invention, and if applicable other chemotherapeutic agents and/or radiation therapy, will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition and size of the patient as well as severity of the disease being treated.
  • the chemotherapeutic agent and/or radiation therapy can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent and/or radiation therapy can be varied depending on the disease being treated and the known effects of the chemotherapeutic agent and/or radiation therapy on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents (i.e., antineoplastic agent or radiation) on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.
  • the administered therapeutic agents i.e., antineoplastic agent or radiation
  • the compounds of the invention need not be administered in the same pharmaceutical composition as a chemotherapeutic agent, and may, because of different physical and chemical characteristics, be administered by a different route.
  • the compounds/compositions may be administered orally to generate and maintain good blood levels thereof, while the chemotherapeutic agent may be administered intravenously.
  • the determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician.
  • the initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
  • compositions of the invention may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the proliferative disease, the condition of the patient, and the actual choice of chemotherapeutic agent and/or radiation to be administered in conjunction (i.e., within a single treatment protocol) with the compound/composition.
  • the compounds/compositions of the invention may be administered first followed by the administration of the chemotherapeutic agent and/or radiation; or the chemotherapeutic agent and/or radiation may be administered first followed by the administration of the compounds/compositions of the invention.
  • This alternate administration may be repeated during a single treatment protocol. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient.
  • the chemotherapeutic agent and/or radiation may be administered first, especially if it is a cytotoxic agent, and then the treatment continued with the administration of the compounds/compositions of the invention followed, where determined advantageous, by the administration of the chemotherapeutic agent and/or radiation, and so on until the treatment protocol is complete.
  • the practicing physician can modify each protocol for the administration of a compound/composition for treatment according to the individual patient's needs, as the treatment proceeds.
  • the attending clinician in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.
  • HSP90 competitive binding assays and functional assays can be performed as known in the art substituting in the compounds of the invention. Chiosis et al., Chemistry & Biology 8:289-299 (2001), describe some of the known ways in which this can be done.
  • competition binding assays using, e.g., geldanamycin or 17-AAG as a competitive binding inhibitor of HSP90 can be used to determine relative HSP90 affinity of the compounds of the invention by immobilizing the compound of interest or other competitive inhibitor on a gel or solid matrix, preincubating HSP90 with the other inhibitor, passing the preincubated mix over the gel or matrix, and then measuring the amount of HSP90 that sticks or does not stick to the gel or matrix.
  • Downstream effects can also be evaluated based on the known effect of HSP90 inhibition on function and stability of various steroid receptors and signaling proteins including, e.g., Raf1 and Her2.
  • Compounds of the present invention induce dose-dependent degradation of these molecules, which can be measured using standard techniques.
  • Inhibition of HSP90 also results in up-regulation of HSP90 and related chaperone proteins that can similarly be measured.
  • Antiproliferative activity on various cancer cell lines can also be measured, as can morphological and functional differentiation related to HSP90 inhibition. For example, the
  • Indirect techniques include nucleic acid hybridization and amplification using, e.g., polymerase chain reaction (PCR). These techniques are known to the person of skill and are discussed, e.g., in Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., Ausubel, et al., Current Protocols in Molecular Biology, John Wiley & Sons, NY, 1994, and, as specifically applied to the quantification, detection, and relative activity of Her-2/neu in patient samples, e.g., in U.S. Pat. Nos. 4,699,877, 4,918,162, 4,968,603, and 5,846,749. A brief discussion of two generic techniques that can be used follows.
  • HER-2 expression in breast cancer cells can be determined with the use of an immunohistochemical assay, such as the Dako HercepTM test Shako Corp., Carpinteria, Calif.).
  • the HercepTM test is an antibody staining assay designed to detect HER-2 overexpression in tumor tissue specimens. This particular assay grades HER-2 expression into four levels: 0, 1, 2, and 3, with level 3 representing the highest level of HER-2 expression.
  • Accurate quantitation can be enhanced by employing an Automated Cellular Imaging System (ACIS) as described, e.g., by Press, M, et al, (2000), Modern Pathology 13:225 A.
  • ACIS Automated Cellular Imaging System
  • Antibodies polyclonal or monoclonal, can be purchased from a variety of commercial suppliers, or may be manufactured using well-known methods, e.g., as described in Harlow et al., Antibodies: A Laboratory Manual, 2nd Ed; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1988).
  • HER-2 overexpression can also be determined at the nucleic acid level since there is a reported high correlation between overexpression of the HER-2 protein and amplification of the gene that codes for it.
  • One way to test this is by using RT-PCR.
  • the genomic and cDNA sequences for HER-2 are known.
  • Specific DNA primers can be generated using standard, well-known techniques, and can then be used to amplify template already present in the cell. An example of this is described in Kurokawa, H et al, Cancer Res. 60: 5887-5894 (2000).
  • PCR can be standardized such that quantitative differences are observed as between normal and abnormal cells, e.g., cancerous and noncancerous cells.
  • Well known methods employing, e.g., densitometry can be used to quantitate and/or compare nucleic acid levels amplified using PCR.
  • FISH fluorescent in situ hybridization
  • other assays can be used, e.g., Northern and/or Southern blotting.
  • FISH fluorescent in situ hybridization
  • this nucleic acid probe can be conjugated to a fluorescent molecule, e.g., fluorescein and/or rhodamine, that preferably does not interfere with hybridization, and which fluorescence can later be measured following hybridization.
  • Immuno and nucleic acid detection can also be directed against proteins other than HSP90 and Her-2, which proteins are nevertheless affected in response to HSP90 inhibition.
  • Step 1 A solution of 5-amino-4,6-dichloropyrimidine (1 mmol) in n-BuOH was treated with Et 3 N (1.2 mmol) and n-Butylamine (1.0 mmol) at 80 C. After 16 h, solvent was removed under reduced pressure. The residue was dissolved in EtOAc, the organic layer washed with water and then dried (MgSO 4 ). Filtration and removal of solvent gave 6-chloro-5-amino-4-butyl pyrimidine as a brown solid.
  • Step 2 To a solution of 2,5-dimethoxyphenylacetic acid (1 mmol) and Et 3 N (1 mmol) in CH 2 Cl 2 was added p-toluenesulfonyl chloride (1 mmol) at rt. After 1 h, the mixture was treated with a solution of the product of step 1, 6-chloro-5-amino-4-butyl pyrimidine (1 mmol in CH 2 Cl 2 ), followed by addition of Et 3 N (2 mmol). The resultant mixture was refluxed for 20 h. Solvent was removed and the residue dissolved into EtOAc, the organic layer washed with water and dried.
  • Step 3 A mixture of N-(4-butylamino-6-chloro-pyrimidin-5-yl)-2-(2,5-dimethoxyphenyl)acetamide (1 mmol) and p-TSA (0.5 mmol) in toluene was refluxed for 72 h. Solvent was removed, diluted with EtOAc and washed with water, bicarbonate and dried. Purification on a silica gel column (200-400 mesh, Fisher Scientific, Tustin, Calif., USA) gave 6-chloro-8-(2,5-dimethoxybenzyl)-N9-butyl purine. R f 0.65 in 1:1 EtOAc:hexane.
  • 8-(2,5-dimethoxybenzyl)-9-butyl adenine can also be prepared from N-(4-butylamino-6-chloro-pyrimidin-5-yl)-2-(2,5-dimethoxyphenyl)acetamide according to the following procedure: A solution of N-(4-butylamino-6-chloro-pyrimidin-5-yl)-2-(2,5-dimethoxyphenyl)acetamide (1 mmol) is taken into 7M NH 3 in MeOH (70 mmol) and the mixture heated at 120 C in a steel bomb for 72 h. Solvent is removed by azeotrope distillation with toluene. Purification on the silica gel column gave pure 8-(2,5-dimethoxybenzyl)-9-butyl adenine.
  • Step 1 2-(2,5-Dimethoxy-phenyl)-N-(2,5,6-triamino-pyrimidin-4-yl)-acetamide, HCl
  • Step 4 8-(2,5-Dimethoxy-benzyl)-2-fluoro-9-pent-4-ynyl-9H-purin-6-ylamine
  • 2-Cl compound was prepared analogously to the method described in Step 4 using HCl and CuCl in place of HBF 4 .
  • HPLC method Agilent Zorbax 300 SB C18, 4.6 ⁇ 150 mm, 5 ⁇ m; Column Temperature: Ambient; Flow Rate: 1.0 ml/mm, Gradient: 10% acetonitrile (0.05% TFA) in water (0.1% TFA) to 100% acetonitrile (0.05% TFA) in 10 minutes, hold at 100% for 1 minutes); Retention times are measured in minutes.
  • organozinc compounds were prepared using the corresponding commercially available organozinc compound; the skilled artisan will recognize that equivalent organnostannane, and organoboron, and organomagnesium coupling partners may be used in place of organozinc compounds.
  • organnostannane, and organoboron, and organomagnesium coupling partners may be used in place of organozinc compounds.
  • organozinc compounds A general review of appropriate methodologies may be found in “Palladium Reagents in Organic Synthesis” Richard F. Heck, Academic Press, 1990.
  • Nitro derivatives (20 mg) are reduced with 10% Pd/C (Aldrich) (20 mg) under H 2 atmosphere in THF at r.t. over 16 h.
  • the resulting aniline can be further monoalkylated (Acetylchloride, CH 2 Cl 2 ) or reductively alkylated (RCHO, NaBH(OAc) 3 , 1,2-dichloroethane, r.t.).
  • Standard procedures gave the corresponding alcohol (NaBH 4 , MeOH, r.t.), tosyl hydrazone (TsNHNH 2 , EtOH, reflux), oximes (RONH 2 .HCl, DMF, 60° C.), amines (R 1 R 2 NH, NaBH(OAc) 3 , Cl—(CH 2 ) 2 —Cl r.t.), homoallylic alcohol (AllSiMe 3 , TiCl 4 ), CH 2 Cl 2 , ⁇ 78° C.), or alkenes.
  • Step 1 Adenine (47 g, 0.35 mole) was suspended in 200 ml of CHCl3 before adding bromine (180 ml, 3.5 mole) in one portion. The suspension was left stirring at room temperature for 72 hours in a closed system that was vented by a 20G needle. The reaction was worked up by adding shaved ice into the suspension before slowly neutralizing with aqueous ammonia to pH 8-9, followed by precipitation of the desired product with acetic acid. The crude product was dried under reduced pressure for 2 days to give 8-Bromoadenine as a light brown powder (45 g, 60% yield).
  • Step 2 8-Bromopurine (2.2 g, 10 mmole) was dissolved in 50 ml of DMF before adding 1-bromo-butane (2.2 ml, 20 mmol) and cesium carbonate (6.7 g, 20 mmol) into the solution. The reaction mixture was left stirring at room temperature for 16 hours before quenching with water and extracting with EtOAc. The organic layer was washed with water and dried with MgSO4 before removing solvent under reduced pressure. A white powder (0.9 g, 33%) of 8-Bromo-9-butyl-9H-purin-6-ylamine was isolated using silica gel column chromatography (50% EtOAc/Hexanes).
  • Step 3 To a mixture of sodium hydride (96 mg, 4 mmol) in DMF (4 ml) was added 3-methoxy-benzenethiol (1.12 g, 8 mmol). After 30 min, a solution of 8-bromo-9-butyl-9H-purin-6-ylamine (0.54 g, 2 mmol) in DMF (6 ml) was added and stirred for 12 h at 70° C.
  • HPLC method used for these compounds Agilent Zorbax 300 SB C18, 4.6 ⁇ 150 mm, 5 ⁇ m; Column Temperature: Ambient; Flow Rate: 1.0 ml/min, Gradient: 5% acetonitrile (0.05% TFA) in water (0.1% TFA) to 100% acetonitrile (0.05% TFA) in 15 minutes, hold at 100% for 2 minutes).
  • Step 4 To a solution of 9-butyl-8-(3-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (0.26 g, 0.73 mmol) in AcOH (4 ml) was added NIS (0.53 g, 2.19 mmol) in portions. The mixture was stirred for 24 h at r.t.
  • N9 substituent (Y) is sensitive to halogenation conditions
  • these may be prepared using iodide already present in the benzenethiol moiety:
  • the compounds in this example were prepared analogously to the method described above in Example 9 using various electrophiles to generate a library of N9 substituted compounds. N9 allylation was done as a final step after the bromine displacement of 8-bromopurine with 2,5-dimethoxy thiophenol.
  • the compounds in this example were prepared using diazonium salts and thiols as coupling partners.
  • Step 1 A suspension of 8-bromo-9-butyl-9H-purin-6-ylamine (0.50 g, 1.85 mmol) and thiourea (1.49 g, 19.6 mmol) in n-butanol (10 ml) was heated to reflux for 14 h. Dilution with CH 2 Cl 2 (70 ml), washing with water and concentration afforded 6-amino-9-butyl-7,9-dihydro-purine-8-thione as a white powder (0.42 g, 1.87 mmol, 100%).
  • 1 H NMR (DMSO-d 6 ) ⁇ 12.35-12.25 (br. s, 1H), 8.13 (s, 1H), 6.92-6.72 (br.
  • Step 2 A solution of the above thione (30.8 mg, 0.138 mmol) and t-BuOK (15.5 mg, 0.138 mmol) in MeOH (0.55 ml) was treated portion-wise with crude 2-iodo-5-methoxy-benzenediazonium tetrafluoroborate (48 mg, 0.138 mmol). The vigorous N 2 evolution ceased after 2 mm. Work-up and preparative TLC (MeOH:CH 2 Cl 2 5:95) yielded the title sulfide.
  • This assay directly measures the binding of biotinylated-geldanamycin biotin-GM) to purified Hsp90 and thus tests the ability of compounds to compete for binding to Hsp90.
  • Purified native Hsp90 protein (mixture of alpha and beta) from HeLa cells (Stressgen Biotechnologies Corp., San Diego, Calif., USA) was coated onto 96-well plates by incubating for 1 hr at 37° C. Uncoated Hsp90 was removed and the wells washed twice in 1 ⁇ PBS (phosphate-buffered saline) buffer. Biotin-GM was then added to the wells, and the reaction was further incubated for 1 hr 37° C. The wells were washed twice with 1 ⁇ PBS, before the addition of 20 ug/ml streptavidin-phycoerythrin, and incubated for 1 hr at 37° C. The wells were again washed twice with 1 ⁇ PBS. The fluorescence was then measured in a Gemini spectrofluorometer (Molecular Devices) using an excitation of 485 nm and emission of 580 nm.
  • Gemini spectrofluorometer Molecular Devices
  • MCF-7 cells are seeded in 24 well plates at a density of approximately 30,000 cells/well and allowed to grow for 16 hours in DMEM supplemented with 10% FBS. Drug is then added at a concentration range of 100 uM to 0.01 uM. Cells are incubated for an additional 24. Drug treated cells and untreated control cells are trypsinized, and incubated at room temperature for 15 minutes with anti Her-2 neu Ab conjugated with phycoerythrin (Becton Dickinson, San Jose Calif.; Cat no. 340552) at a concentration of 0.25 ug/ml, or non-specific control IgG1 conjugated with phycoerythrin (Becton Dickinson, San Jose Calif.; Cat no. 340761).
  • %Her-2 degradation (mfi HER-2 sample)/(mfi HER-2 untreated cells) ⁇ 100
  • Table 5 summarizes the Her-2 degradation ability of various compounds of the invention:
  • Inhibitory Concentration 50 for this assay is the concentration necessary to degrade 50% of Her 2 expression (protein).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Transplantation (AREA)
  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Novel purine compounds and tautomers and pharmaceutically acceptable salts thereof are described, as are pharmaceutical compositions comprising the same, complexes comprising the same, e.g., HSP90 complexes, and methods of using the same.

Description

    RELATED APPLICATIONS
  • This application claims priority to and incorporates by reference in its entirety Kasibhatla et al., U.S. Provisional Patent Application Ser. No. 60/335,391, entitled PURINE ANALOGS HAVING HSP90-INHIBITING ACTIVITY, filed Oct. 30, 2001.
  • FIELD OF THE INVENTION
  • The invention relates in general to purine analogs and their use in inhibiting heat shock protein 90's (HSP90's) to thereby treat or prevent HSP90-dependent diseases, e.g., proliferative disorders such as breast cancer.
  • BACKGROUND
  • The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed inventions, or that any publication specifically or implicitly referenced is prior art.
  • HSP90s are ubiquitous chaperone proteins that are involved in folding, activation and assembly of a wide range of proteins, including key proteins involved in signal transduction, cell cycle control and transcriptional regulation. Researchers have reported that HSP90 chaperone proteins are associated with important signaling proteins, such as steroid hormone receptors and protein kinases, including, e.g., Raf-1, EGFR, v-Src family kinases, Cdk4, and ErbB-2 (Buchner J., 1999, TIBS, 24:136-141; Stepanova, L. et al., 1996, Genes Dev. 10:1491-502; Dai, K. et al., 1996, J. Biol. Chem. 271:22030-4). Studies further indicate that certain co-chaperones, e.g., Hsp70, p60/Hop/Sti1, Hip, Bag1, HSP40/Hdj2/Hsj1, immunophilins, p23, and p50, may assist HSP90 in its function (see, e.g., Caplan, A., Trends in Cell Biol., 9: 262-68 (1999).
  • Ansamycin antibiotics, e.g., herbimycin A (HA), geldanamycin (GM), and 17-AAG are thought to exert their anticancerous effects by tight binding of the N-terminus pocket of HSP90, thereby destabilizing substrates that normally interact with HSP90 (Stebbins, C. et al., 1997, Cell, 89:239-250). This pocket is highly conserved and has weak homology to the ATP-binding site of DNA gyrase (Stebbins, C. et al., supra; Grenert, J. P. et al., 1997, J. Biol. Chem., 272:23843-50). Further, ATP and ADP have both been shown to bind this pocket with low affinity and to have weal ATPase activity (Proromou, C. et al., 1997, Cell, 90: 65-75; Panaretou, B. et al., 1998, EMBO J., 17: 4829-36). In vitro and in vivo studies have demonstrated that occupancy of this N-terminal pocket by ansamycins and other HSP90 inhibitors alters HSP90 function and inhibits protein folding. At high concentrations, ansamycins and other HSP90 inhibitors have been shown to prevent binding of protein substrates to HSP90 (Scheibel, T., H. et al., 1999, Proc. Natl. Acad. Sci. USA 96:1297-302; Schulte, T. W. et al., 1995, J. Biol. Chem. 270:24585-8; Whitesell, L., et al., 1994, Proc. Natl. Acad. Sci. USA 91:8324-8328). Ansamycins have also been demonstrated to inhibit the ATP-dependent release of chaperone-associated protein substrates (Schneider, C., L. et al., 1996, Proc. Natl. Acad. Sci. USA, 93:14536-41; Sepp-Lorenzino et al., 1995, J. Biol. Chem. 270:16580-16587). In either event, the substrates are degraded by a ubiquitin-dependent process in the proteasome (Schneider, C., L., supra; Sepp-Lorenzino, L., et al., 1995, J. Biol. Chem., 270:16580-16587; Whitesell, L. et al., 1994, Proc. Natl. Acad. Sci. USA, 91: 8324-8328).
  • HSP90 substrate destabilization occurs in tumor and non-transformed cells a like and has been shown to be especially effective on a subset of signaling regulators, e.g., Raf (Schulte, T. W. et al., 1997, Biochem. Biophys. Res. Commun. 239:655-9; Schulte, T. W., et al., 1995, J. Biol. Chem. 270:24585-8), nuclear steroid receptors (Segnitz, B., and U. Gehring. 1997, J. Biol. Chem. 272:18694-18701; Smith, D. F. et al., 1995, Mol. Cell. Biol. 15:6804-12), v-src (Whitesell, L., et al., 1994, Proc. Natl. Acad. Sci. USA 91:8324-8328) and certain transmembrane tyrosine kinases (Sepp-Lorenzino, L. et al., 1995, J. Biol. Chem. 270:16580-16587) such as EGF receptor (EGFR) and Her2/Neu (Hartmann, F., et al., 1997, Int. J. Cancer 70:221-9; Miller, P. et al., 1994, Cancer Res. 54:2724-2730; Mimnaugh, E. G., et al., 1996, J. Biol. Chem. 271:22796-801; Schnur, R. et al., 1995, J. Med. Chem. 38:3806-3812), CDK4, and mutant p53. Erlichnman et al., Proc. AACR (2001), 42, abstract 4474. The ansamycin-induced loss of these proteins leads to the selective disruption of certain regulatory pathways and results in growth arrest at specific phases of the cell cycle (Muise-Heimericks, R. C. et al. 1998, J. Biol. Chem. 273:29864-72), and apoptosis, and/or differentiation of cells so treated (Vasilevskaya, A. et al., 1999, Cancer Res., 59:3935-40).
  • In addition to anti-cancer and antitumorgenic activity, HSP90 inhibitors have also been implicated in a wide variety of other utilities, including use as anti-inflammation agents, anti-infectious disease agents, agents for treating autoimmunity, agents for treating ischemia, and agents useful in promoting nerve regeneration (See, e.g., Rosen et al., WO 02/09696; PCT/US01/23640; Degranco et al., WO 99/51223; PCT/US99/07242; Gold, U.S. Pat. No. 6,210,974 B1). There are reports in the literature that fibrogenetic disorders including but not limited to scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis, and pulmonary fibrosis may be treatable. (Strehlow, WO 02/02123; PCT/US01/20578).
  • Ansamycins and other HSP90 inhibitors thus hold great promise for the treatment and/or prevention of many types of disorders. However, their relative insolubility makes them difficult to formulate and administer, and they are not easily synthesized and currently must, at least in part, be generated through fermentation. Further, the dose limiting toxicity of ansamyins is hepatic. Despite the potential of ansamycins, alternative HSP90 inhibitors are therefore needed.
  • Recently, Chiosis et al. described the design and synthesis of purine analogs that mimic geldanamycin and other ansamycins in their ability to bind the ATP binding pocket of, and thus inhibit, HSP90, See International Patent Application PCT/US01/46303 (WO 02/36075; Chemistry & Biology 8:289-299 (2001). The specific compounds that Chiosis et al. described included a trimethoxybenzyl entity substituted at positions 3, 4, and 5. Using gel-binding assays, these were shown to bind HSP90 approximately 20-fold less avidly than the benzoquinone ansamycin, 17-AAG. Chiosis et al. did not attempt a quinone mimic for the methoxybenzyl entity, speculating that to do so would lead to hepatoxicity. Id., pg. 290, col. 1, ¶ 4. Nor did Chiosis et al. teach, suggest, or otherwise report the use of sulfides, sulfoxides, and sulfones as described herein.
  • SUMMARY OF THE INVENTION
  • Applicants herein describe a set of purine-based compounds that have utility in inhibiting HSP90 and diseases that are HSP90-dependent, e.g., a variety of carcinomas, such as melanoma, breast cancer, etc.
  • In one embodiment, the purine or purine analog has structure I, II, III, or IV:
  • Figure US20080125446A1-20080529-C00001
  • wherein A is selected from NR1 2, NHSO2R2, NR1NR1 2, NR1OR4, OR3, SR3, optionally substituted lower alkyl, C(O)N(R4)2, guanidine, amidine, U, halogen, CN, N3 and perhaloalkyl;
  • wherein X is a 1 carbon, 2 carbon, or 3 carbon optionally substituted structure (C1-C3), or else NR1, S, S(O), S(O)2, O, or C(O). For carbon linkers having more than 1 carbon, these may have single, double, or triple bonds between them.
  • wherein Y is selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alicyclic, optionally substituted araalkyl, optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl, alkylaminoalkyl, alkylcarbonylaminoalkyl (—(CH2)n—C(O)—NR—(CH2)n), alkylcarbonyoxylalkyl (—(CH2)n—C(O)—O—(CH2)n), optionally substituted heterocyclic, hydroxyalkyl, haloalkyl, perhaloalkyl, C(O)R2, S(O)2R2, C(O)NHR2, and C(O)OR2;
  • wherein Z is selected from the group consisting of H, halogen, CN, OR3, SR3, perhaloalkyl, optionally substituted allyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alicyclic, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl, optionally substituted heterocyclic, C(O)R2, —S(O)2R2, NHOR4, and C(O)NR4 2;
  • Q is selected from the group consisting of alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl, and heterocyclic, all optionally substituted; e.g.,
  • Figure US20080125446A1-20080529-C00002
  • R1 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclic, C(O)R2, —C(O)OR2, C(O)NR4 2, C(S)OR2, C(S)NR4 2, PO3R4, and SO2R2;
  • R2 is selected from alkyl, heteroalkyl, cycloalkyl, heterocyclic, heteroaryl, and aryl, all optionally substituted;
  • R3 is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclic and C(O)NR4 2; and
  • wherein R4 is selected from either H or from alkyl, cycloalkyl, heteroalkyl, aryl, and heterocyclic, all optionally substituted;
  • wherein R5 is selected from H, OH, and optionally substituted allyl; and
  • wherein R6 is independently selected from H, optionally substituted alkyl, OR3, SR3, NHR3, C(O)R5, NO2, CN, halogen, and S(O)2R2. In some embodiments, the alkyl, alkenyl, and alkynyl substituent are 1 to 8 carbon atoms in length, more preferably 1 to 6 carbon atoms in length, and optionally substituted.
  • The subscript “n” can be 1 to 10 inclusive, with 3 or less being preferred.
  • Other compounds of the invention are based on the following formula, having illustrative species as described in Table 1:
  • TABLE 1
    Figure US20080125446A1-20080529-C00003
    No. Ex. W X Y Z
    1 3.2 2,5-dimethoxy CH2 pent-4-ynyl H
    —(CH2)3 CCH
    2 2,3,5-trimethoxy CH2 pent-4-ynyl H
    3 3,4,5-trimethoxy CH2 pent-4-ynyl H
    4 4.7 2-iodo, 5-methoxy CH2 pent-4-ynyl H
    5 2-bromo, 5-methoxy CH2 pent-4-ynyl H
    6 2-chloro, 5-methoxy CH2 pent-4-ynyl H
    7 2,4-diiodo, CH2 pent-4-ynyl H
    5-methoxy
    8 2,5-diiodo CH2 pent-4-ynyl H
    9 2,4-diiodo CH2 pent-4-ynyl H
    10 2-iodo, 5-SCH3 CH2 pent-4-ynyl H
    11 2-iodo, 5-ethyl CH2 pent-4-ynyl H
    12 2-iodo, 5-propyl CH2 pent-4-ynyl H
    13 2-chloro, 5-SCH3 CH2 pent-4-ynyl H
    14 2-chloro, 5-ethyl CH2 pent-4-ynyl H
    15 2-chloro, 5-propyl CH2 pent-4-ynyl H
    16 2,5-SCH3 CH2 pent-4-ynyl H
    17 2-iodo, 4-fluoro, 5- CH2 pent-4-ynyl H
    methoxy
    18 2-iodo, 3-fluoro, 5- CH2 pent-4-ynyl H
    methoxy
    19 2-iodo, 6-fluoro, 5- CH2 pent-4-ynyl H
    methoxy
    20 2-Chloro, 3-fluoro, CH2 pent-4-ynyl H
    5-methoxy
    21 2-Chloro, 4-fluoro, CH2 pent-4-ynyl H
    5-methoxy
    22 2-chloro-3,4,5- CH2 pent-4-ynyl H
    trimethoxy
    23 2,3-diiodo, CH2 pent-4-ynyl H
    5-methoxy
    24 2,5-dichloro CH2 pent-4-ynyl H
    25 2,5-dibromo CH2 pent-4-ynyl H
    26 2-Iodo, 4-chloro, 5- CH2 pent-4-ynyl H
    methoxy
    27 2-iodo, 4-bromo, 5- CH2 pent-4-ynyl H
    methoxy
    28 2,5-dimethoxy CH2 pent-4-ynyl F
    29 2,3,5-trimethoxy CH2 pent-4-ynyl F
    30 3,4,5-trimethoxy CH2 pent-4-ynyl F
    31 4.10 2-iodo, 5-methoxy CH2 pent-4-ynyl F
    32 2-bromo, 5-methoxy CH2 pent-4-ynyl F
    33 2-chloro, 5-methoxy CH2 pent-4-ynyl F
    34 2,4-diiodo, CH2 pent-4-ynyl F
    5-methoxy
    35 2,5-diiodo CH2 pent-4-ynyl F
    36 2,4-diiodo CH2 pent-4-ynyl F
    37 2-iodo, 5-SCH3 CH2 pent-4-ynyl F
    38 2-iodo, 5-ethyl CH2 pent-4-ynyl F
    39 2-iodo, 5-propyl CH2 pent-4-ynyl F
    40 2-chloro, 5-SCH3 CH2 pent-4-ynyl F
    41 2-chloro, 5-ethyl CH2 pent-4-ynyl F
    42 2-chloro, 5-propyl CH2 pent-4-ynyl F
    43 2,5-SCH3 CH2 pent-4-ynyl F
    44 2-iodo, 4-fluoro, 5- CH2 pent-4-ynyl F
    methoxy
    45 2-iodo, 3-fluoro, 5- CH2 pent-4-ynyl F
    methoxy
    46 2-iodo, 6-fluoro, 5- CH2 pent-4-ynyl F
    methoxy
    47 2-Chloro, 3-fluoro, CH2 pent-4-ynyl F
    5-methoxy
    48 2-Chloro, 4-fluoro, CH2 pent-4-ynyl F
    5-methoxy
    49 2,3,4,5-tetraiodo CH2 pent-4-ynyl F
    50 2,3-diiodo, CH2 pent-4-ynyl F
    5-methoxy
    51 2,5-dichloro CH2 pent-4-ynyl F
    52 2,5-dibromo CH2 pent-4-ynyl F
    53 2-Iodo, 4-chloro, 5- CH2 pent-4-ynyl F
    methoxy
    54 2-iodo, 4-bromo, 5- CH2 pent-4-ynyl F
    methoxy
    55 3.4 2,5-dimethoxy CH2 4-methyl-pent-3-enyl H
    —(CH2)2CHCCMe2
    56 2,3,5-trimethoxy CH2 4-methyl-pent-3-enyl H
    57 3,4,5-trimethoxy CH2 4-methyl-pent-3-enyl H
    58 4.8 2-iodo, 5-methoxy CH2 4-methyl-pent-3-enyl H
    59 2-bromo, 5-methoxy CH2 4-methyl-pent-3-enyl H
    60 2-chloro, 5-methoxy CH2 4-methyl-pent-3-enyl H
    61 2,4-diiodo, CH2 4-methyl-pent-3-enyl H
    5-methoxy
    62 2,5-diiodo CH2 4-methyl-pent-3-enyl H
    63 2,4-diiodo CH2 4-methyl-pent-3-enyl H
    64 2-iodo, 5-SCH3 CH2 4-methyl-pent-3-enyl H
    65 2-iodo, 5-ethyl CH2 4-methyl-pent-3-enyl H
    66 2-iodo, 5-propyl CH2 4-methyl-pent-3-enyl H
    67 2-chloro, 5-SCH3 CH2 4-methyl-pent-3-enyl H
    68 2-chloro, 5-ethyl CH2 4-methyl-pent-3-enyl H
    69 2-chloro, 5-propyl CH2 4-methyl-pent-3-enyl H
    70 2,5-SCH3 CH2 4-methyl-pent-3-enyl H
    71 2-iodo, 4-fluoro, 5- CH2 4-methyl-pent-3-enyl H
    methoxy
    72 2-iodo, 3-fluoro, 5- CH2 4-methyl-pent-3-enyl H
    methoxy
    73 2-iodo, 6-fluoro, 5- CH2 4-methyl-pent-3-enyl H
    methoxy
    74 2-Chloro, 3-fluoro, CH2 4-methyl-pent-3-enyl H
    5-methoxy
    75 2-Chloro, 4-fluoro, CH2 4-methyl-pent-3-enyl H
    5-methoxy
    76 2-chloro-3,4,5- CH2 4-methyl-pent-3-enyl H
    trimethoxy
    77 2,3-diiodo, CH2 4-methyl-pent-3-enyl H
    5-methoxy
    78 2,5-dichloro CH2 4-methyl-pent-3-enyl H
    79 2,5-dibromo CH2 4-methyl-pent-3-enyl H
    80 2-iodo, 4-chloro, 5- CH2 4-methyl-pent-3-enyl H
    methoxy
    81 2-iodo, 4-bromo, 5- CH2 4-methyl-pent-3-enyl H
    methoxy
    82 2,5-dimethoxy CH2 4-methyl-pent-3-enyl F
    83 2,3,5-trimethoxy CH2 4-methyl-pent-3-enyl F
    84 3,4,5-trimethoxy CH2 4-methyl-pent-3-enyl F
    85 4.9 2-iodo, 5-methoxy CH2 4-methyl-pent-3-enyl F
    86 2-bromo, 5-methoxy CH2 4-methyl-pent-3-enyl F
    87 2-chloro, 5-methoxy CH2 4-methyl-pent-3-enyl F
    88 2,4-diiodo, CH2 4-methyl-pent-3-enyl F
    5-methoxy
    89 2,5-diiodo CH2 4-methyl-pent-3-enyl F
    90 2,4-diiodo CH2 4-methyl-pent-3-enyl F
    91 2-iodo, 5-SCH3 CH2 4-methyl-pent-3-enyl F
    92 2-iodo, 5-ethyl CH2 4-methyl-pent-3-enyl F
    93 2-iodo, 5-propyl CH2 4-methyl-pent-3-enyl F
    94 2-chloro, 5-SCH3 CH2 4-methyl-pent-3-enyl F
    95 2-chloro, 5-ethyl CH2 4-methyl-pent-3-enyl F
    96 2-chloro, 5-propyl CH2 4-methyl-pent-3-enyl F
    97 2,5-SCH3 CH2 4-methyl-pent-3-enyl F
    98 2-iodo, 4-fluoro, 5- CH2 4-methyl-pent-3-enyl F
    methoxy
    99 2-iodo, 3-fluoro, 5- CH2 4-methyl-pent-3-enyl F
    methoxy
    100 2-iodo, 6-fluoro, 5- CH2 4-methyl-pent-3-enyl F
    methoxy
    101 2-chloro, 3-fluoro, CH2 4-methyl-pent-3-enyl F
    5-methoxy
    102 2-chloro, 4-fluoro, CH2 4-methyl-pent-3-enyl F
    5-methoxy
    103 2-chloro-3,4,5- CH2 4-methyl-pent-3-enyl F
    trimethoxy
    104 2,3-diiodo, CH2 4-methyl-pent-3-enyl F
    5-methoxy
    105 2,5-dichloro CH2 4-methyl-pent-3-enyl F
    106 2,5-dibromo CH2 4-methyl-pent-3-enyl F
    107 2-iodo, 4-chloro, 5- CH2 4-methyl-pent-3-enyl F
    methoxy
    108 2-iodo, 4-bromo, 5- CH2 4-methyl-pent-3-enyl F
    methoxy
    109 2,5-dimethoxy S pent-4-ynyl H
    110 2,3,5-trimethoxy S pent-4-ynyl H
    112 3,4,5-trimethoxy S pent-4-ynyl H
    113 9.7 2-iodo, 5-methoxy S pent-4-ynyl H
    114 2-bromo, 5-methoxy S pent-4-ynyl H
    115 2-chloro, 5-methoxy S pent-4-ynyl H
    116 2,4-diiodo, S pent-4-ynyl H
    5-methoxy
    117 2,5-diiodo S pent-4-ynyl H
    118 2,4-diiodo S pent-4-ynyl H
    119 2-iodo, 5-SCH3 S pent-4-ynyl H
    120 2-iodo, 5-ethyl S pent-4-ynyl H
    121 2-iodo, 5-propyl S pent-4-ynyl H
    122 2-chloro, 5-SCH3 S pent-4-ynyl H
    123 2-chloro, 5-ethyl S pent-4-ynyl H
    124 2-chloro, 5-propyl S pent-4-ynyl H
    125 2,5-SCH3 S pent-4-ynyl H
    126 2-iodo, 4-fluoro, S pent-4-ynyl H
    5-methoxy
    127 2-iodo, 3-fluoro, 5- S pent-4-ynyl H
    methoxy
    128 2-iodo, 6-fluoro, 5- S pent-4-ynyl H
    methoxy
    129 2-chloro, 3-fluoro, S pent-4-ynyl H
    5-methoxy
    130 2-chloro, 4-fluoro, S pent-4-ynyl H
    5-methoxy
    131 2-chloro-3,4,5- S pent-4-ynyl H
    trimethoxy
    132 2,3-diiodo, S pent-4-ynyl H
    5-methoxy
    133 2,5-dichloro S pent-4-ynyl H
    134 2,5-dibromo S pent-4-ynyl H
    135 2-iodo, 4-chloro, 5- S pent-4-ynyl H
    methoxy
    136 2-iodo, 4-bromo, 5- S pent-4-ynyl H
    methoxy
    137 2,5-dimethoxy S pent-4-ynyl F
    138 2,3,5-trimethoxy S pent-4-ynyl F
    139 3,4,5-trimethoxy S pent-4-ynyl F
    140 2-iodo, 5-methoxy S pent-4-ynyl F
    141 2-bromo, 5-methoxy S pent-4-ynyl F
    142 2-chloro, 5-methoxy S pent-4-ynyl F
    143 2,4-diiodo, S pent-4-ynyl F
    5-methoxy
    144 2,5-diiodo S pent-4-ynyl F
    145 2,4-diiodo S pent-4-ynyl F
    146 2-iodo, 5-SCH3 S pent-4-ynyl F
    147 2-iodo, 5-ethyl S pent-4-ynyl F
    148 2-iodo, 5-propyl S pent-4-ynyl F
    149 2-chloro, 5-SCH3 S pent-4-ynyl F
    150 2-chloro, 5-ethyl S pent-4-ynyl F
    151 2-chloro, 5-propyl S pent-4-ynyl F
    152 2,5-SCH3 S pent-4-ynyl F
    153 2-iodo, 4-fluoro, S pent-4-ynyl F
    5-methoxy
    154 2-iodo, 3-fluoro, 5- S pent-4-ynyl F
    methoxy
    155 2-iodo, 6-fluoro, 5- S pent-4-ynyl F
    methoxy
    156 2-chloro, 3-fluoro, S pent-4-ynyl F
    5-methoxy
    157 2-chloro, 4-fluoro, S pent-4-ynyl F
    5-methoxy
    158 2,3,4,5-tetraiodo S pent-4-ynyl F
    159 2,3-diiodo, S pent-4-ynyl F
    5-methoxy
    160 2,5-dichloro S pent-4-ynyl F
    161 2,5-dibromo S pent-4-ynyl F
    162 2-iodo, 4-chloro, 5- S pent-4-ynyl F
    methoxy
    163 2-iodo, 4-bromo, 5- S pent-4-ynyl F
    methoxy
    164 2,5-dimethoxy S 4-methyl-pent-3-enyl H
    165 2,3,5-trimethoxy S 4-methyl-pent-3-enyl H
    166 3,4,5-trimethoxy S 4-methyl-pent-3-enyl H
    167 9.6 2-iodo, 5-methoxy S 4-methyl-pent-3-enyl H
    168 2-bromo, 5-methoxy S 4-methyl-pent-3-enyl H
    169 2-chloro, 5-methoxy S 4-methyl-pent-3-enyl H
    170 2,4-diiodo, S 4-methyl-pent-3-enyl H
    5-methoxy
    171 2,5-diiodo S 4-methyl-pent-3-enyl H
    172 2,4-diiodo S 4-methyl-pent-3-enyl H
    173 2-iodo, 5-SCH3 S 4-methyl-pent-3-enyl H
    174 2-iodo, 5-ethyl S 4-methyl-pent-3-enyl H
    175 2-iodo, 5-propyl S 4-methyl-pent-3-enyl H
    176 2-chloro, 5-SCH3 S 4-methyl-pent-3-enyl H
    177 2-chloro, 5-ethyl S 4-methyl-pent-3-enyl H
    178 2-chloro, 5-propyl S 4-methyl-pent-3-enyl H
    179 2,5-SCH3 S 4-methyl-pent-3-enyl H
    180 2-iodo, 4-fluoro, 5- S 4-methyl-pent-3-enyl H
    methoxy
    181 2-iodo, 3-fluoro, 5- S 4-methyl-pent-3-enyl H
    methoxy
    182 2-iodo, 6-fluoro, 5- S 4-methyl-pent-3-enyl H
    methoxy
    183 2-chloro, 3-fluoro, S 4-methyl-pent-3-enyl H
    5-methoxy
    184 2-chloro, 4-fluoro, S 4-methyl-pent-3-enyl H
    5-methoxy
    185 2-chloro-3,4,5- S 4-methyl-pent-3-enyl H
    trimethoxy
    186 2,3-diiodo, S 4-methyl-pent-3-enyl H
    5-methoxy
    187 2,5-dichloro S 4-methyl-pent-3-enyl H
    188 2,5-dibromo S 4-methyl-pent-3-enyl H
    189 2-iodo, 4-chloro, 5- S 4-methyl-pent-3-enyl H
    methoxy
    190 2-iodo, 4-bromo, 5- S 4-methyl-pent-3-enyl H
    methoxy
    191 2,5-dimethoxy S 4-methyl-pent-3-enyl F
    192 2,3,5-trimethoxy S 4-methyl-pent-3-enyl F
    193 3,4,5-trimethoxy S 4-methyl-pent-3-enyl F
    194 2-iodo, 5-methoxy S 4-methyl-pent-3-enyl F
    195 2-bromo, 5-methoxy S 4-methyl-pent-3-enyl F
    196 2-chloro, 5-methoxy S 4-methyl-pent-3-enyl F
    197 2,4-diiodo, S 4-mehtyl-pent-3-enyl F
    5-methoxy
    198 2,5-diiodo S 4-methyl-pent-3-enyl F
    199 2,4-diiodo S 4-methyl-pent-3-enyl F
    200 2-iodo, 5-SCH3 S 4-methyl-pent-3-enyl F
    201 2-iodo, 5-ethyl S 4-methyl-pent-3-enyl F
    202 2-iodo, 5-propyl S 4-methyl-pent-3-enyl F
    203 2-chloro, 5-SCH3 S 4-methyl-pent-3-enyl F
    204 2-chloro, 5-ethyl S 4-methyl-pent-3-enyl F
    205 2-chloro, 5-propyl S 4-methyl-pent-3-enyl F
    206 2,5-SCH3 S 4-methyl-pent-3-enyl F
    207 2-iodo, 4-fluoro, 5- S 4-methyl-pent-3-enyl F
    methoxy
    208 2-iodo, 3-fluoro, 5- S 4-methyl-pent-3-enyl F
    methoxy
    209 2-iodo, 6-fluoro, 5- S 4-methyl-pent-3-enyl F
    methoxy
    210 2-chloro, 3-fluoro, S 4-methyl-pent-3-enyl F
    5-methoxy
    211 2-chloro, 4-fluoro, S 4-methyl-pent-3-enyl F
    5-methoxy
    212 2,3,4,5-tetraiodo S 4-methyl-pent-3-enyl F
    213 2,3-diiodo, S 4-methyl-pent-3-enyl F
    5-methoxy
    214 2,5-dichloro S 4-methyl-pent-3-enyl F
    215 2,5-dibromo S 4-methyl-pent-3-enyl F
    216 2-Iodo, 4-chloro, 5- S 4-methyl-pent-3-enyl F
    methoxy
    217 2-iodo, 4-bromo, 5- S 4-methyl-pent-3-enyl F
    methoxy
    218 11.2 2,5-dimethoxy S Pentyl H
    219 9.2 2,5-dimethoxy S Butyl H
    220 11.1 2,5-dimethoxy S H H
    221 11.3 2,5-dimethoxy S pent-4-ynyl H
    222 11.4 2,5-dimethoxy S butyronitrile H
    223 11.5 2,5-dimethoxy S 3,3,3-trifluoropropyl H
    224 11.6 2,5-dimethoxy S 4-chlorobutyl H
    225 11.7 2,5-dimethoxy S 4-acetoxybutyl H
    226 11.8 2,5-dimethoxy S 5-bromopentyl H
    227 11.9 2,5-dimethoxy S 2-[1,3]dioxolan-2-yl- H
    ethyl
    228 11.10 2,5-dimethoxy S 4-methyl-pent-3-enyl H
    229 11.11 2,5-dimethoxy S 4-pentene H
    230 11.12 2,5-dimethoxy S 3-hydroxypropyl H
    231 10.1 2,5-dimethoxy S 4-methyl-pent-3-enyl NH2
    232 10.2 2,5-dimethoxy S 4-methyl-pent-3-enyl F
    233 9.1 3-hydoxy S butyl H
    234 9.3 3-methoxy S butyl H
    235 9.4 2-iodo-5-methoxy S butyl H
    236 9.5 4-iodo-5-methoxy S Butyl H
    237 2,5-dimethoxy CH2 Pentyl H
    238 1.1 2,5-dimethoxy CH2 Butyl H
    239 3.8 2,5-dimethoxy CH2 4-ethylaminobutyl H
    240 2,5-dimethoxy CH2 pent-4-ynyl H
    241 2,5-dimethoxy CH2 butyronitrile H
    242 2,5-dimethoxy CH2 3,3,3-trifluoropropyl H
    243 3.1 2,5-dimethoxy CH2 4-chlorobutyl H
    244 3.11 2,5-dimethoxy CH2 5-acetoxypentyl H
    245 3.5 2,5-dimethoxy CH2 5-bromopentyl H
    246 3.3 2,5-dimethoxy CH2 2-[1,3]dioxolan-2-yl- H
    ethyl
    247 3.12 2,5-dimethoxy CH2 3,3,3-trifluoropropyl H
    248 3.13 2,5-dimethoxy CH2 4-pentene H
    249 2,5-dimethoxy CH2 3-hydroxypropyl H
    250 2,5-dimethoxy CH2 4-methyl-pent-3-enyl NH2
    251 2.2 2,5-dimethoxy CH2 4-methyl-pent-3-enyl F
    252 2,5-dimethoxy CH2 hexyl H
    253 2,5-dimethoxy CH2 heptyl H
    254 2,5-dimethoxy CH2 3-cyclopropylpropyl H
    255 2,5-dimethoxy CH2 3-N,N-dimethylpropyl H
    256 2,5-dimethoxy CH2 pentyl F
    257 2,5-dimethoxy CH2 butyl F
    258 2,5-dimethoxy CH2 4-ethylaminobutyl F
    259 2.1 2,5-dimethoxy CH2 pent-4-ynyl F
    260 2,5-dimethoxy CH2 butyronitrile F
    261 2,5-dimethoxy CH2 3,3,3-trifluoropropyl F
    262 2,5-dimethoxy CH2 4-chlorobutyl F
    263 2,5-dimethoxy CH2 4-acetoxybutyl F
    264 2.4 2,5-dimethoxy CH2 5-bromopentyl F
    265 2,5-dimethoxy CH2 2-[1,3]dioxolan-2-yl- F
    ethyl
    266 2,5-dimethoxy CH2 3,3,3-trifluoropropyl F
    267 2,5-dimethoxy CH2 4-pentene F
    268 2,5-dimethoxy CH2 3-hydroxypropyl F
    269 2,5-dimethoxy CH2 4-cyclopropylbutyl F
    270 2,5-dimethoxy CH2 4-ethyl-pent-3-enyl F
    271 2,5-dimethoxy CH2 hexyl F
    272 2,5-dimethoxy CH2 heptyl F
    273 2,5-dimethoxy CH2 3-cyclopropylpropyl F
    274 2,5-dimethoxy CH2 3-N,N-dimethylpropyl F
    275 2,5-dimethoxy O pentyl F
    276 2,5-dimethoxy O butyl F
    277 2,5-dimethoxy O H F
    278 2,5-dimethoxy O pent-4-ynyl F
    279 2,5-dimethoxy O butyronitrile F
    280 2,5-dimethoxy O 3,3,3-trifluoropropyl F
    281 2,5-dimethoxy O 4-chlorobutyl F
    282 2,5-dimethoxy O 4-acetoxybutyl F
    283 2,5-dimethoxy O 5-bromopentyl F
    284 2,5-dimethoxy O 2-[1,3]dioxolan-2-yl- F
    ethyl
    285 2,5-dimethoxy O 4-methyl-pent-3-enyl F
    286 2,5-dimethoxy O 4-pentene F
    287 2,5-dimethoxy O 3-hydroxypropyl F
    288 2,5-dimethoxy O 4-methyl-pent-3-enyl F
    289 2,5-dimethoxy O 4-ethyl-pent-3-enyl F
    290 2,5-dimethoxy O hexyl F
    291 2,5-dimethoxy O heptyl F
    292 2,5-dimethoxy O 3-cyclopropylpropyl F
    293 2,5-dimethoxy O 3-N,N-dimethylpropyl F
    294 2,5-dimethoxy O pentyl H
    295 2,5-dimethoxy O butyl H
    296 2,5-dimethoxy O H H
    297 2,5-dimethoxy O pent-4-ynyl H
    298 2,5-dimethoxy O butyronitrile H
    299 2,5-dimethoxy O 3,3,3-trifluoropropyl H
    300 2,5-dimethoxy O 4-chlorobutyl H
    301 2,5-dimethoxy O 4-acetoxybutyl H
    302 2,5-dimethoxy O 5-bromopentyl H
    303 2,5-dimethoxy O 2-[1,3]dioxolan-2-yl- H
    ethyl
    304 2,5-dimethoxy O 4-methyl-pent-3-enyl H
    305 2,5-dimethoxy O 4-pentene H
    306 2,5-dimethoxy O 3-hydroxypropyl H
    307 2,5-dimethoxy O 4-cyclopropylbutyl H
    308 2,5-dimethoxy O 4-ethyl-pent-3-enyl H
    309 2,5-dimethoxy O hexyl H
    310 2,5-dimethoxy O heptyl H
    311 2,5-dimethoxy O 3-cyclopropylpropyl H
    312 2,5-dimethoxy O 3-N,N-dimethylpropyl H
    313 2-iodo-5-methoxy O pentyl F
    314 2-iodo-5-methoxy O butyl F
    315 2-iodo-5-methoxy O H F
    316 2-iodo-5-methoxy O pent-4-ynyl F
    317 2-iodo-5-methoxy O butyronitrile F
    318 2-iodo-5-methoxy O 3,3,3-trifluoropropyl F
    319 2-iodo-5-methoxy O 4-chlorobutyl F
    320 2-iodo-5-methoxy O 4-acetoxybutyl F
    321 2-iodo-5-methoxy O 5-bromopentyl F
    322 2-iodo-5-methoxy O 2-[1,3]dioxolan-2-yl- F
    ethyl
    323 2-iodo-5-methoxy O 4-methyl-pent-3-enyl F
    324 2-iodo-5-methoxy O 4-pentene F
    325 2-iodo-5-methoxy O 3-hydroxypropyl F
    326 2-iodo-5-methoxy O 4-cyclopropylbutyl F
    327 2-iodo-5-methoxy O 4-ethyl-pent-3-enyl F
    328 2-iodo-5-methoxy O hexyl F
    329 2-iodo-5-methoxy O heptyl F
    330 2-iodo-5-methoxy O 3-cyclopropylpropyl F
    331 2-iodo-5-methoxy O 3-N,N-dimethylpropyl F
    332 2-iodo-5-methoxy O pentyl H
    333 2-iodo-5-methoxy O butyl H
    334 2-iodo-5-methoxy O H H
    335 2-iodo-5-methoxy O pent-4-ynyl H
    336 2-iodo-5-methoxy O butyronitrile H
    337 2-iodo-5-methoxy O 3,3,3-trifluoropropyl H
    338 2-iodo-5-methoxy O 4-chlorobutyl H
    339 2-iodo-5-methoxy O 4-acetoxybutyl H
    340 2-iodo-5-methoxy O 5-bromopentyl H
    341 2-iodo-5-methoxy O 2-[1,3]dioxolan-2-yl- H
    ethyl
    342 2-iodo-5-methoxy O 4-methyl-pent-3-enyl H
    343 2-iodo-5-methoxy O 4-pentene H
    344 2-iodo-5-methoxy O 3-hydroxypropyl H
    345 2-iodo-5-methoxy O 4-cyclopropylbutyl H
    346 2-iodo-5-methoxy O 4-ethyl-pent-3-enyl H
    347 2-iodo-5-methoxy O hexyl H
    348 2-iodo-5-methoxy O heptyl H
    349 2-iodo-5-methoxy O 3-cyclopropylpropyl H
    350 2-iodo-5-methoxy O 3-N,N-dimethylpropyl H
    351 2-iodo-5-methoxy NH pentyl F
    352 2-iodo-5-methoxy NH butyl F
    353 2-iodo-5-methoxy NH H F
    354 2-iodo-5-methoxy NH pent-4-ynyl F
    355 2-iodo-5-methoxy NH butyronitrile F
    356 2-iodo-5-methoxy NH 3,3,3-trifluoropropyl F
    357 2-iodo-5-methoxy NH 4-chlorobutyl F
    358 2-iodo-5-methoxy NH 4-acetoxybutyl F
    359 2-iodo-5-methoxy NH 5-bromopentyl F
    360 2-iodo-5-methoxy NH 2-[1,3]dioxolan-2-yl- F
    ethyl
    361 2-iodo-5-methoxy NH 4-methyl-pent-3-enyl F
    362 2-iodo-5-methoxy NH 4-pentene F
    363 2-iodo-5-methoxy NH 3-hydroxypropyl F
    364 2-iodo-5-methoxy NH 4-cyclopropylbutyl F
    365 2-iodo-5-methoxy NH 4-ethyl-pent-3-enyl F
    366 2-iodo-5-methoxy NH hexyl F
    367 2-iodo-5-methoxy NH heptyl F
    368 2-iodo-5-methoxy NH 3-cyclopropylpropyl F
    369 2-iodo-5-methoxy NH 3-N,N-dimethylpropyl F
    370 2-iodo-5-methoxy NH pentyl H
    371 2-iodo-5-methoxy NH butyl H
    372 2-iodo-5-methoxy NH H H
    373 2-iodo-5-methoxy NH pent-4-ynyl H
    374 2-iodo-5-methoxy NH butyronitrile H
    375 2-iodo-5-methoxy NH 3,3,3-trifluoropropyl H
    376 2-iodo-5-methoxy NH 4-chlorobutyl H
    377 2-iodo-5-methoxy NH 4-acetoxybutyl H
    378 2-iodo-5-methoxy NH 5-bromopentyl H
    379 2-iodo-5-methoxy NH 2-[1,3]dioxolan-2-yl- H
    ethyl
    380 2-iodo-5-methoxy NH 4-methyl-pent-3-enyl H
    381 2-iodo-5-methoxy NH 4-pentene H
    382 2-iodo-5-methoxy NH 3-hydroxypropyl H
    383 2-iodo-5-methoxy NH 4-cyclopropylbutyl H
    384 2-iodo-5-methoxy NH 4-ethyl-pent-3-enyl H
    385 2-iodo-5-methoxy NH hexyl H
    386 2-iodo-5-methoxy NH heptyl H
    387 2-iodo-5-methoxy NH 3-cyclopropylpropyl H
    388 2-iodo-5-methoxy NH 3-N,N-dimethylpropyl H
    389 2,5-dimethoxy NH pentyl F
    390 2,5-dimethoxy NH butyl F
    391 2,5-dimethoxy NH H F
    392 2,5-dimethoxy NH pent-4-ynyl F
    393 2,5-dimethoxy NH butyronitrile F
    394 2,5-dimethoxy NH 3,3,3-trifluoropropyl F
    395 2,5-dimethoxy NH 4-chlorobutyl F
    396 2,5-dimethoxy NH 4-acetoxybutyl F
    397 2,5-dimethoxy NH 5-bromopentyl F
    398 2,5-dimethoxy NH 2-[1,3]dioxolan-2-yl- F
    ethyl
    399 2,5-dimethoxy NH 4-methyl-pent-3-enyl F
    400 2,5-dimethoxy NH 4-pentene F
    401 2,5-dimethoxy NH 3-hydroxypropyl F
    402 2,5-dimethoxy NH 4-cyclopropylbutyl F
    403 2,5-dimethoxy NH 4-ethyl-pent-3-enyl F
    404 2,5-dimethoxy NH hexyl F
    405 2,5-dimethoxy NH heptyl F
    406 2,5-dimethoxy NH 3-cyclopropylpropyl F
    407 2,5-dimethoxy NH 3-N,N-dimethylpropyl F
    408 2,5-dimethoxy NH pentyl H
    409 2,5-dimethoxy NH butyl H
    410 2,5-dimethoxy NH H H
    411 2,5-dimethoxy NH pent-4-ynyl H
    412 2,5-dimethoxy NH butyronitrile H
    413 2,5-dimethoxy NH 3,3,3-trifluoropropyl H
    414 2,5-dimethoxy NH 4-chlorobutyl H
    415 2,5-dimethoxy NH 4-acetoxybutyl H
    416 2,5-dimethoxy NH 5-bromopentyl H
    417 2,5-dimethoxy NH 2-[1,3]dioxolan-2-yl- H
    ethyl
    418 2,5-dimethoxy NH 4-methyl-pent-3-enyl H
    419 2,5-dimethoxy NH 4-pentene H
    420 2,5-dimethoxy NH 3-hydroxypropyl H
    421 2,5-dimethoxy NH 4-cyclopropylbutyl H
    422 2,5-dimethoxy NH 4-ethyl-pent-3-enyl H
    423 2,5-dimethoxy NH hexyl H
    424 2,5-dimethoxy NH heptyl H
    425 2,5-dimethoxy NH 3-cyclopropylpropyl H
    426 2,5-dimethoxy NH 3-N,N-dimethylpropyl H
    427 2,5-dimethoxy S pentyl F
    428 2,5-dimethoxy S 4-ethylaminobutyl H
    429 2,5-dimethoxy S 4-ethylaminobutyl F
    430 2,5-dimethoxy S pent-4-ynyl F
    431 2,5-dimethoxy S butyronitrile F
    432 2,5-dimethoxy S 3,3,3-trifluoropropyl F
    433 2,5-dimethoxy S 4-chlorobutyl F
    434 2,5-dimethoxy S 4-acetoxybutyl F
    435 2,5-dimethoxy S 5-bromopentyl F
    436 2,5-dimethoxy S 2-[1,3]dioxolan-2-yl- F
    ethyl
    437 2,5-dimethoxy S butyl F
    438 2,5-dimethoxy S 4-pentene F
    439 2,5-dimethoxy S 3-hydroxypropyl F
    440 2,5-dimethoxy S 4-methyl-pent-3-enyl F
    441 2,5-dimethoxy S 4-ethyl-pent-3-enyl F
    442 3-hydoxy S butyl F
    443 2,5-dimethoxy S 2-(dimethyl- F
    bicyclo[3.1.1]hept-2-
    en-2-yl]-ethyl
    444 2-Iodo-5-methoxy S butyl F
    445 4-Iodo-5-methoxy S butyl F
    446 2,5-dimethoxy S hexan-6-ol H
    447 2,5-dimethoxy S pentan-5-ol H
    448 2,5-dimethoxy S butan-4-ol H
    449 2,5-dimethoxy S hexan-6-ol F
    450 2,5-dimethoxy S pentan-5-ol F
    451 2,5-dimethoxy S butan-4-ol F
    452 2-iodo-5-methoxy S hexan-6-ol H
    453 2-iodo-5-methoxy S pentan-5-ol H
    454 2-iodo-5-methoxy S butan-4-ol H
    455 2-iodo-5-methoxy S hexan-6-ol F
    456 2-iodo-5-methoxy S pentan-5-ol F
    457 2-iodo-5-methoxy S butan-4-ol F
    458 2-iodo-5-methoxy S hexan-6-ol H
    459 2-iodo-5-methoxy S pentan-5-ol H
    460 2,5-dimethoxy CH2 hexan-6-ol H
    461 2,5-dimethoxy CH2 pentan-5-ol H
    462 2,5-dimethoxy CH2 butan-4-ol H
    463 3.9 2,5-dimethoxy CH2 hexan-6-ol F
    464 2,5-dimethoxy CH2 pentan-5-ol F
    465 2,5-dimethoxy CH2 butan-4-ol F
    466 2-iodo-5-methoxy CH2 hexan-6-ol H
    467 2-iodo-5-methoxy CH2 pentan-5-ol H
    468 2-iodo-5-methoxy CH2 butan-4-ol H
    469 2-iodo-5-methoxy CH2 hexan-6-ol F
    470 2-iodo-5-methoxy CH2 pentan-5-ol F
    471 2-iodo-5-methoxy CH2 butan-4-ol F
    472 2-iodo-5-methoxy CH2 hexan-6-ol H
    473 2-iodo-5-methoxy CH2 pentan-5-ol H
    474 2.3 2,5-dimethoxy CH2 pent-4-enyl F
    475 3.6 2,5-dimethoxy CH2 5-bromo-3-methyl- H
    pentyl
    476 3.6 2,5-dimethoxy CH2 5-chloro-pentyl H
    477 3.10 2,5-dimethoxy CH2 dimethyl- H
    bicyclo[3.1.1]hept-2-
    en-2-yl)-ethyl
    478 2-iodo-5-methoxy CH2 pentyl H
    479 4.1 2-iodo-5-methoxy CH2 butyl H
    480 2-iodo-5-methoxy CH2 4-ethylaminobutyl H
    481 2-iodo-5-methoxy CH2 pent-4-ynyl H
    482 2-iodo-5-methoxy CH2 butyronitrile H
    483 2-iodo-5-methoxy CH2 3,3,3-trifluoropropyl H
    484 2-iodo-5-methoxy CH2 4-chlorobutyl H
    485 2-iodo-5-methoxy CH2 5-acetoxypentyl H
    486 2-iodo-5-methoxy CH2 5-bromopentyl H
    487 2-iodo-5-methoxy CH2 2-[1,3]dioxolan-2-yl- H
    ethyl
    488 2-iodo-5-methoxy CH2 3,3,3-trifluoropropyl H
    489 2-iodo-5-methoxy CH2 4-pentene H
    490 2-iodo-5-methoxy CH2 3-hydroxypropyl H
    491 4.2 5-iodo-2-methoxy CH2 butyl H
    492 2-iodo-5-methoxy CH2 4-methyl-pent-3-enyl F
    493 2-iodo-5-methoxy CH2 hexyl H
    494 2-iodo-5-methoxy CH2 heptyl H
    495 2-iodo-5-methoxy CH2 3-cyclopropylpropyl H
    496 2-iodo-5-methoxy CH2 3-N,N-dimethylpropyl H
    497 4.3 5-ethyl-2-methoxy CH2 butyl H
    498 4.4 2-bromo-5-methoxy CH2 butyl H
    499 4.5 2-bromo-5-methoxy CH2 4-methyl-pent-3-enyl H
    500 4.6 2-bromo-5-methoxy CH2 pent-4-ynyl H
    501 5.1 5-ethyl-2-methoxy CH2 butyl H
    502 5.2 5-butyl-2-methoxy CH2 butyl H
    503 5.3 5-vinyl-2-methoxy CH2 butyl H
    504 6.1 2,5-dimethoxy-4- CH2 pent-4-ynyl F
    nitro
    505 6.2 3,5-dimethoxy-2- CH2 butyl H
    nitro
    506 6.3 3,5-dimethoxy-4- CH2 4-methyl-pent-3-enyl H
    amino
    507 6.4 2,5-dimethoxy-4- CH2 butyl H
    amino
    508 6.5 3,5-dimethoxy-2- CH2 butyl H
    amino
    509 6.6 4-methoxy CH2 butyl H
    benzaldehyde-O-
    methyl-oxime
    510 7.1 4-methoxy CH2 butyl H
    benzaldehyde
    511 8.1 3,4-dichloro benzyl CH2 butyl H
    512 2-iodo-5-methoxy S pentyl H
    513 2-iodo-5-methoxy S butyl H
    514 2-iodo-5-methoxy S 4-ethylaminobutyl H
    515 2-iodo-5-methoxy S pent-4-ynyl H
    516 2-iodo-5-methoxy S butyronitrile H
    517 2-iodo-5-methoxy S 3,3,3-trifluoropropyl H
    518 2-iodo-5-methoxy S 4-chlorobutyl H
    519 2-iodo-5-methoxy S 5-acetoxypentyl H
    520 2-iodo-5-methoxy S 5-bromopentyl H
    521 2-iodo-5-methoxy S 2-[1,3]dioxolan-2-yl- H
    ethyl
    522 2-iodo-5-methoxy S 3,3,3-trifluoropropyl H
    523 2-iodo-5-methoxy S 4-pentene H
    524 2-iodo-5-methoxy S 3-hydroxypropyl H
    525 2-iodo-5-methoxy S 4-methyl-pent-3-enyl NH2
    526 2-iodo-5-methoxy S 4-methyl-pent-3-enyl F
    527 2-iodo-5-methoxy S hexyl H
    528 2-iodo-5-methoxy S heptyl H
    529 2-iodo-5-methoxy S 3-cyclopropylpropyl H
    530 2-iodo-5-methoxy S 3-N,N-dimethylpropyl H
    531 2-iodo-5-methoxy S pentyl F
    532 2-iodo-5-methoxy S butyl F
    533 2-iodo-5-methoxy S 4-ethylaminobutyl F
    534 2-iodo-5-methoxy S pent-4-ynyl F
    536 2-iodo-5-methoxy S butyronitrile F
    537 2-iodo-5-methoxy S 3,3,3-trifluoropropyl F
    538 2-iodo-5-methoxy S 4-chlorobutyl F
    539 2-iodo-5-methoxy S 4-acetoxybytyl F
    540 2-iodo-5-methoxy S 5-bromopentyl F
    541 2-iodo-5-methoxy S 2-[1,3]dioxolan-2-yl- F
    ethyl
    542 2-iodo-5-methoxy S 3,3,3-trifluoropropyl F
    543 2-iodo-5-methoxy S 4-pentene F
    544 2-iodo-5-methoxy S 3-hydroxypropyl F
    545 2-iodo-5-methoxy S 4-cyclopropylbutyl F
    546 2-iodo-5-methoxy S 4-ethyl-pent-3-enyl F
    547 2-iodo-5-methoxy S hexyl F
    548 2-iodo-5-methoxy S heptyl F
    549 2-iodo-5-methoxy S 3-cyclopropylpropyl F
    550 2-iodo-5-methoxy S 3-N,N-dimethylpropyl F
    551 2-iodo-5-methoxy S pentyl Cl
    552 2-iodo-5-methoxy S butyl Cl
    553 2-iodo-5-methoxy S 4-ethylaminobutyl Cl
    554 2-iodo-5-methoxy S pent-4-ynyl Cl
    555 2-iodo-5-methoxy S butyronitrile Cl
    556 2-iodo-5-methoxy S 3,3,3-trifluoropropyl Cl
    557 2-iodo-5-methoxy S 4-chlorobutyl Cl
    558 2-iodo-5-methoxy S 4-acetoxybytyl Cl
    559 2-iodo-5-methoxy S 5-bromopentyl Cl
    560 2-iodo-5-methoxy S 2-[1,3]dioxolan-2-yl- Cl
    ethyl
    561 2-iodo-5-methoxy S 3,3,3-trifluoropropyl Cl
    562 2-iodo-5-methoxy S 4-pentene Cl
    563 2-iodo-5-methoxy S 3-hydroxypropyl Cl
    564 2-iodo-5-methoxy S 4-cyclopropylbutyl Cl
    565 2-iodo-5-methoxy S 4-ethyl-pent-3-enyl Cl
    566 2-iodo-5-methoxy S hexyl Cl
    567 2-iodo-5-methoxy S heptyl Cl
    568 2-iodo-5-methoxy S 3-cyclopropylpropyl Cl
    569 2-iodo-5-methoxy S 3-N,N-dimethylpropyl Cl
    570 2-iodo-5-methoxy S 4-methyl-pent-3-enyl NH2
    571 2-iodo-5-methoxy S 4-methyl-pent-3-enyl Cl
    572 2-iodo-5-methoxy S pent-4-ynyl Cl
    573 9.11 2,5-dichloro S butyl H
    574 9.12 2,4,5-trichloro S butyl H
    575 2.5 2,5-dimethoxy CH2 pent-4-ynyl Cl
  • Particularly preferred in Table 1 are compounds 1, 4, 31, 55, 58, 85, 113, 137, 140, 167, 191, 194, 221, 224, 226, 228, 232, 234, 235, 236, 239, 245, 248, 251, 259, 452, 453, 454, 455, 456, 457, 463, 469, 470, 471, 571 and 572, with the most preferred compounds being 1, 85, 113, 137, 140, 167, 191, 194, 221, 228, 239, 251, 259, 452, 453, 455, 571 and 572.
  • Other compounds of the invention are based on the following formula, having illustrative species as described in Table 2:
  • TABLE 2
    Figure US20080125446A1-20080529-C00004
    No. Ex. E X L Z
    576 9.8 H S S H
    577 9.9 5-chloro S S H
    578 9.10 5-methoxy S S H
  • The foregoing aspects and embodiments can also include tautomers of the compounds. For example, referring to structures I-IV, above, structure II is a tautomeric form of structure I when A is OH (OR3 where R3 is H), structure III is another tautomeric form of structure I (when Z is OH), and structure IV is yet another tautomeric form of structure I in the event that both A and Z are OH. All four tautomeric possibilities can be represented essentially as shown in structure I, except that dashed lines appear between atoms 1 and 6 and 2 and 3, and between A and 6 and Z and 2, e.g., as shown:
  • Figure US20080125446A1-20080529-C00005
  • The foregoing aspects and embodiments can also include prodrugs and/or pharmaceutically acceptable salts of the compounds shown.
  • The foregoing aspects and embodiments can also include varying levels and types of substitution on one or more of entities A, B, Q, W, X, Y and Z, above, where that entity is not already solely hydrogen but rather is a multi-atom substituent that contains one or more hydrogens that can be substituted for, e.g., with a halogen or combination of other atoms or chemical group(s). In some embodiments, there may be a range of from 0 to 25 or more collective substitutions (for all of A, B, Q, W, X, Y and Z), and any range in between. The substitutions may be made or included at any point in the synthesis of the final compounds, as appropriate, including, e.g., in the starting reagents or intermediates of the reaction scheme(s) used, or following the synthesis of one final product to convert it into another. The following embodiments are illustrative:
  • Figure US20080125446A1-20080529-C00006
  • In another aspect, the invention features pharmaceutical compositions containing one or more of the compounds or pharmaceutically acceptable salts thereof described for the preceding aspects. These additionally include one or more pharmaceutically acceptable carriers and/or excipients.
  • Another aspect of the invention features methods of making the compounds of the preceding aspects. These are described in greater detail in the next section and the examples to follow. Related aspects of the invention embrace intermediates of/in these synthetic methods to the extent they are novel, either alone or standing in the context of the specific synthesis objective.
  • In yet another aspect, the invention features methods of inhibiting an HSP90 molecule with a compound according to any of the previous aspects and embodiments. HSP90 proteins are highly conserved in nature (see, e.g., NCBI accession it's P07900 and XM 004515 (human α and β HSP90, respectively), P11499 (mouse), AAB2369 (rat), P46633 (chinese hamster), JC1468 (chicken), AAF69019 (flesh fly), AAC21566 (zebrafish), AAD30275 (salmon), O02075 (pig), NP 015084 (yeast), and CAC29071 (frog). Grp94 and Trap-1 are related molecules falling within the definition of an HSP90—as used herein. There are thus many different HSP90s, all with expected similar effect and inhibition capabilities. The HSP90 inhibitors of the invention may be specifically directed against an HSP90 of the specific host patient or may be identified based on reactivity against an HSP90 homolog from a different species, or an HSP90 variant. The methods feature contacting a cell having an HSP90 with a pharmaceutically effective amount of a compound or pharmaceutical composition according to any one of the preceding aspects. The cell is preferably a mammalian cell, and more preferably a human cell, although any cell-type from any life-form that contains an HSP90, including non-mammalian lines, is contemplated for the invention. The method can be “in vitro”, e.g., contacting a cell line in culture, or else can be “in vivo”, e.g., contacting a cell inside a live organism. One type of in vivo administration is made “in situ”, or directly to a specific cell or group of cells within an organism, e.g., intratumorally. “Ex vivo” procedures are also envisioned wherein the cells are first removed from a patient, treated by contacting them with the compounds or compositions of the invention, and then administered back to a patient or “the” patient. The compounds and compositions can be administered in a variety of ways, e.g., intravenously, parenterally, orally, bucally, intramuscularly, sublingually, topically, by aerosol, subcutaneously, intramuscularly, intraperitoneally, rectally, vaginally, intratumorally, or peritumorally.
  • In some aspects, the compounds or compositions are administered to treat or prevent a cancer, e.g., a breast cancer, melanoma, lung cancer, etc. In some embodiments, these compounds may be used in combination with or as an adjuvant/sensitizer for any chemotherapy regimen. Such regimens may include the use of other anti-cancer compounds, e.g., taxol, Herceptin, Gleevac, etc. The additions may be made simultaneously or sequentially and, if the latter, in any order.
  • In other aspects, the compounds or compositions are used for non-oncology applications, e.g., treating inflammation, infectious disease, autoimmune disease, and ischemia.
  • Any of the above described aspects and embodiments of the invention can be combined where practical. The individual methods prescribed do not preclude the utilization of other, unspecified steps, and those of ordinary skill in the art will appreciate that additional steps and compounds may also be usefully incorporated within the spirit of the invention.
  • Advantages of the invention depend on the specific aspect and embodiment and may include one or more of: ease of synthesis and/or formulation, solubility, and IC50 relative to previously existing compounds in the same or different classes of HSP90 inhibitors. Other advantages, aspects, and embodiments will be apparent from the figures, the detailed description and claims to follow.
  • BRIEF DESCRIPTION OF THE FIGURES
  • FIG. 1 shows IC50 values for compounds of Table 3, Example 3, as measured using Her-2 degradation studies.
  • DETAILED DESCRIPTION OF THE INVENTION Definitions
  • A “pharmaceutically acceptable salt” may be prepared for any compound of the invention having a functionality capable of forming a salt, for example an acid or base functionality. Pharmaceutically acceptable salts may be derived from organic or inorganic acids and bases.
  • Compounds of the invention that contain one or more basic functional groups, e.g., amino or alkylamino, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable organic and inorganic acids. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, gluconic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, 1,2 ethanesulfonic acid (edisylate), galactosyl-d-gluconic acid, and the like. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of this invention and their pharmaceutically acceptable acid addition salts. See, e.g., Berge et al. “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19 (1977).
  • Compounds of the present invention that contain one or more acidic functional groups are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases. The term “pharmaceutically-acceptable salts” in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Illustrative examples of some of the bases that can be used include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. See, for example, Berge et al., supra.
  • “Prodrugs” are derivative compounds derivatized by the addition of a group that endows greater solubility to the compound desired to be delivered. Once in the body, the prodrug is typically acted upon by an enzyme, e.g., an esterase, amidase, or phosphatase, to generate the active compound. Suitable positions for derivatization of the compounds of the invention to create “prodrugs” include but are not limited to the Y group, the phenyl ring of the purines, and the Q group. Those of ordinary skill in the art have the knowledge and means to accomplish this without undue experimentation.
  • “Tautomers” are compounds whose structures differ in arrangements of atoms, but which exist in equilibrium. By way of example, the structure shown below and designated T is in equilibrium with a second tautomeric form designated T.
  • Figure US20080125446A1-20080529-C00007
  • The predominance of one tautomer versus another is controlled by factors which include but are not limited to the nature of the solvent, temperature, pressure, the presence or absence of other molecules, and the nature of substituents on the molecule having tautomeric forms.
  • The term “alkyl,” alone or in combination, refers to an optionally substituted straight-chain, optionally substituted branched-chain, or optionally substituted cyclic alkyl radical having from 1 to about 30 carbons, more preferably 1 to 12 carbons. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like. The term “cycloalkyl” embraces cyclic configurations, is subsumed within the definition of alkyl and specifically refers to a monocyclic, bicyclic, tricyclic, and higher multicyclic alkyl radicals wherein each cyclic moiety has from 3 to about 8 carbon atoms. Examples of cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. A “lower alkyl” is a shorter alkyl, e.g., one containing from 1 to about 6 carbon atoms.
  • The term “alkenyl,” alone or in combination, refers to an optionally substituted straight-chain, optionally substituted branched-chain, or optionally substituted cyclic alkenyl hydrocarbon radical having one or more carbon-carbon double-bonds and having from 2 to about 30 carbon atoms, more preferably 2 to about 18 carbons. Examples of alkenyl radicals include ethenyl, propenyl, butenyl, 1,4-butadienyl and the like. The term can also embrace cyclic alkenyl structures. A “lower alkenyl” refers to an alkenyl having from 2 to about 6 carbons.
  • The term “alkynyl,” alone or in combination, refers to an optionally substituted straight-chain, optionally substituted branched-chain, or cyclic alkynyl hydrocarbon radical having one or more carbon-carbon triple-bonds and having from 2 to about 30 carbon atoms, more preferably 2 to about 12 carbon atoms. The term also includes optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon radicals having one or more carbon-carbon triple bonds and having from 2 to about 6 carbon atoms as well as those having from 2 to about 4 carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl, butynyl and the like.
  • The terms heteroalkyl, heteroalkenyl and heteroalkynyl include optionally substituted alkyl, alkenyl and alkynyl structures, as described above, and which have one or more skeletal chain atoms selected from an atom other that carbon, e.g., oxygen, nitrogen, sulfur, phosphorous or combinations thereof.
  • The term “carbon chain” may embrace any alkyl, alkenyl, alkynyl, or heteroalkyl, heteroalkenyl, or heteroalkynyl group, and may be linear, cyclic, or any combination thereof. If part of a linker and that linker comprises one or more rings as part of the core backbone, for purposes of calculating chain length, the “chain” only includes those carbon atoms that compose the bottom or top of a given ring and not both, and where the top and bottom of the ring(s) are not equivalent in length, the shorter distance shall be used in determining chain length. If the chain contains heteroatoms as part of the backbone, those atoms are not calculated as part of the carbon chain length.
  • The term “alkoxy,” alone or in combination, refers to an alkyl ether radical, alkyl-O—, wherein the term alkyl is defined as above. Examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
  • The term “aryloxy,” alone or in combination, refers to an aryl ether radical wherein the term aryl is defined as below. Examples of aryloxy radicals include phenoxy, benzyloxy and the like.
  • The term “alkylthio,” alone or in combination, refers to an alkyl thio radical, alkyl-S—, wherein the term alkyl is defined as above.
  • The term “arylthio,” alone or in combination, refers to an aryl thio radical, aryl-S—, wherein the term aryl is defined as below.
  • The term “oxo” refers to ═O.
  • The term “aryl,” alone or in combination, refers to an optionally substituted aromatic ring system. The term aryl includes monocyclic aromatic rings, polyaromatic rings and polycyclic aromatic ring systems containing from six to about twenty carbon atoms. The term aryl also includes monocyclic aromatic rings, polyaromatic rings and polycyclic ring systems containing from 6 to about 12 carbon atoms, as well as those containing from 6 to about 10 carbon atoms. The polyaromatic and polycyclic aromatic rings systems may contain from two to four rings. Examples of aryl groups include, without limitation, phenyl, biphenyl, naphthyl and anthryl ring systems.
  • The term “heteroaryl” refers to optionally substituted aromatic ring systems containing from about five to about 20 skeletal ring atoms and having one or more heteroatoms such as, for example, oxygen, nitrogen, sulfur, and phosphorus. The term heteroaryl also includes optionally substituted aromatic ring systems having from 5 to about 12 skeletal ring atoms, as well as those having from 5 to about 10 skeletal ring atoms. The term heteroaryl may include five- or six-membered heterocyclic rings, polycyclic heteroaromatic ring systems and polyheteroaromatic ring systems where the ring system has two, three or four rings. The terms heterocyclic, polycyclic heteroaromatic and polyheteroaromatic include ring systems containing optionally substituted heteroaromatic rings having more than one heteroatom as described above (e.g., a six membered ring with two nitrogens), including polyheterocyclic ring systems of from two to four rings. The term heteroaryl includes ring systems such as, for example, furanyl, benzofuranyl, chromenyl, pyridyl, pyrrolyl, indolyl, quinolinyl, N-alkyl pyrrolyl, pyridyl-N-oxide, pyrimidoyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, benzothiophenyl, purinyl, indolizinyl, thienyl and the like.
  • The term “heteroarylalkyl” refers to a C1-C4 alkyl group containing a heteroaryl group, each of which may be optionally substituted.
  • The term “heteroarylthio” refers to the group —S-heteroaryl.
  • The term “acyloxy” refers to the ester group —OC(O)—R, where R is H, alkyl, alkenyl, alkynyl, aryl, or arylalkyl, wherein the alkyl, alkenyl, alkynyl and arylalkyl groups may be optionally substituted.
  • The term “carboxy esters” refers to —C(O)OR where R is alkyl, aryl or arylalkyl, wherein the alkyl, aryl and arylalkyl groups may be optionally substituted.
  • The term “carboxamido” refers to
  • Figure US20080125446A1-20080529-C00008
  • where each of R and R′ are independently selected from the group consisting of H, alkyl, aryl and arylalkyl, wherein the alkyl, aryl and arylalkyl groups may be optionally substituted.
  • The term “arylalkyl,” alone or in combination, refers to an alkyl radical as defined above in which one H atom is replaced by an aryl radical as defined above, such as, for example, benzyl, 2-phenylethyl and the like.
  • The term “alklaryl,” alone or in combination, refers to an aryl radical as defined above in which one H atom is replaced by an alkyl radical as defined above, such as, for example, tolyl, xylyl and the like.
  • The terms haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy include alkyl, alkenyl, alkynyl and alkoxy structures, as described above, that are substituted with one or more fluorines, chlorines, bromines or iodines, or with combinations thereof.
  • The terms cycloalkyl, aryl, arylalkyl, heteroaryl, alkyl, alkynyl, alkenyl, haloalkyl and heteroalkyl include optionally substituted cycloalkyl, aryl, arylalkyl, heteroaryl, alkyl, alkynyl, alkenyl, haloalkyl and heteroalkyl groups.
  • The term “carbocycle” includes optionally substituted, saturated or unsaturated, three- to eight-membered cyclic structures in which all of the skeletal atoms are carbon.
  • The term “heterocycle” includes optionally substituted, saturated or unsaturated, three- to eight-membered cyclic structures in which one or more skeletal atoms is oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Illustrative examples include pyridine, pyran, thiophan, pyrrole, furan, thiophen, pentatonic and hexatomic lactam rings, and the like.
  • The term “membered ring” can embrace any cyclic structure, including carbocycles and heterocycles as described above. The term “membered” is meant to denote the number of skeletal atoms that constitute the ring. Thus, for example, pyridine, pyran, and thiophan are 6 membered rings and pyrrole, furan, and thiophen are 5 membered rings.
  • The term “acyl” includes alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl substituents attached to a compound via a carbonyl functionality (e.g., —CO-alkyl, —CO-aryl, —CO-arylalkyl or —CO-heteroarylalkyl, etc.).
  • “Optionally substituted” groups may be substituted or unsubstituted. The substituents of an “optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or designated subsets thereof: alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxy, aryloxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylthio, arylthio, heteroarylthio, oxo, carboxyesters, carboxamido, acyloxy, halogens, CN, NO2, NH2, N3, NHCH3, N(CH3)2, SH, SCH3, OH, OCH3, OCF3, CH3, CF3, C(O)CH3, CO2CH3, CO2H, C(O)NH2, pyridinyl, thiophene, furanyl, indole, indazol, esters, amides, phosphonates, phosphates, phosphoramides, sulfonates, sulfates, sulphonamides, carbamates, ureas, thioureas, thioamides, thioalkyls. An optionally substituted group may be unsubstituted (e.g., —CH2CH3), fully substituted (e.g., —CF2CF3), monosubstituted (e.g., —CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., —CH2CF3).
  • The term “halogen” includes F, Cl, Br and I.
  • The term sulfide refers to a sulfur atom covalently linked to two atoms; the formal oxidation state of said sulfur is (II). The term “thioether” may used interchangeably with the term “sulfide”.
  • The term “sulfoxide” refers to a sulfur atom covalently linked to three atoms, at least one of which is an oxygen atom; the formal oxidation state of said sulfur atom is (IV).
  • The term “sulfone” refers to a sulfur atom covalently linked to four atoms, at least two of which are oxygen atoms; the formal oxidation state of said sulfur atom is (VI).
  • Some of the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms. The scope of the present invention is intended to cover all isomers per se, as well as mixtures of cis and trans isomers, mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers) as well. Further, it is possible using well known techniques to separate the various forms, and some embodiments of the invention may feature purified or enriched species of a given enantiomer or diasteriomer.
  • A “pharmacological composition” refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof with other chemical components, such as pharmaceutically acceptable carriers and/or excipients. The purpose of a pharmacological composition is to facilitate administration of a compound to an organism.
  • The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringers solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. A physiologically acceptable carrier should not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • An “excipient” refers to an inert substance added to a pharmacological composition to further facilitate administration of a compound. Examples of excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • A “pharmaceutically effective amount” means an amount which is capable of providing a therapeutic and/or prophylactic effect. The specific dose of compound administered according to this invention to obtain therapeutic and/or prophylactic effect will, of course, be determined by the particular circumstances surrounding the case, including, for example the specific compound administered, the route of administration, the condition being treated, and the individual being treated. A typical daily dose (administered in single or divided doses) will contain a dosage level of from about 0.01 mg/kg to about 50-100 mg/kg of body weight of an active compound of the invention. Preferred daily doses generally will be from about 0.05 mg/kg to about 20 mg/kg and ideally from about 0.1 mg/kg to about 10 mg/kg. Factors such as clearance rate and half-life and maximum tolerated dose (MTD) have yet to be determined but one of ordinary skill in the art can determine these using standard procedures.
  • In some method embodiments, the preferred therapeutic effect is the inhibition, to some extent, of the growth of cells characteristic of a proliferative disorder, e.g., breast cancer. A therapeutic effect will also normally, but need not, relieve to some extent one or more of the symptoms other than cell growth or size of cell mass. A therapeutic effect may include, for example, one or more of 1) a reduction in the number of cells; 2) a reduction in cell size; 3) inhibition (i.e., slowing to some extent, preferably stopping) of cell infiltration into peripheral organs, e.g., in the instance of cancer metastasis; 3) inhibition (i.e., slowing to some extent, preferably stopping) of tumor metastasis; 4) inhibition, to some extent, of cell growth; and/or 5) relieving to some extent one or more of the symptoms associated with the disorder.
  • In some method embodiments of the invention, the “IC50” value of a compound of the invention can be greater for normal cells than for cells exhibiting a proliferative disorder, e.g., breast cancer cells. The value depends on the assay used.
  • By a “standard” is meant a positive or negative control. A negative control in the context of HER-2 expression levels is, e.g., a sample possessing an amount of HER-2 protein that correlates with a normal cell. A negative control may also include a sample that contains no HER-2 protein. By contrast, a positive control does contain HER-2 protein, preferably of an amount that correlates with overexpression as found in proliferative disorders, e.g., breast cancers. The controls may be from cell or tissue samples, or else contain purified ligand (or absent ligand), immobilized or otherwise. In some embodiments, one or more of the controls may be in the form of a diagnostic “dipstick.”
  • By “selectively targeting” is meant affecting one type of cell to a greater extent than another, e.g., in the case of cells with high as opposed to relatively low or normal Her-2 levels.
  • Synthesis of the Compounds of the Invention
  • The following synthesis scheme 1 is applicable to various of the compounds, compositions, methods, and formulations of the invention:
  • Figure US20080125446A1-20080529-C00009
  • Synthesis of compounds of formula 1 (when X═C) in scheme 1 may include some or all of the following general steps. The 8-substituted purine analogs of formula 5 or 2 can be prepared from 4,5-diaminopyrimidines and the carboxylates or their derivatives, such as amides, esters, nitriles, orthoesters, imidates etc (see, e.g., Townsend Chemistry of Nucleosides and Nucleotides, Vol. 1; Plenum Press, New York and London, page 148-158; Tetrahedron Lett. 36, 4249, 1995). Substituted 4,5-diaminopyrimidines can be obtained commercially or from substituted 2-chloro-3-amino pyrimidine or 2-chloro-3-nitropyrimidines as known in the art. See, e.g., Tetrahedron, 40, 1433 (1984); J. Am, Chem. Soc., 118, 135 (1975); Synthesis 135 (1975); J. Med. Chem. 39, 4099 (1996).
  • Compounds of formula 5 can be converted to compounds of formula 2 by simple alkylation with alkylhalides, alkyltosylates, mesolates or triflates in polar solvents like THF, DMF or DMSO using bases like NaH, Cs2CO3 or K2CO3, or by the well-known Mitsunobu alkylation method.
  • Compounds of formula 2 can be further modified to give compounds of formula 1 or the intermediates to prepare compounds of formula 1, e.g., substitution of 6-chloropurine by ammonia or alkylamines. C-2 substitution of purines, e.g., halogenation with F, Cl or Br can be introduced via 2-aminopurines as described by Eaton et al., J. Org. Chem. 34(3), 747-8 (1969) or by nucleophilic substitution as described, e.g., in, J. Med. Chem. 36, 2938 (1993) and Heterocycles, 30, 435, (1990). These C-2 substitutions also can be introduced via metalation as described, e.g., in J. Org. Chem. 62(20), 6833 (1997), followed by addition of desired electrophile. General purine substitution can be accomplished as described in J. Med. Chem. 42, 2064 (1999).
  • Alternatively, intermediates of formula 2 can be prepared from chloroaminopyrimidines such as formula 6 by the following two steps: (1) treatment of the compounds of formula 6 with corresponding amine (Y—NH2), e.g., butylamine, in presence of base such as triethyl amine or N,N-diisopropyl amine in polar solvents such as n-BuOH to give the substituted diamine compounds of formula 4; (2) treatment of the compounds of formula 4 using the same methods as described earlier going from formula 7 to formula 5. Similar methods as described earlier can be used to introduce the C-2 substitution (point at which Z or G moiety attaches).
  • Compounds of formula 1 where A is other than NH2, e.g., halogen, methoxy, alkyl, or trifluoro alkyl, can be prepared starting with the corresponding substituent in place (if it can withstand the transformations), or, for halogen or substituted amines, these can be prepared from the 6-amine.
  • The compounds of formula 1 can also be prepared from formula 3, where L is halogen, using Negishi-type couplings (e.g., as described in J. Org. Chem. 2001, 66, 7522; J. Org. Chem. 1991, 56, 1445).
  • Compounds of formula 1 wherein X is a heteroatom such as S, O or N can be prepared by the following scheme 2. In general, these compounds are linked via their C-8 to one of the heteroatoms X═S, O, or N and can be prepared from the corresponding 8-halo (e.g., bromo, iodo or chloro) compounds such as formula 10 using nucleophiles such as sulfides, alkyl or arylthiols, amines, azides, and alcohols.
  • Figure US20080125446A1-20080529-C00010
  • With reference to scheme 2, substituted adenines or purines of formula 8 can be treated with halogenating agents such as bromine or iodine, followed by alkylation at N-9 to give compounds of formula 10, wherein M is halogen such as bromine or iodine sang et. al. PCT, WO 98/39344). Compounds of formula 16 can be prepared from trihalopyrimidines such as those of formula 12 by nitration to give compounds of formula 13. Subsequent displacement of the halogen with amine (YNH2) and reduction of the nitrogroup gives the diamines of formula 15. Alternatively, reduction of the nitrogroup may precede halogen displacement. Diamines of formula 15 can be readily cyclized to the imidazole ring of the compounds of formula 16, wherein L is H, SH, OH or NH2 (Org. Syn. Collective Vol. 2, 65; Org. Syn. Collective Vol. 4, 569). The compounds of formula 1 can also be synthesized from the compounds of formula 16, wherein L is SH, OH, or NH2, by reacting with aromatic halides, boronic acids, triflates, or their equivalents in presence of a catalyst such as palladium or copper (Buchwald, S. L. et. al. J. Am. Chem. Soc., 1998, 120, 213-214; Buchwald, S. L. et. al. Ace. Chem. Res. 1998, 31, 805; Buchwald, S. L. et. al Org. Lett., 2002, 4, 3517-3520).
  • Alternately, compounds of formulae 1 and 11 (wherein X═S or O) can be synthesized by coupling of the diazonium salts of the compounds of formulae 10 or 16 (wherein M or L is N2.BF4, N2.HCl, N2.H2SO4 etc.) with HXE or HXQ (wherein X═S or O) in the presence of base such as t-BuOK, NaH, etc. in solvents such as DMF, MeOH, etc.
  • Z-groups of formula 1 can be introduced by modifying existing 2-substituents such as G. For example, 2-halopurines of formula 1 can be prepared from 2-aminopurines (G=NH2) via chemistry well described in the literature. Other substitutions such as S-alkyl or aryl, O-alkyl can be made from nucleophilic substitution reactions; metal-catalysed reactions, etc. (see, e.g., Aerschot et. al., J. Med. Chem. 36:2938 (1993); Buchwald, S. L. et. al., Heterocycles, 30: 435 (1990).
  • The E component (aromatic or heteroaromatic or alkyl) of the compounds of formula 11 can be further modified as needed using well known procedures including, e.g., nucleophilic additions, electrophilic additions, halogenations, etc. to give Q (see, e.g., Advanced Organic Chemistry, March. J. Wiley Interscience).
  • Compounds of formula 1, wherein X is S(O) or S(O)2 can be prepared by the oxidation of the compounds of formula 1, wherein X═S, using reagents such as MCPBA, H2O2, NaIO4, Oxone, etc. in solvents such as CHCl3, CH2Cl2 etc. Also, these sulfone compounds can be made by coupling of sulfonyl salts such as Li, Na, K (ArS(O)2Li) and compounds of formulae 10 or 16 (wherein M or L is halogen such as Br or D in polar solvents such as DMF. (Chem. Abstr. 1952, 4549). With controlled reduction of these sulfones, one can make compounds of formula 1 where X is S(O) and S(O)2.
  • Pharmaceutical Compositions, Dosaging and Modes of Administration
  • Those of ordinary skill in the art are familiar with formulation and administration techniques that can be employed with the compounds and methods of the invention, e.g., as discussed in Goodman and Gilman's, The Pharmacological Basis of Therapeutics, current edition; Pergamon Press; and Remington's Pharmaceutical Sciences (current edition.) Mack Publishing Co., Easton, Pa.
  • The compounds utilized in the methods of the instant invention may be administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • For example, the therapeutic or pharmaceutical compositions of the invention can be administered locally to the area in need of treatment. This may be achieved by, for example, but not limited to, local infusion during surgery, topical application, e.g., cream, ointment, injection, catheter, or implant, said implant made, e.g., out of a porous, non-porous, or gelatinous material, including membranes, such as silastic membranes, or fibers. The administration can also be by direct injection at the site (or former site) of a tumor or neoplastic or pre-neoplastic tissue.
  • Still further, the compounds or compositions of the invention can be delivered in a vesicle, e.g., a liposome (see, for example, Langer, 1990, Science, 249:1527-1533; Treat et al., 1989, Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Bernstein and Fidler (eds.), Liss, N.Y., pp. 353-365).
  • The compounds and pharmaceutical compositions used in the methods of the present invention can also be delivered in a controlled release system. In one embodiment, a pump may be used (see, Sefton, 1987, CRC Crit. Ref Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery, 88:507; Saudek et al., 1989, N. Engl. J. Med., 321:574). Additionally, a controlled release system can be placed in proximity of the therapeutic target. (see, Goodson, 1984, Medical Applications of Controlled Release, Vol. 2, pp. 115-138).
  • The pharmaceutical compositions used in the methods of the instant invention can also contain the active ingredient in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be un-coated or coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, or cellulose acetate butyrate may be employed as appropriate.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending a gent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • The compounds and pharmaceutical compositions used in the methods of the instant invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • The pharmaceutical compositions may be in the form of a sterile injectable aqueous solutions. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.
  • The injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.
  • The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
  • The Compounds of the present invention used in the methods of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the inhibitors with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing an compound or composition of the invention can be used. As used herein, topical application can include mouth washes and gargles.
  • The compounds used in the methods of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • The methods, compounds and compositions of the instant invention may also be used in conjunction with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents. Further, the instant methods and compounds may also be useful in combination with other inhibitors of parts of the signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
  • The methods of the present invention may also be useful with other agents that inhibit angiogenesis and thereby inhibit the growth and invasiveness of tumor cells, including, but not limited to VEGF receptor inhibitors, including ribozymes and antisense targeted to VEGF receptors, angiostatin and endostatin.
  • Examples of antineoplastic agents that can be used in combination with the compounds and methods of the present invention include, in general, and as appropriate, alkylating agents, anti-metabolites; epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes; biological response modifiers and growth inhibitors; hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors. Exemplary classes of antineoplastics include the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the epothilones, discodermolide, the pteridine family of drugs, diynenes and the podophyllotoxins. Particularly useful members of those classes include, for example, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leuosine, paclitaxel and the like. Other useful antineoplastic agents include estramustine, carboplatin, cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.
  • When a compound or composition of the invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer, for example, breast cancer. Administration typically occurs in an amount of between about 0.01 mg/kg of body weight to about 100 mg/kg of body weight per day (administered in single or divided doses), more preferably at least about 0.1 mg/kg of body weight per day. A particular therapeutic dosage can include, e.g., from about 0.01 mg to about 1000 mg of compound, and preferably includes, e.g., from about 1 mg to about 1000 mg. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, preferably from about 1 mg to 300 mg, more preferably 10 mg to 200 mg, according to the particular application. The amount administered will vary depending on the particular IC50 value of the compound used and the judgment of the attending clinician taking into consideration factors such as health, weight, and age. In combinational applications in which the compound is not the sole active ingredient, it may be possible to administer lesser amounts of compound and still have therapeutic or prophylactic effect.
  • Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • The amount and frequency of administration of the compounds and compositions of the present invention used in the methods of the present invention, and if applicable other chemotherapeutic agents and/or radiation therapy, will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition and size of the patient as well as severity of the disease being treated.
  • The chemotherapeutic agent and/or radiation therapy can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent and/or radiation therapy can be varied depending on the disease being treated and the known effects of the chemotherapeutic agent and/or radiation therapy on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents (i.e., antineoplastic agent or radiation) on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.
  • Also, in general, the compounds of the invention need not be administered in the same pharmaceutical composition as a chemotherapeutic agent, and may, because of different physical and chemical characteristics, be administered by a different route. For example, the compounds/compositions may be administered orally to generate and maintain good blood levels thereof, while the chemotherapeutic agent may be administered intravenously. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
  • The particular choice of compound (and where appropriate, chemotherapeutic agent and/or radiation) will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol.
  • The compounds/compositions of the invention (and where appropriate chemotherapeutic agent and/or radiation) may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the proliferative disease, the condition of the patient, and the actual choice of chemotherapeutic agent and/or radiation to be administered in conjunction (i.e., within a single treatment protocol) with the compound/composition.
  • In combinational applications and uses, f the compound/composition and the chemotherapeutic agent and/or radiation are not administered simultaneously or essentially simultaneously, then the initial order of administration of the compound/composition, and the chemotherapeutic agent and/or radiation, may not be important. Thus, the compounds/compositions of the invention may be administered first followed by the administration of the chemotherapeutic agent and/or radiation; or the chemotherapeutic agent and/or radiation may be administered first followed by the administration of the compounds/compositions of the invention. This alternate administration may be repeated during a single treatment protocol. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient. For example, the chemotherapeutic agent and/or radiation may be administered first, especially if it is a cytotoxic agent, and then the treatment continued with the administration of the compounds/compositions of the invention followed, where determined advantageous, by the administration of the chemotherapeutic agent and/or radiation, and so on until the treatment protocol is complete.
  • Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of a compound/composition for treatment according to the individual patient's needs, as the treatment proceeds.
  • The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.
  • Assays to Determine HSP90 Binding and Downstream Effect
  • A variety of in vitro and in vivo assays are available to test the effect of the compounds of the invention on HSP90. HSP90 competitive binding assays and functional assays can be performed as known in the art substituting in the compounds of the invention. Chiosis et al., Chemistry & Biology 8:289-299 (2001), describe some of the known ways in which this can be done. For example, competition binding assays using, e.g., geldanamycin or 17-AAG as a competitive binding inhibitor of HSP90 can be used to determine relative HSP90 affinity of the compounds of the invention by immobilizing the compound of interest or other competitive inhibitor on a gel or solid matrix, preincubating HSP90 with the other inhibitor, passing the preincubated mix over the gel or matrix, and then measuring the amount of HSP90 that sticks or does not stick to the gel or matrix.
  • Downstream effects can also be evaluated based on the known effect of HSP90 inhibition on function and stability of various steroid receptors and signaling proteins including, e.g., Raf1 and Her2. Compounds of the present invention induce dose-dependent degradation of these molecules, which can be measured using standard techniques. Inhibition of HSP90 also results in up-regulation of HSP90 and related chaperone proteins that can similarly be measured. Antiproliferative activity on various cancer cell lines can also be measured, as can morphological and functional differentiation related to HSP90 inhibition. For example, the
  • Many different types of methods are known in the art for determining protein concentrations and measuring or predicting the level of proteins within cells and in fluid samples. Indirect techniques include nucleic acid hybridization and amplification using, e.g., polymerase chain reaction (PCR). These techniques are known to the person of skill and are discussed, e.g., in Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., Ausubel, et al., Current Protocols in Molecular Biology, John Wiley & Sons, NY, 1994, and, as specifically applied to the quantification, detection, and relative activity of Her-2/neu in patient samples, e.g., in U.S. Pat. Nos. 4,699,877, 4,918,162, 4,968,603, and 5,846,749. A brief discussion of two generic techniques that can be used follows.
  • The determination of whether cells overexpress or contain elevated levels of HER-2 can be determined using well known antibody techniques such as immunoblotting, radioimmunoassays, western blotting, immunoprecipitation, enzyme-linked immunosorbant assays ELISA), and derivative techniques that make use of antibodies directed against HER-2. As an example, HER-2 expression in breast cancer cells can be determined with the use of an immunohistochemical assay, such as the Dako Hercep™ test Shako Corp., Carpinteria, Calif.). The Hercep™ test is an antibody staining assay designed to detect HER-2 overexpression in tumor tissue specimens. This particular assay grades HER-2 expression into four levels: 0, 1, 2, and 3, with level 3 representing the highest level of HER-2 expression. Accurate quantitation can be enhanced by employing an Automated Cellular Imaging System (ACIS) as described, e.g., by Press, M, et al, (2000), Modern Pathology 13:225 A.
  • Antibodies, polyclonal or monoclonal, can be purchased from a variety of commercial suppliers, or may be manufactured using well-known methods, e.g., as described in Harlow et al., Antibodies: A Laboratory Manual, 2nd Ed; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1988).
  • HER-2 overexpression can also be determined at the nucleic acid level since there is a reported high correlation between overexpression of the HER-2 protein and amplification of the gene that codes for it. One way to test this is by using RT-PCR. The genomic and cDNA sequences for HER-2 are known. Specific DNA primers can be generated using standard, well-known techniques, and can then be used to amplify template already present in the cell. An example of this is described in Kurokawa, H et al, Cancer Res. 60: 5887-5894 (2000). PCR can be standardized such that quantitative differences are observed as between normal and abnormal cells, e.g., cancerous and noncancerous cells. Well known methods employing, e.g., densitometry, can be used to quantitate and/or compare nucleic acid levels amplified using PCR.
  • Similarly, fluorescent in situ hybridization (FISH) assays and other assays can be used, e.g., Northern and/or Southern blotting. These rely on nucleic acid hybridization between the HER-2 gene or mRNA and a corresponding nucleic acid probe that can be designed in the same or a similar way as for PCR primers, above. See, e.g., Mitchell M S, and Press M F., 1999, Semin. Oncol., Suppl. 12:108-16. For FISH, this nucleic acid probe can be conjugated to a fluorescent molecule, e.g., fluorescein and/or rhodamine, that preferably does not interfere with hybridization, and which fluorescence can later be measured following hybridization. See, e.g., Kurokawa, H et al, Cancer Res. 60: 5887-5894 (2000) (describing a specific nucleic acid probe having sequence 5′-FAM-NucleicAcid-TAMRA-p-3′ sequence), ACIS-based approaches as described above can be employed to make the assay more quantitative (de la Torre-Bueno, J, et al, 2000, Modern Pathology 13:221A).
  • Immuno and nucleic acid detection can also be directed against proteins other than HSP90 and Her-2, which proteins are nevertheless affected in response to HSP90 inhibition.
  • The following examples are offered by way of illustration only and are not intended to be limiting of the full scope and spirit of the invention.
  • EXAMPLES
  • The chemical reagents used below are all available commercially, e.g., from Aldrich Chemical Co., Milwaukee, Wis., USA, and/or their facile preparation known to one of ordinary skill in the art, or otherwise described or referenced herein.
  • Carbon Linker Compounds: Example 1 Synthesis of 8-(2,5-dimethoxybenzyl)-N9-butyladenine
  • Step 1. A solution of 5-amino-4,6-dichloropyrimidine (1 mmol) in n-BuOH was treated with Et3N (1.2 mmol) and n-Butylamine (1.0 mmol) at 80 C. After 16 h, solvent was removed under reduced pressure. The residue was dissolved in EtOAc, the organic layer washed with water and then dried (MgSO4). Filtration and removal of solvent gave 6-chloro-5-amino-4-butyl pyrimidine as a brown solid. Rf=0.5 in 1:1 EtOAc:hexane, 1H NMR (CDCl3) δ 8.07 (s, 1H), 4.88 (br s, 1H), 3.49 (m, 2H), 3.35 (br s, 2H), 1.6 (m, 2H), 1.44 (m, 2H), 0.95 (t, 3H).
  • Step 2: To a solution of 2,5-dimethoxyphenylacetic acid (1 mmol) and Et3N (1 mmol) in CH2Cl2 was added p-toluenesulfonyl chloride (1 mmol) at rt. After 1 h, the mixture was treated with a solution of the product of step 1, 6-chloro-5-amino-4-butyl pyrimidine (1 mmol in CH2Cl2), followed by addition of Et3N (2 mmol). The resultant mixture was refluxed for 20 h. Solvent was removed and the residue dissolved into EtOAc, the organic layer washed with water and dried. The crude compound was taken into acetone, and precipitated product filtered out and washed with a small amount of acetone to give N-(4-butylamino-6-chloro-pyrimidin-5-yl)-2-(2,5-dimethoxyphenyl)acetamide. Rf=0.45 in 1:1 EtOAc:hexane. 1H NMR (DMSO-d6) δ 9.37 (s, 1H), 8.17 (s, 1H), 7.11 (t, 1H), 6.9 (d, 1H), 6.88 (d, 1H), 6.78 (dd, 1H), 3.73 (s, 3H), 3.69 (s, 3H), 3.63 (s, 3H), 3.35 (m, 2H), 1.48 (m, 2H), 1.29 (m, 2H), 0.88 (t, 3H).
  • Step 3: A mixture of N-(4-butylamino-6-chloro-pyrimidin-5-yl)-2-(2,5-dimethoxyphenyl)acetamide (1 mmol) and p-TSA (0.5 mmol) in toluene was refluxed for 72 h. Solvent was removed, diluted with EtOAc and washed with water, bicarbonate and dried. Purification on a silica gel column (200-400 mesh, Fisher Scientific, Tustin, Calif., USA) gave 6-chloro-8-(2,5-dimethoxybenzyl)-N9-butyl purine. Rf 0.65 in 1:1 EtOAc:hexane. 1H NMR (DMSO-d6) δ 8.7 (s, 1H), 6.96 (d, 1H), 6.84 (m, 1H), 6.8 (dd, 1H), 4.28 (s, 2H), 4.23 (t, 2H), 3.69 (s, 3H), 3.67 (s, 3H), 1.62 (m, 2H), 1.25 (m, 2H), 0.88 (t, 3H).
  • Step 4: To a solution of 6-chloro-8-(2,5-dimethoxybenzyl)-N9-butyl purine (1 mmol) in dioxane was added 28% NH4OH (50 mmol) and the mixture was then heated at 100 C in a seal tube for 48 h. Solvent was removed by azeotrope distillation with toluene. Purification on a silica gel column (see above) gave pure 8-(2,5-dimethoxybenzyl)-9-butyl adenine, 1.1. Rf=0.35 in 5% MeOH in EtOAc. 1H NMR (DMSO-d6) δ 8.08 (s, 1H), 7.04 (br s, 2H), 6.94 (d, 1H), 6.80 (dd, 1H), 6.66 (d, 1H), 4.14 (s, 2H), 4.04 (t, 2H), 3.72 (s, 3H), 3.63 (s, 3H), 1.52 (m, 2H), 1.22 (m, 2H), 0.82 (t, 3H).
  • Alternatively, 8-(2,5-dimethoxybenzyl)-9-butyl adenine can also be prepared from N-(4-butylamino-6-chloro-pyrimidin-5-yl)-2-(2,5-dimethoxyphenyl)acetamide according to the following procedure: A solution of N-(4-butylamino-6-chloro-pyrimidin-5-yl)-2-(2,5-dimethoxyphenyl)acetamide (1 mmol) is taken into 7M NH3 in MeOH (70 mmol) and the mixture heated at 120 C in a steel bomb for 72 h. Solvent is removed by azeotrope distillation with toluene. Purification on the silica gel column gave pure 8-(2,5-dimethoxybenzyl)-9-butyl adenine.
  • Example 2 Synthesis of 8-(2,5-dimethoxybenzyl)-N9-pentynyl-2-fluoro adenine Step 1: 2-(2,5-Dimethoxy-phenyl)-N-(2,5,6-triamino-pyrimidin-4-yl)-acetamide, HCl
  • A solution of 2,4,5,6-tetraaminopyrimidine (52.8 g, 378 mmol) in NMP (750 ml) was treated at 70° C. with 2,5-dimethoxyphenyl acetyl chloride (90 g, 419 mmol). After cooling to r.t., the precipitate was collected by filtration and washed with EtOAc to give the title compounds as a pale yellow powder (127 g, 95%). 1H NMR (DMSO-d6) δ 9.12 (s, 1H), 7.80-7.40 (m, 3H), 6.22 (s, 2H), 6.04 (s, 4H), 4.41 (s, 3H), 4.29 (s, 3H), 4.25 (s, 2H); MS 319 (M+1).
  • Step 2: 8-(2,5-Dimethoxy-benzyl)-9H-purine-2,6-diamine
  • Sodium metal (2.3 g, 100 mmol) was dissolved in n-BuOH (50 ml) at 70° C. To this was added the acetamide of step 1, above (5.0 g, 14.1 mmol, and the mixture was heated to reflux for 1.5 h. Neutralization with 6N HCl to pH 8-9, extraction with EtOAc, drying, and evaporation gave the title compound as a pale yellow powder (3.2 g, 76%). Rf=0.45 in 1:3 MeOH:EtOAc. 1H NMR (DMSO-d6) δ 12.3-11.7 (br. s, 1H), 6.92 (d, J=10.0 Hz, 1H), 6.82 (dd, J=10.0 & 3.0 Hz, 1H), 6.73 (s, 1H), 6.70-6.50 (br. s, 2H), 5.85-5.70 (br. s, 2H), 3.95 (s, 2H), 3.74 (s, 3H), 3.67 (s, 3H); MS 301 (M+1).
  • Step 3: 8-(2,5-Dimethoxy-benzyl)-9-pent-4-ynyl-9H-purine-2,6-diamine
  • A mixture of the purine 8-(2,5-Dimethoxy-benzyl)-9H-purine-2,6-diamine (19.0 g, 63 mmol), 5-chloro-pent-1-yne (12.3 ml, 116 mmol), and Cs2CO3 (37.8 g, 116 mmol) in DMF (180 g) was heated to 50° C. for 16 h. Filtration and washing (2×200 ml 120) afforded some desired product (5.8 g, 25%). The mother liquor was concentrated, diluted with EtOAc, and heated to reflux for 1 h to yield additional product (6.0 g, 26%). After cooling to room temperature, addition of 1 volume hexane to the EtOAc mother liquor gave additional product (2.6 g, 11%). Final work-up (CH2Cl2:MeOH 4:1—water) yielded additional product (5.3 g, containing 1 equivalent penty-4-yn-1-ol, 18%). Rf=0.65 in 1:10 MeOH:EtOAc. 1H NMR DMSO-d6) δ 6.92 (d, J=8.9 Hz, 1H), 6.98 (dd, J=8.9 & 3.0 Hz, 1H), 6.59 (s, J=2.9 Hz, 1H), 6.58-4.53 (br. s, 2H), 5.72-5.68 (br. s, 2H), 4.02 (s, 2H), 3.92 (t, J=7.4 Hz, 2H), 3.73 (s, 3H), 3.62 (s, 3H), 2.84 (t, J=2.5 Hz, 1H), 2.13 (td, J=7.0 & 1.7 Hz, 2H), 1.74 (quint., J=7.3 Hz, 2H); MS 367 (M+1).
  • Step 4: 8-(2,5-Dimethoxy-benzyl)-2-fluoro-9-pent-4-ynyl-9H-purin-6-ylamine
  • A solution of the above purine-2,6-diamine (11.8 g, 32.2 mmol) in 48% aq. HBF4 (250 ml) was treated at −10° C. with iso-amyl nitrite (5.20 ml, 38.8 mmol), and warmed to r.t over 2.5 h. The reaction mixture was diluted with MeOH (400 ml) and CH2Cl2 (1500 ml), and carefully neutralized with a solution of K2CO3 (125 g) in water (500 ml). Caution: vigorous gas evolution. The aqueous layer was re-extracted with MeOH:CH2Cl2 (500 ml, 1:5). Concentration of the organic phase and two flash chromatography purifications (CH2Cl2:EtOAc:hexane:MeOH:Et3N 1500:750:750:50:10→1500:750:750:150:10) yielded 8-(2,5-Dimethoxy-benzyl)-2-fluoro-9-pent-4-ynyl-9H-purin-6-ylamine (4.5 g, 38%), 2.1 as a colorless powder. Rf=0.45 in 1:1 EtOAc:hexane. 1H NMR (DMSO-d6) δ 6.82 (d, J=8.9 Hz, 1H), 6.75 (dd, J=8.9 & 3.0 Hz, 1H), 6.68 (d, J=2.9 Hz, 1H), 6.25-6.10 (br. s, 2H), 4.20 (s, 2H), 4.13 (t, J=7.4 Hz, 2H), 3.79 (s, 3H), 3.70 (s, 3H), 2.16 (td, J=7.0 & 2.6 Hz, 2H), 1.97 (t, J=2.6 Hz, 1H), 1.95 (quint, J=7.3 Hz, 2H); MS 370 (M+1).
  • The following compounds, 2.2-2.4, were prepared using essentially the same procedures described for Example 2, except that in step 3 the electrophiles 1-bromo-4-methyl-pent-3-ene, 1-chloro-pent-4-ene, and 1,5-bromopentane were used in place of 5-chloro-pent-1-yne:
  • 2.2 8-(2,5-Dimethoxy-benzyl)-2-fluoro-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylamine isolated as solid, retention time=7.70.
  • 2.3 8-(2,5-Dimethoxy-benzyl)-2-fluoro-9-pent-4-enyl-9H-purin-6-ylamine isolated as solid, retention time=7.61.
  • 2.4 8-(2,5-Dimethoxy-benzyl)-2-fluoro-9-(5-bromo-pentyl)-9H-purin-6-ylamine isolated as solid, retention time=7.86.
  • Similarly, 2-Cl compound was prepared analogously to the method described in Step 4 using HCl and CuCl in place of HBF4.
  • 2.5 8-(2,5-Dimethoxy-benzyl)-2-chloro-9-pent-4-ynyl-9H-purin-6-ylamine; Rt=8.02 1H NMR (CDCl3) d 6.83 (d, J=8.9 Hz, 1H), 6.77 (dd, J=8.9 & 3.0 Hz, 1H), 6.68 (d, J=3.0 Hz, 1H), 6.18-6.00 (s, 2H), 4.20 (s, 2H), 4.18 (t, J=7.4 Hz, 2H), 3.78 (s, 3H), 4.93 (s, 3H), 2.20 (td, J=7.0 & 2.4 Hz, 2H), 2.63 (t, 2.4 Hz, 1H), 1.97 (quint., J=7.3 Hz, 2H).
  • HPLC method: Agilent Zorbax 300 SB C18, 4.6×150 mm, 5 μm; Column Temperature: Ambient; Flow Rate: 1.0 ml/mm, Gradient: 10% acetonitrile (0.05% TFA) in water (0.1% TFA) to 100% acetonitrile (0.05% TFA) in 10 minutes, hold at 100% for 1 minutes); Retention times are measured in minutes.
  • Example 3
  • The above procedures can similarly be applied to produce compounds wherein Z is H by starting with 4,5,6, triaminopyrimidine sulfate and using electrophiles as shown in Table 3:
  • TABLE 3
    Ex. # Electrophile Final Compound/Structure/Name/HPLC RT (min.)/CF#
    3.1 1-bromo-4-chlorobutane 9-(4-Chloro-butyl)-8-(2,5-dimethoxy-benzyl)-9H-purin-6-
    ylamine isolated as solid; rt = 6.34.
    3.2 1-chloro-pent-4-yne 8-(2,5-Dimethoxy-benzyl)-9-pent-4-ynyl-9H-purin-6-ylamine
    isolated as solid rt = 5.88 min.
    3.3 1-chloro-3-[1,3]dioxolan-2- 8-(2,5-Dimethoxy-benzyl)-9-(2-[1,3]dioxolan-2-yl-ethyl)-9H-
    yl]propane purin-6-ylamine isolated as solid, rt = 5.36.
    3.4 1-bromo-4-methyl-pent-3-ene 8-(2,5-Dimethoxy-benzyl)-9-(4-methyl-pent-3-enyl)-9H-purin-
    6-ylamine isolated as solid., rt = 6.60.
    3.5 1,5-dibromopentane 9-(5-Bromo-pentyl)-8-(2,5-dimethoxy-benzyl)-9H-purin-6-
    ylamine isolated as solid, rt = 6.94.
    3.6 1,5-dibromo-3-methylpentane 9-(5-Bromo-3-methyl-pentyl)-8-(2,5-dimethoxy-benzyl)-9H-
    purin-6-ylamine isolated as solid, rt = 7.32.
    3.7 1-bromo-5-Chloropentane 9-(5-Chloro-pentyl)-8-(2,5-dimethoxy-benzyl)-9H-purin-6-
    ylamine isolated as solid, rt = 6.34.
    3.8 1-bromo-4-chlorobutane 8-(2,5-Dimethoxy-benzyl)-9-(4-ethylamino-butyl)-9H-purin-6-
    alkylation followed by ylamine isolated as solid, rt = 3.9.
    treatment with ethylamine
    gave 4-ethylaminobutyl
    3.9 1-bromohexan-6-ol 6-[6-Amino-8-(2,5-dimethoxy-benzyl)-purin-9-yl]-hexan-1-ol
    isolated as solid.
    3.10 2-(dimethyl- 8-(2,5-Dimethoxy-benzyl)-9-[2-(dimethyl-bicyclo[3.1.1]hept-
    bicyclo[3.1.1]hept-2-en-2-yl)- 2-en-2-yl)-ethyl]-9H-purin-6-ylamine isolated as solid.
    3-bromopropane
    3.11 1-bromo-5acetyloxypentane Acetic acid 5-[6-amino-8-(2,5-dimethoxy-benzyl)-purin-9-yl]-
    pentyl ester isolated as solid; rt = 6.06.
    3.12 1-bromo-3,3,3-trifluoro- 8-(2,5-Dimethoxy-benzyl)-9-(3,3,3-trifluoro-propyl)-9H-purin-
    propane 6-ylamine isolated as solid;
    3.13 1-chloro-pent-4-yne 8-(2,5-Dimethoxy-benzyl)-9-pent-4-ynyl-9H-purin-6-ylamine
    isolated as solid; rt = 5.88.
  • Example 4 Halogenation of Benzene Ring
  • 4.1 To a solution of 9-butyl-8-(3-methoxy-benzyl)-9H-purin-6-ylamine (1.24 g, 4 mmol) in AcOH (6 ml) was added N-iodo-succinamide (NIS) (1.8 g, 8 mmol). After 3 h at r.t., additional MS (1.8 g, 8 mmol) was added, and the mixture was stirred for another 24 h. The reaction mixture was diluted with CH2Cl2 (500 ml), and carefully neutralized with a solution of sat. aq. K2CO3 (2×100 ml), then washed with 0.1 N Na2S2O3 (3×100 ml), brine (3×100 ml), dried Na2SO4), evaporated, and purified by flash chromatography (CH2Cl2:MeOH=100:5) to give the 9-Butyl-8-(2-iodo-5-methoxy-benzyl)-9H-purin-6-ylamine (4.1), as a colorless powder (0.53 g, 30%); rt=7.7 min.; 1HNMR (CDCl3-d) δ 8.36 (s, 1H), 7.77 (d, J=7.9 Hz, 1H), 6.68 (s, 1H), 6.61 (d, J=7.9 Hz, 1H), 5.62 (s, 2H), 4.33 (s, 2H), 4.06 (t, J=7.7 Hz, 2H), 3.72 (s, 3H), 1.67 (quint., J=7.7 Hz, 2H), 1.36 (sext., J=7.5 Hz, 2H), 0.92 (t, J=7.4 Hz, 3H).
  • Bromo and chloro derivatives were made using the same procedure, substituting NBS and NCS for NIS as appropriate. The following compounds were also synthesized according to essentially the same procedure, using as appropriate MS, NCS or NBS:
  • 4.2 9-Butyl-8-(5-iodo-2-methoxy-benzyl)-9H-purin-6-ylamine was made from 9-Butyl-8-(2-methoxy-benzyl)-9H-purin-6-ylamine as starting material in 48% yield; 1H NMR (CDCl3) δ 8.32 (s, 1H), 7.55 (dd, J=8.7, 2.2 Hz, 1H), 7.37 (d, J=2.2 Hz, 1H), 6.68 (d, J=8.7 Hz, 1H), 6.05-5.85 (br. s, 2H), 4.17 (s, 2H), 4.07 (t, J=7.6 Hz, 2H), 3.82 (s, 3H), 1.62 (quint., J=7.5 Hz, 2H), 1.30 (sext., J=7.5 Hz, 2H), 0.89 (t, J=7.4 Hz, 3H).
  • 4.3 9-Butyl-8-(5-ethyl-2-methoxy-benzyl)-9H-purin-6-ylamine; Rt=7.59; 1H NMR (CDCl3-d) δ 8.35 (s, 1H), 7.34 (d, J=8.8 Hz, 1H), 6.79 (dd, J=8.7, 2.8 Hz, 1H), 6.69 (d, J=2.7 Hz, 1H), 5.64 (s, 2H), 4.36 (s, 2H), 4.07 (t, J=7.7 Hz, 2H), 3.73 (s, 3H), 1.64 (quint., J=7.7 Hz, 2H), 1.32 (sext., J=7.5 Hz, 2H), 0.90 (t, J=7.4 Hz, 3H).
  • 4.4 8-(2-Bromo-5-methoxy-benzyl)-9-butyl-9H-purin-6-ylamine; Rt=7.66; 1HNMR (CDCl3-d) δ 8.36 (s, 1H), 7.52 (d, J=8.7 Hz, 1H), 6.74 (dd, J=8.7, 3.0 Hz, 1H), 6.89 (d, J=3.0 Hz, 1H), 5.64 (s, 2H), 4.36 (s, 2H), 4.07 (t, J=7.7 Hz, 2H), 3.72 (s, 3H), 1.64 (quint., J=7.6 Hz, 2H), 1.34 (sext., J=7.5 Hz, 2H), 0.90 (t, J=7.4 Hz, 3H).
  • 9-Butyl-8-(2-methoxy-benzyl)-9H-purin-6-ylamine and 9-butyl-8-(3-methoxy-benzyl)-9H-purin-6-ylamine were prepared from 4,5,6-triaminopyrimidine sulfate and, respectively 2-methoxyphenyl acetyl chloride or 3-methoxyphenyl acetic acid, by procedures analogous to the one described above. 2-Fluoro purine analogs were also prepared from 2,4,5,6-tetraminopyrimidine, by procedures analogous to those described above. See Example 2, step 4.
  • For the following compounds, in which the N9 substituent (Y) is sensitive to halogenation, addition of the N9 substituent (Y) was done as a final step:
  • 4.5 8-(2-Bromo-5-methoxy-benzyl)-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylamine; Rt=8.22; 1HNMR (CDCl3-d) δ 8.37 (s, 1H), 7.51 (d, J=8.7 Hz, 1H), 6.73 (dd, J=8.7 Hz, 3.0 Hz, 1H), 6.65 (d, J=3.0 Hz, 1H), 5.53 (s, 2H), 5.12 (t, J=7.1 Hz, 2H), 4.35 (s, 2H), 4.07 (t, J=7.1 Hz, 2H), 3.72 (s, 3H), 2.43 (quart., J=7.1 Hz, 2H), 1.65 (s, 3H), 1.40 (s, 3H).
  • 4.6 8-(2-Bromo-5-methoxy-benzyl)-9-pent-4-ynyl-9H-purin-6-ylamine; Rt=8.17; 1HNMR (CDCl3-d) δ 8.35 (s, 1H), 7.52 (d, J=8.8 Hz, 1H), 6.74 (dd, J=8.8 Hz, 2.9 Hz, 1H), 6.66 (d, J=2.9 Hz, 1H), 5.61 (s, 2H), 4.39 (s, 2H), 4.21 (t, J=7.4 Hz, 2H), 3.73 (s, 3H), 2.24 (d, J=6.8 Hz, 2.5 Hz, 2H), 2.03 (t, J=2.5 Hz, 1H), 1.99 (quint., J=7.2 Hz, 2H).
  • 4.7 8-(2-Iodo-5-methoxy-benzyl)-9-pent-4-ynyl-9H-purin-6-ylamine; Rt=7.35; 1HNMR (CDCl3-d) δ 8.36 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 6.64-6.60 (m, 2H), 5.56 (s, 2H), 4.35 (s, 2H), 4.20 (t, J=7.4 Hz, 2H), 3.73 (s, 3H), 2.26 (td, J=6.9 Hz, 2.7 Hz, 2H), 2.03 (t, J=2.7 Hz, 1H), 2.02 (quint., J=7.0 Hz, 2H).
  • 4.8 8-(2-Iodo-5-methoxy-benzyl)-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylamine; Rt=8.17; 1HNMR (CDCl3-d) δ 8.58 (s, 1H), 8.33 (d, J=8.6 Hz, 1H), 6.60 (d, J=2.9 Hz, 1H), 6.57 (dd, J=8.6, 2.9 Hz, 1H), 6.15 (s, 2H), 5.12 (t, J=7.4 Hz, 2H), 4.29 (s, 2H), 4.04 (t, J=7.3 Hz, 2H), 3.67 (s, 3H), 2.42 (quart., J=7.2 Hz, 2H), 1.65 (s, 3H), 1.39 (s, 3H).
  • 4.9 2-Fluoro-8-(2-iodo-5-methoxy-benzyl)-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylamine; Rt=10.04; 1HNMR (CDCl3-d) δ 7.76 (d, J=8.6 Hz, 1H), 6.65 (d, J=2.5 Hz, 1H), 6.60 (dd, J=8.6, 2.5 Hz, 1H), 6.14 (s, 2H), 5.13 (t, J=6.9 Hz, 1H), 4.26 (s, 2H), 4.01 (t, J=7.0 Hz, 2H), 3.72 (s, 3H), 2.43 (quint., J=7.0 Hz, 2H), 1.68 (s, 3H), 1.42 (s, 3H).
  • 4.10 2-Fluoro-8-(2-iodo-5-methoxy-benzyl)-9-pent-4-ynyl-9H-purin-6-ylamine; Rt=8.75; 1HNMR (CDCl3-d) δ 7.77 (d, J=8.7 Hz, 1H), 6.67 (d, J=2.7 Hz, 1H), 6.62 (dd, J=8.7, 2.7 Hz, 1H), 5.99 (s, 2H), 4.32 (s, 2H), 4.16 (t, J=7.2 Hz, 2H), 3.74 (s, 3H), 2.26 (td, J=6.7, 2.6 Hz, 2H), 2.02 (t, J=2.4 Hz, 1H), 1.99 (quint., J=6.9 Hz, 2H); MP: 172-177° C.
  • Example 5 General Procedure for Palladium-Mediated Couplings
  • A mixture of 9-Butyl-8-(5-iodo-2-methoxy-benzyl)-9H-purin-6-ylamine (50 mg, 0.1 mmol) and Pd(PPh3)4 (12 mg, 0.01 mmol) was treated under N2 at r.t. with a 1M solution of the organometallic coupling partner (0.5 ml, 0.5 mmol). Reactions were performed typically in THF at r.t. for 10 min with organomagnesium compounds in THF at r.t. for 16 h with organozinc compounds, or in DMF at 80° C. for 3 h with organostannanes. After work-up, the product was purified by chromatography on preparative plates (1000 uM, SiO2), eluting with CH2Cl2:EtOAc:hexane:MeOH:Et3N 1500:750:750:50:10.
  • The following compounds were prepared using the corresponding commercially available organozinc compound; the skilled artisan will recognize that equivalent organnostannane, and organoboron, and organomagnesium coupling partners may be used in place of organozinc compounds. A general review of appropriate methodologies may be found in “Palladium Reagents in Organic Synthesis” Richard F. Heck, Academic Press, 1990.
  • 5.1 9-Butyl-8-(5-ethyl-2-methoxy-benzyl)-9H-purin-6-ylamine; Rt=8.23; 1H NMR (CDCl3) δ 8.30 (s, 1H), 7.07 (dd, J=8.4 & 2.0 Hz, 1H), 6.91 (d, J=2.0 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 5.65-5.55 (s, 2H), 4.23 (s, 2H), 4.04 (t, J=7.6 Hz, 2H), 3.83 (s, 3H), 2.51 (q, J=7.6 Hz, 2H) 1.65-1.55 (m, 2H), 1.30-1.25 (m, 2H), 1.41 (t, J=7.6 Hz, 3H), 0.86 (1, J=7.3 Hz, 3H).
  • 5.2 9-Butyl-8-(5-butyl-2-methoxy-benzyl)-9H-purin-6-ylamine; Rt=9.24; 1H NMR (CDCl3) δ 8.33 (s, 1H), 7.05 (dd, J=8.4 & 1.9 Hz, 1H), 6.88 (d, J=1.8 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 5.58-5.48 (s, 2H), 4.23 (s, 2H), 4.04 (t, J=7.6 Hz, 2H), 3.83 (s, 3H), 2.47 (q, J=7.6 Hz, 2H), 1.57 (quint., J=7.5 Hz, 2H), 1.48 (quint., J=7.6 Hz, 2H), 1.32-1.22 (m, 4H), 0.87 (t, J=7.3 Hz, 3H), 0.86 (t, J=7.3 Hz, 3H).
  • 5.3 9-Butyl-8-(2-methoxy-5-vinyl-benzyl)-9H-purin-6-ylamine; Rt=7.91; 1H NMR (CDCl3) δ 8.31 (s, 1H), 7.31 (dd, J=8.5 & 2.3 Hz, 1H), 7.16 (d, J=2.2 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.59 (dd, J=17.6 & 10.9 Hz, 1H), 5.82-5.72 (s, 2H), 5.53 (dd, J=17.6 & 0.7 Hz, 1H), 5.09 (dd, J=10.9 & 0.7 Hz, 1H), 4.22 (s, 2H), 4.06 (t, J=7.6 Hz, 2H), 3.85 (s, 3H), 1.62 (quint., J=7.7 Hz, 2H), 1.30 (sext., J=7.4 Hz, 2H), 0.87 (t, J=7.4 Hz, 3H).
  • Example 6 General Procedure for the Nitration of Benzene Ring and Derivatizations
  • A solution of purine in H2SO4 or in H2SO4:AcOH 1:4 was treated at 0° C. with 1 equiv HNO3. The mixture was diluted with EtOAc, neutralized with NaHCO3 and purified by chromatography on SiO2 preparative plates (1000 uM) with CH2Cl2:EtOAc:hexane:MeOH:Et3N 1500:750:750:50:10.
  • Nitro derivatives (20 mg) are reduced with 10% Pd/C (Aldrich) (20 mg) under H2 atmosphere in THF at r.t. over 16 h. The resulting aniline can be further monoalkylated (Acetylchloride, CH2Cl2) or reductively alkylated (RCHO, NaBH(OAc)3, 1,2-dichloroethane, r.t.).
  • The following compounds were prepared by this method:
  • 6.1 8-(2,5-Dimethoxy-4-nitro-benzyl)-2-fluoro-9-pent-4-ynyl-9H-purin-6-ylamine (CF310), Rt=8.05; 1H NMR (CDCl3) δ 7.94 (s, 1H), 6.85 (s, 1H), 6.37-6.27 (s, 2H), 4.06 (s, 2H), 4.01 (t, J=7.3 Hz, 2H), 3.69 (s, 3H), 3.66 (s, 3H), 2.13 (td, J=7.0 & 2.6 Hz, 2H), 1.87 (t, J=2.6 Hz, 1H), 1.82 (quint., J=7.3 Hz, 2H).
  • 6.2 9-Butyl-8-(3,5-dimethoxy-2-nitro-benzyl)-9H-purin-6-ylamine; sulfuric acid salt; Rt=7.33; 1H NMR (DMSO-d6) δ 8.27 (s, 1H), 8.15-7.90 (br. s, 2H), 6.78 (d, J=2.4 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 4.32 (s, 2H), 4.12 (t, J=7.3 Hz, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 1.58 (quint., J=7.5 Hz, 2H), 1.21 (sext., J=7.5 Hz, 2H), 0.84 (t, J=7.4 Hz, 3H).
  • 6.3 8-(4-Amino-3,5-dimethoxy-benzyl)-9-butyl-9H-purin-6-ylamine; Rt=805; 1H NMR (CDCl3) δ 8.31 (s, 1H), 7.31 (dd, J=8.5 & 2.3 Hz, 1H), 7.16 (d, J=2.2 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.59 (dd, J=17.6 & 10.9 Hz, 1H), 5.82-5.72 (s, 2H), 5.53 (dd, J=17.6 & 0.7 Hz, 1H), 5.09 (dd, J=10.9 & 0.7 Hz, 1H), 4.22 (s, 2H), 4.06 (t, J=7.6 Hz, 2H), 3.85 (s, 3H), 1.62 (quint., J=7.7 Hz, 2H), 1.30 (sext., J=7.4 Hz, 2H), 0.87 (t, J=7.4 Hz, 3H).
  • 6.4 8-(4-Amino-2,5-dimethoxy-benzyl)-9-butyl-9H-purin-6-ylamine; Rt=6.95; 1H NMR (CDCl3) δ 8.33 (s, 1H), 6.57 (s, 1H), 6.33 (s, 1H), 6.37-6.27 (s, 2H), 4.20 (s, 2H), 4.01 (t, J=7.3 Hz, 2H), 3.74 (s, 3H), 3.68 (s, 3H), 1.59 (quint., J=7.5 Hz, 2H), 1.32 (sext., J=7.5 Hz, 2H), 0.86 (t, J=7.4 Hz, 3H).
  • 6.5 8-(2-Amino-3,5-dimethoxy-benzyl)-9-butyl-9H-purin-6-ylamine; 1H NMR (CDCl3) δ 8.28 (s, 1H), 6.40 (d, J=2.5 Hz, 1H), 6.30 (d, J=2.5 Hz, 1H), 5.85-5.75 (s, 2H), 4.14 (s, 2H), 4.13 (t, J=7.6 Hz, 2H), 3.80 (s, 3H), 3.73 (s, 3H), 1.62 (quint., J=7.5 Hz, 2H), 1.48 (sext., J=7.5 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H).
  • 6.6 2-(6-Amino-9-butyl-9H-purin-8-ylmethyl)-4-methoxy-benzaldehyde-O-methyl-oxime; Rt=7.69; 1H NMR (CDCl3) δ 8.88 (s, 1H), 8.31 (s, 1H), 7.72 (d, J=7.9 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.74 (s, 1H), 5.80-5.76 (s, 2H), 4.24 (s, 2H), 4.00 (t, J=7.7 Hz, 2H), 3.94 (s, 3H), 3.76 (s, 3H), 1.58 (quint., J=7.7 Hz, 2H), 1.28 (sext., J=7.5 Hz, 2H), 0.86 (t, J=7.3 Hz, 3H).
  • Example 7 Formylation of Benzene Ring and Derivatization
  • A solution of 9-butyl-8-(3-methoxy-benzyl)-9H-purin-6-ylamine (100 mg, 0.32 mmol), 1,1-dichlorodimethyl ether (40 mg, 0.35 mmol) and TiCl4 (133 mg, 0.70 mmol) in CH2Cl2 (10 ml) was prepared at 0° C. and stirred at r.t. overnight. Dilution with CH2Cl2, washing (Na2SO4, NH4Cl), drying, and preparative thin layer chromatography gave the title aldehyde as a yellow glass (47 mg, 43%).
  • Standard procedures gave the corresponding alcohol (NaBH4, MeOH, r.t.), tosyl hydrazone (TsNHNH2, EtOH, reflux), oximes (RONH2.HCl, DMF, 60° C.), amines (R1R2NH, NaBH(OAc)3, Cl—(CH2)2—Cl r.t.), homoallylic alcohol (AllSiMe3, TiCl4), CH2Cl2, −78° C.), or alkenes.
  • 7.1 2-(6-Amino-9-butyl-9H-purin-8-ylmethyl)-4-methoxy-benzaldehyde; Rt=6.52; 1HNMR (CDCl3-d) δ 10.39 (s, 1H), 8.32 (s, 1H), 7.76 (d, J=7.8 Hz, 1H), 6.87 (m, 2H), 6.22 (s, 2H), 4.28 (s, 2H), 4.03 (t, J=7.6 Hz, 2H), 3.85 (s, 3H), 1.61 (quint., J=7.3 Hz, 2H), 1.29 (sext., J=7.4 Hz, 2H), 0.86 (t, J=7.2 Hz, 3H).
  • Example 8 Negishi Couplings
  • A mixture of 3,4-dichlorobenzyl bromide (0.47 g, 1.96 mmol) and Rieke Zinc (3.0 ml, 5 g/100 ml THF, 2.35 mmol) was stirred overnight at r.t. in a flame-dried Schlenk tube and decanted to provide a 0.65M stock solution of 3,4-dichlorobenzyl zinc bromide. A solution of 8-bromo-9-butyl-9H-purin-6-ylamine (42.7 mg, 0.158 mol), Pd(dppf)Cl2 (16.8 mg, 0.020 mmol), and 3,4-dichlorobenzyl zinc bromide (0.61 ml, 0.65M in THF) was stirred in a flame-dried Schlenk tube at 66° C. overnight, quenched with sat, aq. NH4Cl and sat. aq. EDTA., extracted into EtOAc, dried and concentrated. Preparative TLC purification (EtOAc/CH2Cl2/MeOH 14:14:2) provided the title compound as a colorless oil (approx. 15 mg, 20%).
  • 8.1 9-Butyl-8-(3,4-dichloro-benzyl)-9H-purin-6-ylamine, compound isolated as solid, Rt=7.98.
  • S-Linker Compounds Example 9 9-Butyl-8-(2-iodo, 5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine
  • Step 1: Adenine (47 g, 0.35 mole) was suspended in 200 ml of CHCl3 before adding bromine (180 ml, 3.5 mole) in one portion. The suspension was left stirring at room temperature for 72 hours in a closed system that was vented by a 20G needle. The reaction was worked up by adding shaved ice into the suspension before slowly neutralizing with aqueous ammonia to pH 8-9, followed by precipitation of the desired product with acetic acid. The crude product was dried under reduced pressure for 2 days to give 8-Bromoadenine as a light brown powder (45 g, 60% yield). 1H NMR (DMSO-d6) δ 8.12 (s, 1H), 7.22 (s, 2H). Rf (75% EtOAc/Hex)=0.4.
  • Step 2: 8-Bromopurine (2.2 g, 10 mmole) was dissolved in 50 ml of DMF before adding 1-bromo-butane (2.2 ml, 20 mmol) and cesium carbonate (6.7 g, 20 mmol) into the solution. The reaction mixture was left stirring at room temperature for 16 hours before quenching with water and extracting with EtOAc. The organic layer was washed with water and dried with MgSO4 before removing solvent under reduced pressure. A white powder (0.9 g, 33%) of 8-Bromo-9-butyl-9H-purin-6-ylamine was isolated using silica gel column chromatography (50% EtOAc/Hexanes). 1H NMR (CDCl3) δ 8.32, (s, 1H), 5.81 (s, 2H), 4.20 (t, 2H), 1.82 (m, 2H), 1.40 (m, 2H), 0.96 (t, 3H). Rf (75% EtOAc/Hex)=0.6.
  • Step 3: To a mixture of sodium hydride (96 mg, 4 mmol) in DMF (4 ml) was added 3-methoxy-benzenethiol (1.12 g, 8 mmol). After 30 min, a solution of 8-bromo-9-butyl-9H-purin-6-ylamine (0.54 g, 2 mmol) in DMF (6 ml) was added and stirred for 12 h at 70° C. The reaction mixture was quenched by addition of MeOH (4 ml), diluted with EtOAc (400 ml), washed with Na2CO3 (3×100 ml), brine (3×100 ml), dried (Na2SO4), evaporated, purified with flash chromatography (CH2Cl2:MeOH=100:5) to give the title sulfide as a colorless powder (0.59 g, 89%).
  • HPLC method used for these compounds: Agilent Zorbax 300 SB C18, 4.6×150 mm, 5 μm; Column Temperature: Ambient; Flow Rate: 1.0 ml/min, Gradient: 5% acetonitrile (0.05% TFA) in water (0.1% TFA) to 100% acetonitrile (0.05% TFA) in 15 minutes, hold at 100% for 2 minutes).
  • The following compounds were prepared using the corresponding thiol in place of the 3-methoxybenzene thiol used in step 3:
  • 9.1 3-(6-Amino-9-butyl-9H-purin-8-ylsulfanyl)-phenol; Rt=6.75 min 1HNMR (DMSO-d6): δ 9.69 (s, 1H), 8.17 (s, 1H), 7.45 (s, 2H), 7.17 (t, J=7.9 Hz, 1H), 6.76 (d, J=7.4 Hz, 1H), 6.68 (d, J=8.2 Hz, 1H), 6.62 (s, 1H), 4.11 (t, J=7.0 Hz, 2H), 1.57 (quint., J=7.3 Hz, 2H), 1.19 (sext., J=6.8 Hz, 2H), 0.81 (t, J=7.4 Hz, 3H).
  • 9.2 9-Butyl-8-(3-methoxy-phenylsulfanyl)-9H-purin-6-ylamine; Rt=8.6 min; 1H NMR (DMSO-d6) δ 0.80 (t, J=7.4 Hz, 3H, CH3), 1.20 (m, 2H, CH2), 1.61 (m, 2H, CH2), 3.60 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 4.13 (t, J=7.4 Hz, 2H, CH2), 6.46 (s, 1H, Ar—H), 6.85 (d, J=8.9 Hz, 1H, Ar—H), 7.02 (d, J=8.9 Hz, 1H, Ar—H), 7.41 (bs, 2H, NH2), 8.15 (s, 1H, purine-H).
  • 9.3 9-Butyl-8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine); Rt=7.62 min; 1HNMR (CDCl3-d): δ 8.30 (s, 1H), 7.18 (t, J=8.2 Hz, 1H), 6.90 (m, 2H), 6.77 (m, 3H), 4.17 (t, J=7.6 Hz, 2H), 3.70 (s, 3H), 1.67 (quint., J=7.5 Hz, 2H), 1.28 (sext., J=7.5 Hz, 2H), 0.86 (t, J=7.4 Hz, 3H).
  • Step 4: To a solution of 9-butyl-8-(3-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (0.26 g, 0.73 mmol) in AcOH (4 ml) was added NIS (0.53 g, 2.19 mmol) in portions. The mixture was stirred for 24 h at r.t. The reaction mixture was diluted with EtOAc (200 ml), and carefully neutralized with a solution of K2CO3 (2×50 ml), them washed with Na2S2O3 (3×50 ml), brine (3×50 ml), dried (Na2SO4), evaporated, purified by preparative TLC chromatography (CH2Cl2:MeOH=100:5) to give the 2-iodo isomer (60 mg), and the 4-iodo isomer (65 mg).
  • 9.4 9-Butyl-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine; Rt=8.45 min; 1HNMR (CDCl3-d): δ 8.38 (s, 1H), 7.73 (d, J=8.7 Hz, 1H), 6.71 (d, J=2.7 Hz, 1H), 6.58 (dd, J=8.7, 2.7 Hz, 1H), 5.91 (s, 2H), 4.22 (t, J=7.4 Hz, 2H), 3.68 (s, 3H), 1.75 (quint., J, 7.7 Hz, 2H), 1.37 (sext., J=7.5 Hz, 2H), 0.93 (t, J=7.4 Hz, 3H).
  • 9.5 9-Butyl-8-(4-iodo-3-methoxy-phenylsulfanyl)-9H-purin-6-ylamine; Rt=8.63 min; 1HNMR (CDCl3-d): δ 8.38 (s, 1H), 7.72 (d, J=8.1 Hz, 1H), 6.92 (d, J=1.8 Hz, 1H), 6.58 (dd, J=8.1, 1.8 Hz, 1H), 5.82 (s, 2H), 4.22 (t, J=7.4 Hz, 2H), 3.85 (s, 3H), 1.75 (quint., J=7.7 Hz, 2H), 1.37 (sext., J=7.5 Hz, 2H), 0.93 (t, J=7.4 Hz, 3H).
  • For compounds in which the N9 substituent (Y) is sensitive to halogenation conditions, these may be prepared using iodide already present in the benzenethiol moiety:
  • To a suspension of sodium hydride (96 mg, 4 mmol) in DMF (3 ml) was added 2-iodo-5-methoxy-benzenethiol (1.06 g, 4 mmol; J. Org. Chem., 2001, 66(13), 4525-4542). After 30 min, a solution of 8-bromo-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylamine (296 mg, 1 mmol) in DMF (3 ml) was added, and the mixture was stirred for 12 h at 70° C. The reaction was quenched by addition of MeOH (2 ml), diluted with EtOAc (200 ml), washed with Na2CO3 (3×50 ml), brine (3×50 ml), dried (Na2SO4), evaporated, and purified by flash chromatography (CH2Cl2:MeOH=100:5) to give 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylamine as a colorless powder (280 mg, 58%).
  • The following compounds were prepared by this method using, respectively, the electrophiles 1-bromo-4-methyl-pent-3-ene and 1-chloro-pent-4-yn:
  • 9.6 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylamine; Rt=9.14 min; 1HNMR (CDCl3-d); δ 8.39 (s, 1H), 7.72 (d, J=8.7 Hz, 1H), 6.72 (d, J=2.7 Hz, 1H), 6.58 (dd, J=8.7, 2.7 Hz, 1H), 5.81 (s, 2H), 5.15 (t, J=7.3 Hz, 1H), 4.25 (t, J=7.4 Hz, 2H), 3.69 (s, 3H), 2.50 (quint., J=7.3 Hz, 2H), 1.66 (s, 3H), 1.44 (s, 3H); MP: 167-167.5° C.
  • 9.7 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine; Rt=7.93 min; 1HNMR (CDCl3-d): δ 8.38 (s, 1H), 7.75 (d, J=8.7 Hz, 1H), 6.74 (d, J=2.7 Hz, 1H), 6.60 (dd, J=8.7, 2.7 Hz, 1H), 5.72 (s, 2H), 4.32 (t, J=7.3 Hz, 2H), 3.70 (s, 3H), 2.28 (td, J=6.8, 2.6 Hz, 2H), 2.06 (quint., J=7.3 Hz, 2H), 2.00 (t, J=2.4 Hz, 1H); MP: 168-169° C.
  • The following compounds were prepared using the corresponding thiol in place of the 3-methoxybenzene thiol and base t-BuOK in place of NaH used in step 3:
  • 9.8 8-(Benzothiazole-2-ylsulfanyl)-9-butyl-9H-purin-6-ylamine; Rt=6.53 min; 1H NMR (CDCl3) 8.41 (s, 1H), 7.94 (d, 1H), 7.74 (d, 1H), 7.47 (t, 1H), 7.38 (t, 1H), 6.01 (s, 2H), 4.32 (t, 2H), 1.79 (m, 2H), 1.35 (m, 2H), 0.89 (t, 3H).
  • 9.9 9-Butyl-8-(5-chloro-benzothiazole-2-ylsulfanyl)-9H-purin-6-ylamine; Mass (M+1)=391.8 et (M+3) 393.8; 1H NMR (CDCl3) 8.43 (s, 1H), 7.92 (s, 1H), 7.65 (d, 1H), 7.35 (d, 1H), 6.01 (s, 2H), 4.32 (t, 2H), 1.79 (m, 2H), 1.35 (m, 2H), 0.89 (t, 3H).
  • 9.10 9-Butyl-8-(5-methoxy-benzothiazole-2-ylsulfanyl)-9H-purin-6-ylamine; 1H NMR (CDCl3) 8.42 (s, 1H), 7.60 (d, 1H), 7.43 (s, 1H), 7.02 (d, 1H), 5.82 (s, 2H), 4.33 (t, 2H), 3.99 (s, 3H), 1.80 (m, 2H), 1.35 (m, 2H), 0.89 (t, 3H).
  • 9.11 9-Butyl-8-(2,5-dichloro-phenylylsulfanyl)-9H-purin-6-ylamine; 1H NMR (CDCl3) 8.37 (s, 1H), 7.35 (d, 1H), 7.20 (dd, 1H), 7.14 (d, 1H), 5.72 (s, 2H), 4.24 (t, 2H), 1.79 (m, 2H), 1.35 (m, 2H), 0.89 (t, 3H).
  • 9.12 9 Butyl-8-(2,4,5-trichloro-phenylylsulfanyl)-9H-purin-6-ylamine; Rt=7.8 min; 1H NMR (CDCl3) 8.37 (s, 1H), 7.62 (s, 1H), 7.35 (s, 1H), 5.98 (s, 2H), 4.27 (t, 2H), 1.80 (m, 2H), 1.36 (m, 2H), 0.92 (t, 3H).
  • Example 10
  • 8-(2,5-dimethoxy-phenylsulfanyl)-2-fluoro-9(4-methyl-pent-3-enyl)-9H-purin-6-ylamine and 8-(2,5-dimethoxy-phenylsulfanyl)-2-amino-9(4-methyl-pent-3-enyl)-9H-purin-6-ylamine were prepared from 2,6-diaminopurine by procedures analogous to the one described above in Example 9. The final conversion of amino to fluoro was done by method similar to that reported in Example 2, step 4.
  • 10.1 8-(2,5-dimethoxy-phenylsulfanyl)-2-amino-9(4-methyl-pent-3-enyl)-9H-purin-6-ylamine; 1H NMR (DMSO-d6) δ 1.28 (s, 3H, CH3), 1.58 (s, 3H, CH3), 2.35 (m, 2H, CH2), 3.60 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 4.12 (t, J=7.0 Hz, 2H, CH2), 5.05 (t, J=7 Hz, 1H, CH═), 6.50 (s, 1H, Ar—H), 6.91 (d, J=8.9 Hz, 1H, Ar—H), 7.05 (d, J=8.9 Hz, 1H, Ar—H).
  • 10.2 8-(2,5-dimethoxy-phenylsulfanyl)-2-fluoro-9(4-methyl-pent-3-enyl)-9H-purin-6-ylamine; 1H NMR DMSO-d6) δ 1.30 (s, 3H, CH3), 1.55 (s, 3H, CH3), 2.35 (m, 2H, CH2), 3.60 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 4.10 (t, J=7.0 Hz, 2H, CH2), 5.05 (t, J=7 Hz, 1H, CH═), 6.47 (s, 1H, Ar—H), 6.86 (d, J=8.9 Hz, 1H, Ar—H), 7.02 (d, J=8.9 Hz, 1H, Ar—H); MS (m/z) 426 (M+Na).
  • Example 11
  • The compounds in this example were prepared analogously to the method described above in Example 9 using various electrophiles to generate a library of N9 substituted compounds. N9 allylation was done as a final step after the bromine displacement of 8-bromopurine with 2,5-dimethoxy thiophenol.
  • 11.1 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine; 1H NMR (DMSO-d6) δ 3.62 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 6.61 (s, 1H, Ar—H), 6.85 (d, J=8.9 Hz, 1H, Ar—H), 7.02 (d, J=8.9 Hz, 1H, Ar—H), 7.24 (bs, 2H, NH2), 8.13 (s, 1H, purine-H) 13.33 (s, 1H, purine-NH); electrophile: No substitution on N9.
  • 11.2 8-(2,5-dimethoxy-phenylsulfanyl)-9-pentyl-9H-purin-6-ylamine; 1H NMR (DMSO-d6) δ 0.80 (t, J=7.4 Hz, 3H, CH3), 1.20 (m, 4H, 2CH2), 1.61 (m, 2H, CH2), 3.60 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 4.13 (t, J=7.4 Hz, 2H, CH2), 6.46 (s, 1H, Ar—H), 6.85 (d, J=8.9 Hz, 1H, Ar—H), 7.02 (d, J=8.9 Hz, 1H, Ar—H), 7.41 (bs, 2H, NH2), 8.15 (s, 1H, purine-H); electrophile: 1-bromopentyl.
  • 11.3 8-(2,5-dimethoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine; 1H NMR (DMSO-d6) δ 1.89 (m, 2H, CH2), 2.20 (t, J=8.0 Hz, 2H, CH2), 2.78 (s, 1H, CH≡), 3.62 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 4.23 (t, J=7.4 Hz, 2H, CH2), 6.46 (s, 1H, Ar—H), 6.85 (d, J=8.9 Hz, 1H, Ar—H), 7.02 (d, J=8.9 Hz, 1H, Ar—H), 7.41 (bs, 2H, NH2), 8.15 (s, 1H, purine-H); electrophile: 1-chloro-pent-4-yne.
  • 11.4 4-[6-Amino-8(2,5-dimethoxysulfanyl)-purin-9-yl]-butyronitrile; 1H NMR (DMSO-d6) δ 1.89 (m, 2H, CH2), 2.20 (t, J=8.0 Hz, 2H, CH2), 3.62 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 4.23 (t, J=7.4 Hz, 2H, CH2), 6.46 (s, 1H, Ar—H), 6.85 (d, J=8.9 Hz, 1H, Ar—H), 7.02 (d, J=8.9 Hz, 1H, Ar—H), 7.41 (bs, 2H, NH2), 8.15 (s, 1H, purine-H); electrophile: 1-bromobutyronitrile.
  • 11.5 8-(2,5-dimethoxy-phenylsulfanyl)-9(3,3,3-trifluoromethylpropyl)-9H-purin-6-ylamine; 1H NMR (DMSO-d6) δ2.54 (t, J=8.0 Hz, 2H, CH2), 3.62 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 4.46 (t, J=8.0 Hz, 2H, CH2), 6.46 (s, 1H, Ar—H), 6.85 (d, J=8.9 Hz, 1H, Ar—H), 7.02 (d, J=8.9 Hz, 1H, Ar—H), 7.41 (bs, 2H, NH2), 8.30 (s, 1H, purine-H); electrophile: 1-bromo-3,3,3-trifluoro-propane.
  • 11.6 8-(2,5-dimethoxy-phenylsulfanyl)-9(4-chlorobutyl)-9H-purin-6-ylamine; 1H NMR (DMSO-d6) δ 1.82 (m, 2H, CH2), 1.98 (m, 2H, CH2), 3.56 (t, J=6.4 Hz, 2H, CH2), 3.75 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 4.23 (t, J=7.4 Hz, 2H, CH2), 6.46 (s, 1H, Ar—H), 6.85 (d, J=8.9 Hz, 1H, Ar—H), 7.02 (d, J=8.9 Hz, 1H, Ar—H), 7.41 (bs, 2H, NH2), 8.15 (s, 1H, purine-H); electrophile: 1-bromo-4-chlorobutane.
  • 11.7 8-(2,5-dimethoxy-phenylsulfanyl)-9(4-acetyloxybutyl)-9H-purin-6-ylamine; 1H NMR (DMSO-d6) δ1.70 (m, 2H, CH2), 1.90 (m, 2H, CH2), 2.02 (s, 3H, CH3), 3.75 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 4.10 (t, J=6.4 Hz, 2H, CH2), 4.30 (t, J=7.4 Hz, 2H, CH2), 6.46 (s, 1H, Ar—H), 6.85 (d, J=8.9 Hz, 1H, Ar—H), 7.02 (d, J=8.9 Hz, 1H, Ar—H), 7.41 (bs, 2H, NH2), 8.15 (s, 1H, purine-H); electrophile: 1-bromo-4-acetyloxybutane.
  • 11.8 8-(2,5-dimethoxy-phenylsulfanyl)-9(5-bromopentyl)-9H-purin-6-ylamine; 1H NMR (DMSO-d6) δ1.46 (m, 2H, CH2), 1.85 (m, 4H, 2CH2), 3.36 (t, J=6.7 Hz, 2H, CH2), 3.72 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 4.30 (t, J=7.4 Hz, 2H, CH2), 6.46 (s, 1H, Ar—H), 6.85 (d, J=8.9 Hz, 1H, Ar—H), 7.02 (d, J=8.9 Hz, 1H, Ar—H), 7.41 (bs, 2H, NH2), 8.15 (s, 1H, purine-H); electrophile: 1,5-dibromopentane.
  • 11.9 8-(2,5-dimethoxy-phenylsulfanyl)-9(2-[1,3]dioxolan-2-yl-ethyl)-9H-purin-6-ylamine; 1H NMR (DMSO-d6) δ 2.26 (m, 2H, CH2), 3.75 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.85 (t, J=7.0 Hz, 2H, CH2), 3.98 (t, J=7.0 Hz, 2H, CO2), 4.46 (t, J=7.4 Hz, 2H, CH2), 4.96 (t, J=4.1 Hz, 1H, CH), 6.46 (s, 1H, Ar—H), 6.85 (d, J=8.9 Hz, 1H, Ar—H), 7.02 (d, J=8.9 Hz, 1H, Ar—H), 7.41 (bs, 2H, NH2), 8.15 (s, 1H, purine-H); electrophile: 2-(2-Chloro-ethyl)-[1,3]dioxolane.
  • 11.10 8-(2,5-dimethoxy-phenylsulfanyl)-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylamine; 1H NMR (DMSO-d6) δ 1.28 (s, 3H, CH3), 1.54 (s, 3H, CH3), 2.35 (m, 2H, CH2), 3.60 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 4.15 (t, J=7.0 Hz, 2H, CH2), 5.05 (t, J=7 Hz, 1H, CH═), 6.46 (s, 1H, Ar—H), 6.86 (d, J=8.9 Hz, 1H, Ar—H), 7.02 (d, J=8.9 Hz, 1H, Ar—H), 7.42 (bs, 2H, NH2), 8.17 (s, 1H, purine-H); electrophile: 1-bromo-4-methyl-pent-3-ene; MP: 148-150° C.
  • 11.11 8-(2,5-dimethoxy-phenylsulfanyl)-9-(pent-4-enyl)-9H-purin-6-ylamine; 1H NMR (DMSO-d6) δ 1.89 (m, 2H, CH2), 2.19 (t, J=8.0 Hz, 2H, CH2), 3.62 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 4.23 (t, J=7.4 Hz, 2H, CH2), 5.05 (m, 2H, CH2═), 5.82 (m, 1H, CH═), 6.46 (s, 1H, Ar—H), 6.85 (d, J=8.9 Hz, 1H, Ar—H), 7.02 (d, J=8.9 Hz, 1H, Ar—H), 7.41 (bs, 2H, NH2), 8.15 (s, 1H, purine-H); electrophile: 1-chloro-pent-4-yne.
  • 11.12 8-(2,5-dimethoxy-phenylsulfanyl)-9-(3-hydroxypropyl)-9H-purin-6-ylamine; 1H NMR (DMSO-d6) δ 1.82 (m, 2H, CH2), 3.60 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 4.12 (m, 2H, CH2), 4.21 (t, J=7.0 Hz, 2H, CH2), 6.47 (s, 1H, Ar—H), 6.86 (d, J=8.9 Hz, 1H, Ar—H), 7.02 (d, J=8.9 Hz, 1H, Ar—H); 8.15 (s, 1H, purine-H; electrophile: 1-bromo-3-hydroxypropane.
  • Example 12
  • The compounds in this example were prepared using diazonium salts and thiols as coupling partners.
  • 12.1 9-Butyl-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine
  • Step 1: A suspension of 8-bromo-9-butyl-9H-purin-6-ylamine (0.50 g, 1.85 mmol) and thiourea (1.49 g, 19.6 mmol) in n-butanol (10 ml) was heated to reflux for 14 h. Dilution with CH2Cl2 (70 ml), washing with water and concentration afforded 6-amino-9-butyl-7,9-dihydro-purine-8-thione as a white powder (0.42 g, 1.87 mmol, 100%). 1H NMR (DMSO-d6) δ 12.35-12.25 (br. s, 1H), 8.13 (s, 1H), 6.92-6.72 (br. s., 2H), 4.09 (t, J=7.6 Hz, 2H), 1.71 (quint., J=7.5 Hz, 2H), 1.29 (sext., J=7.5 Hz, 2H), 0.87 (t, J=7.4 Hz, 3H).
  • Step 2: A solution of the above thione (30.8 mg, 0.138 mmol) and t-BuOK (15.5 mg, 0.138 mmol) in MeOH (0.55 ml) was treated portion-wise with crude 2-iodo-5-methoxy-benzenediazonium tetrafluoroborate (48 mg, 0.138 mmol). The vigorous N2 evolution ceased after 2 mm. Work-up and preparative TLC (MeOH:CH2Cl2 5:95) yielded the title sulfide.
  • 9-Butyl-8-(2-iodo-5-methoxy-benzyl)-9H-purin-6-ylamine; Rt=8.45 min; 1HNMR (CDCl3-d): δ 8.38 (s, 1H), 7.73 (d, J=8.7 Hz, 1H), 6.71 (d, J=2.7 Hz, 1H, 6.58 (dd, J=8.7, 2.7 Hz, 1H), 5.91 (s, 2H), 4.22 (t, J=7.4 Hz, 2H), 3.68 (s, 3H), 1.75 (quint., J=7.7 Hz, 2H), 1.34 (sext., J=7.5 Hz, 2H), 0.93 (t, J=7.4 Hz, 3H).
  • Example 13 Fluorescence-Based Competitive Binding Assay for Biotinylated-Geldanamycin to Purified Hsp90
  • This assay directly measures the binding of biotinylated-geldanamycin biotin-GM) to purified Hsp90 and thus tests the ability of compounds to compete for binding to Hsp90.
  • Purified native Hsp90 protein (mixture of alpha and beta) from HeLa cells (Stressgen Biotechnologies Corp., San Diego, Calif., USA) was coated onto 96-well plates by incubating for 1 hr at 37° C. Uncoated Hsp90 was removed and the wells washed twice in 1×PBS (phosphate-buffered saline) buffer. Biotin-GM was then added to the wells, and the reaction was further incubated for 1 hr 37° C. The wells were washed twice with 1×PBS, before the addition of 20 ug/ml streptavidin-phycoerythrin, and incubated for 1 hr at 37° C. The wells were again washed twice with 1×PBS. The fluorescence was then measured in a Gemini spectrofluorometer (Molecular Devices) using an excitation of 485 nm and emission of 580 nm.
  • The compounds in Table 4 were synthesized and evaluated for HSP90 binding ability based on the above assay:
  • TABLE 4
    Example # IC50 μM
    Figure US20080125446A1-20080529-C00011
    10
    Figure US20080125446A1-20080529-C00012
    2.0
    Figure US20080125446A1-20080529-C00013
    6
    Figure US20080125446A1-20080529-C00014
    2
    Figure US20080125446A1-20080529-C00015
    0.9
    Figure US20080125446A1-20080529-C00016
    1.5
    Figure US20080125446A1-20080529-C00017
    1.8
    Figure US20080125446A1-20080529-C00018
    4.0
    Figure US20080125446A1-20080529-C00019
    2.8
    Figure US20080125446A1-20080529-C00020
    1.1
    Figure US20080125446A1-20080529-C00021
    1.3
    Figure US20080125446A1-20080529-C00022
    1.1
    Figure US20080125446A1-20080529-C00023
    2.3
    Figure US20080125446A1-20080529-C00024
    0.9
    Figure US20080125446A1-20080529-C00025
    0.9
    Figure US20080125446A1-20080529-C00026
    0.8
  • Example 14 HER2 Inhibition Assay
  • MCF-7 cells are seeded in 24 well plates at a density of approximately 30,000 cells/well and allowed to grow for 16 hours in DMEM supplemented with 10% FBS. Drug is then added at a concentration range of 100 uM to 0.01 uM. Cells are incubated for an additional 24. Drug treated cells and untreated control cells are trypsinized, and incubated at room temperature for 15 minutes with anti Her-2 neu Ab conjugated with phycoerythrin (Becton Dickinson, San Jose Calif.; Cat no. 340552) at a concentration of 0.25 ug/ml, or non-specific control IgG1 conjugated with phycoerythrin (Becton Dickinson, San Jose Calif.; Cat no. 340761). Samples were analyzed using a FACS Calibur flow cytometer (Becton Dickinson) equipped with Argon-ion laser that which emits 15 mW of 488 nm light for excitation of the phycoerythrin fluorochrome. 10,000 events were collected per sample. A fluorescence histogram was generated and the mean fluorescence intensity (mfi) of each sample was determined using Cellquest software. The background was defined as the mfi generated from cells incubated with control IgG, and was subtracted from each sample stained with the HER-2/neu Ab. Percent degradation of Her-2 was calculated as follows:

  • %Her-2 degradation=(mfi HER-2 sample)/(mfi HER-2 untreated cells)×100
  • Table 5 summarizes the Her-2 degradation ability of various compounds of the invention:
  • TABLE 5
    Example # IC50 μM
    Figure US20080125446A1-20080529-C00027
    6.0
    Figure US20080125446A1-20080529-C00028
    1.0
    Figure US20080125446A1-20080529-C00029
    1.5
    Figure US20080125446A1-20080529-C00030
    0.6
    Figure US20080125446A1-20080529-C00031
    0.8
    Figure US20080125446A1-20080529-C00032
    1.5
    Figure US20080125446A1-20080529-C00033
    2.0
    Figure US20080125446A1-20080529-C00034
    1.4
    Figure US20080125446A1-20080529-C00035
    1.5
    Figure US20080125446A1-20080529-C00036
    0.5
    Figure US20080125446A1-20080529-C00037
    0.7
    Figure US20080125446A1-20080529-C00038
    1.5
    Figure US20080125446A1-20080529-C00039
    1.0
    Figure US20080125446A1-20080529-C00040
    0.8
    Figure US20080125446A1-20080529-C00041
    0.3
    Figure US20080125446A1-20080529-C00042
    0.3
  • Inhibitory Concentration 50 (IC50) for this assay is the concentration necessary to degrade 50% of Her 2 expression (protein).
  • The foregoing examples are not limiting and merely illustrative of various aspects and embodiments of the present invention. All documents cited herein are indicative of the levels of skill in the art to which the invention pertains and are incorporated by reference herein in their entireties. None, however, is admitted to be prior art.
  • One skilled in the art will readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The methods and compositions described illustrate preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Certain modifications and other uses will occur to those skilled in the art, and are encompassed within the spirit of the invention, as defined by the scope of the claims.
  • The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described, or portions thereof. It is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments, optional features, modifications and variations of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the description and the appended claims.
  • In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group, and exclusions of individual members as appropriate, or by proviso.
  • Other embodiments are within the following claims.

Claims (58)

1. A compound of formula
Figure US20080125446A1-20080529-C00043
or tautomer or pharmaceutically acceptable salt thereof,
wherein A is selected from H, halogen, CN, N3, NR1 2, NR1S(O)2R2, OR3, SR3, lower alkyl, C(O)N(R4)2, guanidine, amidine, NR1NR1 2, NR1OR4, and perhaloalkyl;
wherein Q is selected from alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl, and heterocyclic, all optionally substituted; e.g.,
Figure US20080125446A1-20080529-C00044
wherein X is selected from the group S, S(O), and S(O)2;
wherein Y is selected from the group consisting of H, C(O)R2, S(O)2R2, C(O)NR4 2, and C(O)OR2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alicyclic, optionally substituted araalkyl) optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl) optionally substituted heterocyclic alkylaminoalkyl, optionally substituted alkylcarbonylaminoalkyl, (—(CH2)n—C(O)—NR4—(CH2)n), optionally substituted alkylcarbonyloxyalkyl (—(CH2)n—C(O)—O—(CH2)n), hydroxyalkyl, haloalkyl, perhaloalkyl, C(O)R2, S(O)2R2, C(O)NR4 2, and C(O)OR2;
wherein Y is selected from the group consisting of H, optionally substituted alkyl) optionally substituted alkenyl) optionally substituted alkynyl, optionally substituted aryl, optionally substituted alicyclic, optionally substituted araalkyl, optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl, alkylaminoalkyl, allylcarbonylaminoalkyl (—(CH2)n—C(O)—NR4—(CH2)n), alkylcarbonyloxyalkyl (—(CH2)n—C(O)—O—(CH2)n), optionally substituted heterocyclic, hydroxyalkyl, haloalkyl, perhaloalkyl, C(O)R2, S(O)2R2, C(O)NR4 2) and C(O)OR2;
wherein Z is selected from the group consisting of H, halogen, CN)OR3, SR3, 7perhaloalkyl, optionally substituted alkyl) optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alicyclic, optionally substituted araalkyl, optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl, optionally substituted heterocyclic C(O)R2, S(O)2R2, guanidine, amidine, and C(O)NR4 2;
wherein R1 is independently selected from H, optionally substituted alkyl) optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclic, C(O)R2, —C(O)OR2, C(O)NR4 2, C(S)OR2, C(S)NR2 2, PO3R4, SO2R2;
wherein R2 is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclic, heteroaryl, and aryl, all optionally substituted;
wherein R3 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclic and C(O)NR4 2;
wherein R4 is independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, and optionally substituted heterocyclic;
wherein R5 is selected from H, OH, and optionally substituted alkyl; and
wherein R6 is independently selected from H, optionally substituted alkyl, OR3, SR3, NHR3, C(O)NR4 2, (O)R5, NO2, CN, halogen, and S(O)2R2, and wherein n is from 1 to 3.
2. The compound, tautomer, or pharmaceutically acceptable salt of claim 1 wherein A is further selected from the group consisting of H, halogen, NR1 2, OR3, SR3, optionally substituted lower alkyl, and C(O)N(R4)2.
3. The compound, tautomer, or pharmaceutically acceptable salt of claim 1 wherein Z is further selected from the group consisting of H, halogen, CN, OR3, SR3, optionally substituted lower perhaloalkyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, and optionally substituted lower aryl;
4. The compound, tautomer, or pharmaceutically acceptable salt of claim 1 wherein X is further selected from S and S(O) (sulfoxide).
5. The compound, tautomer, or pharmaceutically acceptable salt of claim 1 wherein Y is further selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower aryl, and optionally substituted lower alicyclic.
6. The compound, tautomer, or pharmaceutically acceptable salt of claim 1 wherein Q is further selected from optionally substituted aryl and optionally substituted heteroaryl.
7. The compound, tautomer, or pharmaceutically acceptable salt of claim 1 wherein X is S;
wherein A is selected from the group consisting of Cl, NH2, and CH3;
wherein Z is selected from the group consisting of H, F, Cl, Br and CF3;
wherein Y is selected from the group consisting of optionally substituted C3-C8 alkyl, optionally substituted C3-C8 alkenyl, optionally substituted C3-C8 alkynyl, optionally substituted C1-C10 lower aryl, and optionally substituted C3-C10 alicyclic; and
wherein Q is selected from the group consisting of optionally substituted aryl optionally substituted heterocyclic, and optionally substituted heteroaryl, e.g.,
Figure US20080125446A1-20080529-C00045
wherein R1 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclic, C(O)R2, —C(O)OR2, C(O)NR42, C(S)OR2, C(S)NR42, SO2R2, PO3R4;
wherein R5 is selected from H, OH, and optionally substituted alkyl;
wherein R6 is independently selected from H, optionally substituted alkyl, aryl, OR3; SR3, NR3 2, C(O)R5, NO2, CN, and halogen, and
wherein R3 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclic and C(O)NR4 2.
8. The compound, tautomer, or pharmaceutically acceptable salt of claim 7, wherein A is NH2; Z is selected from H, Cl and F; Y is selected from —(CH2)2CH═C(CH3)2, —(CH2)3CCH, —(CH2)4Br, —(CH2)4Cl, —(CH2)4OAc, —(CH2)4NHEt, —(CH2)4OH, —(CH2)5Br, —(CH2)5Cl, —(CH2)OAc, —(CH2)2—OiPr, and —(CH2)5OH; and Q is selected from 2,5-dimethoxyphenyl, 2-iodo-5-methoxyphenyl, 4-iodo-5-methoxyphenyl, 2-iodo-4-fluoro-5-methoxyphenyl, 2-bromo-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 2-iodo-4-iodo-5-methoxyphenyl, 2-iodo-4-bromo-5-methoxyphenyl, 2-iodo-4-chloro-5-methoxyphenyl, and 2-chloro-3,4,5-trimethoxyphenyl.
9. (canceled)
10. (canceled)
11. (canceled)
12. (canceled)
13. (canceled)
14. (canceled)
15. (canceled)
16. (canceled)
17. (canceled)
18. (canceled)
19. A pharmaceutical composition comprising the compound, tautomer, or pharmaceutically acceptable salt of claim 1 and one or more pharmaceutical carriers or excipients.
20. A method of inhibiting an HSP90, comprising:
contacting a cell having an HSP90 with a compound, tautomer or pharmaceutically acceptable salt or pharmaceutical composition according to claim 1.
21. (canceled)
22. (canceled)
23. (canceled)
24. (canceled)
25. (canceled)
26. (canceled)
27. (canceled)
28. (canceled)
29. (canceled)
30. (canceled)
31. (canceled)
32. (canceled)
33. (canceled)
34. (canceled)
35. (canceled)
36. (canceled)
37. (canceled)
38. (canceled)
39. (canceled)
40. (canceled)
41. (canceled)
42. (canceled)
43. (canceled)
44. (canceled)
45. (canceled)
46. (canceled)
47. (canceled)
48. (canceled)
49. (canceled)
50. A complex comprising the compound, tautomer, or pharmaceutically acceptable salt of claim 1 and at least one other compound.
51. The complex of claim 50 wherein one of said at least one other compound is an HSP90.
52. The complex of claim 51 wherein said HSP90 is human.
53. (canceled)
54. (canceled)
55. (canceled)
56. (canceled)
57. (canceled)
58. (canceled)
US11/772,496 2001-10-30 2007-07-02 Purine analogs having HSP90-inhibiting activity Abandoned US20080125446A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/772,496 US20080125446A1 (en) 2001-10-30 2007-07-02 Purine analogs having HSP90-inhibiting activity

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US33539101P 2001-10-30 2001-10-30
US10/494,414 US7241890B2 (en) 2001-10-30 2002-10-30 Purine analogs having HSP90-inhibiting activity
PCT/US2002/035069 WO2003037860A2 (en) 2001-10-30 2002-10-30 Purine analogs having hsp90-inhibiting activity
US11/772,496 US20080125446A1 (en) 2001-10-30 2007-07-02 Purine analogs having HSP90-inhibiting activity

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US10/494,414 Continuation US7241890B2 (en) 2001-10-30 2002-10-30 Purine analogs having HSP90-inhibiting activity
PCT/US2002/035069 Continuation WO2003037860A2 (en) 2001-10-30 2002-10-30 Purine analogs having hsp90-inhibiting activity

Publications (1)

Publication Number Publication Date
US20080125446A1 true US20080125446A1 (en) 2008-05-29

Family

ID=23311571

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/494,414 Expired - Lifetime US7241890B2 (en) 2001-10-30 2002-10-30 Purine analogs having HSP90-inhibiting activity
US11/772,496 Abandoned US20080125446A1 (en) 2001-10-30 2007-07-02 Purine analogs having HSP90-inhibiting activity

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US10/494,414 Expired - Lifetime US7241890B2 (en) 2001-10-30 2002-10-30 Purine analogs having HSP90-inhibiting activity

Country Status (6)

Country Link
US (2) US7241890B2 (en)
EP (2) EP1440072A4 (en)
JP (1) JP4397691B2 (en)
AU (1) AU2002343604C1 (en)
CA (1) CA2464031A1 (en)
WO (1) WO2003037860A2 (en)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090202626A1 (en) * 2008-02-07 2009-08-13 Carson Dennis A Treatment of bladder diseases with a tlr7 activator
US20090324551A1 (en) * 2005-08-22 2009-12-31 The Regents Of The University Of California Office Of Technology Transfer Tlr agonists
US20100210598A1 (en) * 2009-02-11 2010-08-19 Regents Of The University Of California, San Diego Toll-like receptor modulators and treatment of diseases
US20110098294A1 (en) * 2006-05-31 2011-04-28 Carson Dennis A Purine analogs
WO2011060253A2 (en) * 2009-11-13 2011-05-19 Myrexis, Inc. Methods of treating diseases, pharmaceutical compositions, and pharmaceutical dosage forms
US8357374B2 (en) 2007-02-07 2013-01-22 The Regents Of The University Of California Conjugates of synthetic TLR agonists and uses therefor
US9050319B2 (en) 2010-04-30 2015-06-09 Telormedix, Sa Phospholipid drug analogs
US9066940B2 (en) 2009-02-06 2015-06-30 Telormedix, Sa Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration
US9173935B2 (en) 2010-04-30 2015-11-03 Telormedix Sa Phospholipid drug analogs
WO2017123766A1 (en) * 2016-01-12 2017-07-20 Sperovie Biosciences, Inc. Compounds and compositions for the treatment of disease
US11697851B2 (en) 2016-05-24 2023-07-11 The Regents Of The University Of California Early ovarian cancer detection diagnostic test based on mRNA isoforms

Families Citing this family (87)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7439359B2 (en) * 2000-11-02 2008-10-21 Sloan-Kettering Institute For Cancer Research Small molecule compositions for binding to hsp90
US6872715B2 (en) 2001-08-06 2005-03-29 Kosan Biosciences, Inc. Benzoquinone ansamycins
EP1440072A4 (en) * 2001-10-30 2005-02-02 Conforma Therapeutic Corp Purine analogs having hsp90-inhibiting activity
WO2003066005A2 (en) 2002-02-08 2003-08-14 Conforma Therapeutics Corporation Ansamycins having improved pharmacological and biological properties
US20050020556A1 (en) * 2003-05-30 2005-01-27 Kosan Biosciences, Inc. Method for treating diseases using HSP90-inhibiting agents in combination with platinum coordination complexes
US7691838B2 (en) * 2003-05-30 2010-04-06 Kosan Biosciences Incorporated Method for treating diseases using HSP90-inhibiting agents in combination with antimitotics
GB0320300D0 (en) * 2003-08-29 2003-10-01 Cancer Rec Tech Ltd Pyrimidothiophene compounds
AU2004268820B2 (en) 2003-08-29 2011-07-21 Cancer Research Technology Ltd Pyrimidothiophene compounds
CA2539548A1 (en) 2003-09-18 2005-03-31 Conforma Therapeutics Corporation Novel heterocyclic compounds as hsp90-inhibitors
WO2005033079A1 (en) * 2003-09-30 2005-04-14 Eisai Co., Ltd. Novel antifungal agent comprising heterocyclic compound
GB0323810D0 (en) * 2003-10-10 2003-11-12 Cancer Rec Tech Ltd Pyridothiophene compounds
EP1704856A4 (en) * 2003-12-26 2009-08-19 Kyowa Hakko Kirin Co Ltd Hsp90 family protein inhibitor
GB0416168D0 (en) * 2004-07-20 2004-08-18 Vernalis Cambridge Ltd Pyrmidothiophene compounds
WO2006025490A1 (en) * 2004-09-01 2006-03-09 Mitsubishi Pharma Corporation Molecular chaperone function regulator
US7834181B2 (en) 2005-02-01 2010-11-16 Slaon-Kettering Institute For Cancer Research Small-molecule Hsp90 inhibitors
US9403828B2 (en) 2005-02-01 2016-08-02 Sloan-Kettering Institute For Cancer Research Small-molecule Hsp90 inhibitors
AU2006223070B2 (en) * 2005-03-14 2012-02-09 High Point Pharmaceuticals, Llc Benzazole derivatives, compositions, and methods of use as B-secretase inhibitors
BRPI0609509A2 (en) * 2005-03-30 2010-04-13 Conforma Therapeutics Corp pharmaceutically acceptable compound or a polymorph, solvate, tautomer, enantiomer, prodrug or salt thereof, pharmaceutical composition, and, use of the pharmaceutically acceptable compound, polymorph, solvate, tautomer, enantiomer, prodrug or salt
WO2006130469A1 (en) * 2005-05-27 2006-12-07 Oregon Health & Science University Stimulation of neurite outgrowth by small molecules
DE102005037733A1 (en) * 2005-08-10 2007-02-15 Merck Patent Gmbh adenine
GB0519245D0 (en) * 2005-09-20 2005-10-26 Vernalis R&D Ltd Purine compounds
WO2007035963A2 (en) * 2005-09-23 2007-03-29 Conforma Therapeutics Corporation Anti-tumor methods using multi drug resistance independent synthetic hsp90 inhibitors
TWI385169B (en) 2005-10-31 2013-02-11 Eisai R&D Man Co Ltd Heterocyclic substituted pyridine derivatives and antifungal agent containing same
WO2007075572A2 (en) * 2005-12-22 2007-07-05 Conforma Therapeutics Corporation Orally active purine-based inhibitors of heat shock protein 90
PE20080145A1 (en) 2006-03-21 2008-02-11 Janssen Pharmaceutica Nv TETRAHYDRO-PYRIMIDOAZEPINE AS MODULATORS OF TRPV1
JP2009536960A (en) * 2006-05-12 2009-10-22 ミリアド ジェネティクス, インコーポレイテッド Therapeutic compounds and their use in cancer
AR061185A1 (en) 2006-05-26 2008-08-13 Chugai Pharmaceutical Co Ltd HETEROCICLICAL COMPOUNDS AS INHIBITORS OF HSP90. PHARMACEUTICAL COMPOSITIONS.
DK2034839T3 (en) * 2006-06-30 2017-12-04 Sloan-Kettering Institute For Cancer Res TREATMENT OF NEURODEGENERATIVE DISEASES BY INHIBITION OF HSP90
WO2008035726A1 (en) 2006-09-21 2008-03-27 Eisai R & D Management Co., Ltd. Pyridine derivative substituted by heteroaryl ring, and antifungal agent comprising the same
WO2008045529A1 (en) * 2006-10-12 2008-04-17 Serenex, Inc. Purine and pyrimidine derivatives for treatment of cancer and inflammatory diseases
CL2007002994A1 (en) * 2006-10-19 2008-02-08 Wyeth Corp HETEROCICLIC DERIVATIVE COMPOUNDS CONTAINING SULFAMOIL, INHIBITORS OF HSP90; PHARMACEUTICAL COMPOSITION; AND USE FOR THE TREATMENT OF CANCER, SUCH AS CANCER OF BREAST, COLON AND PROSTATE, BETWEEN OTHERS.
GB0622084D0 (en) 2006-11-06 2006-12-13 Chroma Therapeutics Ltd Inhibitors of HSP90
JP2010514672A (en) * 2006-12-29 2010-05-06 武田薬品工業株式会社 Fused heterocyclic compounds having CRF antagonist activity
US7799781B2 (en) 2007-02-01 2010-09-21 Astrazeneca Ab 5,6,7,8-tetrahydropteridine derivatives as HSP90 inhibitors
TW200904435A (en) 2007-03-01 2009-02-01 Chugai Pharmaceutical Co Ltd Macrocyclic compounds
JP5401329B2 (en) * 2007-03-20 2014-01-29 キュリス,インコーポレイテッド Condensed aminopyridines as HSP90 inhibitors
WO2008115262A2 (en) * 2007-03-20 2008-09-25 Curis, Inc. Hsp90 inhibitors containing a zinc binding moiety
TW200841879A (en) 2007-04-27 2008-11-01 Eisai R&D Man Co Ltd Pyridine derivatives substituted by heterocyclic ring and phosphonoamino group, and anti-fungal agent containing same
CN101622251B (en) 2007-04-27 2012-07-04 卫材R&D管理有限公司 Salt of heterocycle-substituted pyridine derivative or crystal thereof
WO2009007399A1 (en) * 2007-07-12 2009-01-15 Crystax Pharmaceuticals, S.L. New compounds as hsp90 inhibitors
US8119616B2 (en) * 2007-09-10 2012-02-21 Curis, Inc. Formulation of quinazoline based EGFR inhibitors containing a zinc binding moiety
GB2467670B (en) 2007-10-04 2012-08-01 Intellikine Inc Chemical entities and therapeutic uses thereof
EP2224929B1 (en) 2007-12-17 2016-05-04 Janssen Pharmaceutica, N.V. Imidazolo-, oxazolo-, and thiazolopyrimidine modulators of trpv1
US20090156598A1 (en) * 2007-12-17 2009-06-18 Lebsack Alec D Imidazolopyrimidine modulators of TRPV1
US8513287B2 (en) 2007-12-27 2013-08-20 Eisai R&D Management Co., Ltd. Heterocyclic ring and phosphonoxymethyl group substituted pyridine derivatives and antifungal agent containing same
US8895701B2 (en) 2008-01-05 2014-11-25 Sloan-Kettering Institute For Cancer Research Peptide-conjugated oligonucleotide therapeutic and method of making and using same
US8637542B2 (en) 2008-03-14 2014-01-28 Intellikine, Inc. Kinase inhibitors and methods of use
US8993580B2 (en) 2008-03-14 2015-03-31 Intellikine Llc Benzothiazole kinase inhibitors and methods of use
LT5623B (en) 2008-04-30 2010-01-25 Biotechnologijos Institutas, , 5-aryl-4-(5-substituted 2,4-dihydroxyfenil)-1,2,3-thiadiazoles as inhibitors of hsp90 chaperone and the intermediates for production thereof
US9096611B2 (en) 2008-07-08 2015-08-04 Intellikine Llc Kinase inhibitors and methods of use
US8188119B2 (en) 2008-10-24 2012-05-29 Eisai R&D Management Co., Ltd Pyridine derivatives substituted with heterocyclic ring and γ-glutamylamino group, and antifungal agents containing same
US8476282B2 (en) 2008-11-03 2013-07-02 Intellikine Llc Benzoxazole kinase inhibitors and methods of use
NZ594414A (en) * 2009-01-16 2013-08-30 Curis Inc Fused amino pyridines for the treatment of brain tumors
US9328114B2 (en) * 2009-10-07 2016-05-03 Sloan-Kettering Institute For Cancer Research Hsp90 inhibitors
CN106619647A (en) 2011-02-23 2017-05-10 因特利凯有限责任公司 Combination of mtor inhibitors and pi3-kinase inhibitors and uses thereof
MX360390B (en) 2011-04-05 2018-10-31 Sloan Kettering Inst Cancer Res Hsp90 inhibitors.
MX354215B (en) 2011-04-05 2018-02-19 Sloan Kettering Inst Cancer Res Hsp90 inhibitors.
JP2015531395A (en) 2012-10-04 2015-11-02 ファイザー・リミテッドPfizer Limited Pyrrolo [3,2-C] pyridine tropomyosin-related kinase inhibitor
BR112015019276A2 (en) 2013-02-19 2017-07-18 Pfizer azabenzimidazole compounds as inhibitors of pde4 isoenzymes for the treatment of snc disorders and other disorders
KR102319582B1 (en) * 2013-08-16 2021-11-04 메모리얼 슬로안 케터링 캔서 센터 Selective grp94 inhibitors and uses thereof
EP3172210B1 (en) 2014-07-24 2020-01-15 Pfizer Inc Pyrazolopyrimidine compounds
PT3177624T (en) 2014-08-06 2019-07-11 Pfizer Imidazopyridazine compounds
MD3483164T2 (en) 2017-03-20 2020-07-31 Forma Therapeutics Inc Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators
US10508115B2 (en) 2017-08-16 2019-12-17 Bristol-Myers Squibb Company Toll-like receptor 7 (TLR7) agonists having heteroatom-linked aromatic moieties, conjugates thereof, and methods and uses therefor
US10457681B2 (en) 2017-08-16 2019-10-29 Bristol_Myers Squibb Company Toll-like receptor 7 (TLR7) agonists having a tricyclic moiety, conjugates thereof, and methods and uses therefor
US10472361B2 (en) 2017-08-16 2019-11-12 Bristol-Myers Squibb Company Toll-like receptor 7 (TLR7) agonists having a benzotriazole moiety, conjugates thereof, and methods and uses therefor
US10494370B2 (en) 2017-08-16 2019-12-03 Bristol-Myers Squibb Company Toll-like receptor 7 (TLR7) agonists having a pyridine or pyrazine moiety, conjugates thereof, and methods and uses therefor
US10487084B2 (en) 2017-08-16 2019-11-26 Bristol-Myers Squibb Company Toll-like receptor 7 (TLR7) agonists having a heterobiaryl moiety, conjugates thereof, and methods and uses therefor
CN107573346A (en) * 2017-09-29 2018-01-12 华南理工大学 N9 is alkylated the simple synthesis of nucleoside analog on a kind of purine skeleton
KR101937054B1 (en) 2017-10-18 2019-01-09 계명대학교 산학협력단 Composition for preventing or treating for breast cancer
WO2019209811A1 (en) 2018-04-24 2019-10-31 Bristol-Myers Squibb Company Macrocyclic toll-like receptor 7 (tlr7) agonists
US11554120B2 (en) 2018-08-03 2023-01-17 Bristol-Myers Squibb Company 1H-pyrazolo[4,3-d]pyrimidine compounds as toll-like receptor 7 (TLR7) agonists and methods and uses therefor
CN113226356A (en) 2018-09-19 2021-08-06 福马治疗股份有限公司 Activating pyruvate kinase R
CN113166060B (en) 2018-09-19 2024-01-09 诺沃挪第克健康护理股份公司 Treatment of sickle cell disease with pyruvate kinase-activating compounds
KR20220132590A (en) 2020-01-27 2022-09-30 브리스톨-마이어스 스큅 컴퍼니 1H-pyrazolo[4,3-d]pyrimidine compounds as toll-like receptor 7 (TLR7) agonists
WO2021154668A1 (en) 2020-01-27 2021-08-05 Bristol-Myers Squibb Company 1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS
CN115210236A (en) 2020-01-27 2022-10-18 百时美施贵宝公司 1H-pyrazolo [4,3-d ] pyrimidine compounds as Toll-like receptor 7 (TLR 7) agonists
US20230144824A1 (en) 2020-01-27 2023-05-11 Bristol-Myers Squibb Company 1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS
KR20220132594A (en) 2020-01-27 2022-09-30 브리스톨-마이어스 스큅 컴퍼니 1H-pyrazolo[4,3-d]pyrimidine compounds as toll-like receptor 7 (TLR7) agonists
JP2023512206A (en) 2020-01-27 2023-03-24 ブリストル-マイヤーズ スクイブ カンパニー 1H-pyrazolo[4,3-d]pyrimidine compounds as Toll-like receptor 7 (TLR7) agonists
WO2021154664A1 (en) 2020-01-27 2021-08-05 Bristol-Myers Squibb Company 1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS
KR20220132595A (en) 2020-01-27 2022-09-30 브리스톨-마이어스 스큅 컴퍼니 C3-substituted 1H-pyrazolo[4,3-d]pyrimidine compounds as toll-like receptor 7 (TLR7) agonists
CN115210235A (en) 2020-01-27 2022-10-18 百时美施贵宝公司 1H-pyrazolo [4,3-d ] pyrimidine compounds as Toll-like receptor 7 (TLR 7) agonists
EP4146639A1 (en) 2020-05-06 2023-03-15 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors
US12043632B2 (en) 2020-12-23 2024-07-23 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US12128035B2 (en) 2021-03-19 2024-10-29 Novo Nordisk Health Care Ag Activating pyruvate kinase R
US11970494B2 (en) 2021-11-09 2024-04-30 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors

Citations (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4294831A (en) * 1974-09-02 1981-10-13 Burroughs Wellcome Co. Purine derivatives
US4495190A (en) * 1980-12-22 1985-01-22 Astra Lakemedel Aktiebolag Derivatives of guanine for combating herpes virus infections
US4547573A (en) * 1983-12-02 1985-10-15 Ici Pharma Process for preparing cephalosporin derivatives
US4617304A (en) * 1984-04-10 1986-10-14 Merck & Co., Inc. Purine derivatives
US4748177A (en) * 1984-03-26 1988-05-31 Warner-Lambert Company Guanine derivatives
US4772606A (en) * 1985-08-22 1988-09-20 Warner-Lambert Company Purine derivatives
US4774325A (en) * 1984-09-20 1988-09-27 Pierrel Spa New 8-substituted nucleoside and purine derivatives, the process for the preparation thereof and the pharmaceutical compositions containing them
US4806642A (en) * 1984-10-05 1989-02-21 Warner-Lambert Company Purine derivatives
US4971972A (en) * 1989-03-23 1990-11-20 Schering Corporation Phosphodiesterase inhibitors having an optionally substituted purine derivative portion and a benzo- or cyclopenta-furan portion
US5002950A (en) * 1986-10-24 1991-03-26 Warner-Lambert Co. 7-deazaguanines as immunomodulators
US5110818A (en) * 1988-10-06 1992-05-05 Ciba-Geigy Corporation Anticonvulsive substituted-9-benzyl-9h-purines
US5217866A (en) * 1985-03-15 1993-06-08 Anti-Gene Development Group Polynucleotide assay reagent and method
US5332744A (en) * 1989-05-30 1994-07-26 Merck & Co., Inc. Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
US5602156A (en) * 1993-09-17 1997-02-11 The United States Of America As Represented By The Department Of Health And Human Services Method for inhibiting metalloproteinase expression
US5789394A (en) * 1992-12-23 1998-08-04 Nguyen-Ba; Nghe Anti-viral compounds
US5861503A (en) * 1997-04-30 1999-01-19 The Regents Of The University Of California Process for producing 8-fluoropurines
US5917042A (en) * 1994-02-04 1999-06-29 Glaxo Wellcome Inc. Process for the preparation of 2,5-diamino-4,6-dichloropyrimidine
US5994361A (en) * 1994-06-22 1999-11-30 Biochem Pharma Substituted purinyl derivatives with immunomodulating activity
US6143743A (en) * 1997-07-03 2000-11-07 Dupont Pharmaceuticals Company Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders
US6333331B1 (en) * 1994-08-01 2001-12-25 The United States Of America As Represented By The Department Of Health And Human Services Substituted O6-benzylguanines
US6369092B1 (en) * 1998-11-23 2002-04-09 Cell Pathways, Inc. Method for treating neoplasia by exposure to substituted benzimidazole derivatives
US20020156277A1 (en) * 2001-04-20 2002-10-24 Fick David B. Synthesis and methods of use of purine analogues and derivatives
US20020161014A1 (en) * 2000-04-25 2002-10-31 Chanchal Sadhu Inhibitors of human phosphatidylinositol 3-kinase delta
US20030022864A1 (en) * 2001-04-24 2003-01-30 Ishaq Khalid S. 9-[(5-dihydroxyboryl)-pentyl] purines, useful as an inhibitor of inflammatory cytokines
US6723727B1 (en) * 1996-12-20 2004-04-20 Hoechst Aktiengesellschaft Substituted purine derivatives, processes for their preparation, their use, and compositions comprising them
US20040102458A1 (en) * 2000-11-02 2004-05-27 Gabriela Chiosis Small molecule compositions for binding to hsp90
US7129244B2 (en) * 2003-09-18 2006-10-31 Conforma Therapeutics Corporation Triazolopyrimidines and related analogs as HSP90-inhibitors
US7129239B2 (en) * 2002-10-28 2006-10-31 Pfizer Inc. Purine compounds and uses thereof
US20070129334A1 (en) * 2001-10-30 2007-06-07 Conforma Therapeutics Corporation Orally Active Purine-Based Inhibitors of Heat Shock Protein 90
US7241890B2 (en) * 2001-10-30 2007-07-10 Conforma Therapeutics Corporation Purine analogs having HSP90-inhibiting activity
US20070299258A1 (en) * 2006-05-12 2007-12-27 Myriad Genetics, Incorporated Therapeutic compounds and their use in cancer
US20080253965A1 (en) * 2005-02-01 2008-10-16 Sloan-Kettering Institute For Cancer Research Small-Molecule Hsp90 Inhibitors

Family Cites Families (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US107343A (en) * 1870-09-13 Improved spool show-case
US62A (en) * 1836-10-20 Cooking-stove
US22864A (en) * 1859-02-08 Improvement in the manufacture of cast-steel
US113339A (en) * 1871-04-04 Improvement in apparatus for stripping the top-flats of carding-machines
US113340A (en) * 1871-04-04 Improvement in combs
US78413A (en) * 1868-06-02 bashore
US156277A (en) * 1874-10-27 Improvement in lock-hinges
US161014A (en) * 1875-03-23 Improvement in miter-boxes
US119282A (en) * 1871-09-26 Improvement in machines for stone polishing
US4699877A (en) 1982-11-04 1987-10-13 The Regents Of The University Of California Methods and compositions for detecting human tumors
US4921859A (en) 1983-10-31 1990-05-01 Warner-Lambert Company Purine derivatives
US5098906A (en) 1983-10-31 1992-03-24 Warner-Lambert Company Purine derivatives
DE3578499D1 (en) 1984-02-02 1990-08-09 Merck & Co Inc 5- (AMINO OR SUBSTITUTED AMINO) -1,2,3-TRIAZOLE.
IL76546A (en) 1984-10-12 1988-12-30 Warner Lambert Co 9-(heteroarylalkyl)-6-purine(thi)one derivatives,their preparation and pharmaceutical compositions containing them
JO1406B1 (en) 1984-11-02 1986-11-30 سميث كلاين اند فرينش لابوراتوريز ليمتد Chemical compounds
ATE171185T1 (en) 1985-03-15 1998-10-15 Antivirals Inc POLYNUCLEOTIDE IMMUNOTESTING AGENTS AND METHODS
GB8515934D0 (en) 1985-06-24 1985-07-24 Janssen Pharmaceutica Nv (4-piperidinomethyl and-hetero)purines
US4918162A (en) 1986-05-06 1990-04-17 The Regents Of The University Of California Assays and antibodies for N-MYC proteins
US4968603A (en) 1986-12-31 1990-11-06 The Regents Of The University Of California Determination of status in neoplastic disease
US5204353A (en) 1987-04-07 1993-04-20 Ciba-Geigy Corporation 3-benzyl-3H-1,2,3-triazolo[4,5-d]pyrimidines, compositions thereof, and method of treating epilepsy therewith
SE8801729D0 (en) 1988-05-06 1988-05-06 Astra Ab PURINE DERIVATIVES FOR USE IN THERAPY
US4923885A (en) 1988-08-19 1990-05-08 Merck & Co., Inc. 5-amino-1-(4-naphthoylbenzyl)-1,2,3-triazole-4-carboxamides and analogs as antiproliferative agents
DE69116750T2 (en) 1990-07-04 1996-11-14 Merrell Dow Pharma 9-purinyl-phosphonic acid derivatives
GB9020931D0 (en) 1990-09-26 1990-11-07 Wellcome Found Heterocyclic compounds
DE69230349T2 (en) 1991-03-05 2000-07-27 Ajinomoto Co., Inc. Cyclopropane derivative
CA2093403C (en) 1992-04-08 1999-08-10 Fumio Suzuki Therapeutic agent for parkinson's disease
JPH0680670A (en) 1992-09-03 1994-03-22 Ajinomoto Co Inc Cyclopropane derivative and its production
US6005107A (en) 1992-12-23 1999-12-21 Biochem Pharma, Inc. Antiviral compounds
US5744492A (en) 1993-09-17 1998-04-28 United States Of America Method for inhibiting angiogenesis
JP3769737B2 (en) 1994-03-30 2006-04-26 味の素株式会社 Cyclopropane derivative and process for producing the same
JPH0841035A (en) 1994-08-05 1996-02-13 Ajinomoto Co Inc Cyclopropane derivative and its production
US5846749A (en) 1994-10-12 1998-12-08 The Regents Of The University Of California Quantitative measurement of tissue protein identified by immunohistochemistry and standardized protein determination
JPH08208687A (en) 1994-11-25 1996-08-13 Sankyo Co Ltd Glyceryl oligonucleotide
US5656629A (en) 1995-03-10 1997-08-12 Sanofi Winthrop, Inc. 6-substituted pyrazolo (3,4-d)pyrimidin-4-ones and compositions and methods of use thereof
JPH0920776A (en) 1995-06-30 1997-01-21 Nippon Paper Ind Co Ltd New purine nucleoside derivative, its production and antiviral agent with the same as active ingredient
JPH09169758A (en) 1995-10-18 1997-06-30 Nippon Paper Ind Co Ltd New purine nucleoside derivative, its production and antivirus using the same
JPH1025294A (en) 1996-03-26 1998-01-27 Akira Matsuda Condensed heterocyclic derivative, its production and malignant tumor therapeutic agent containing the same
ZA975946B (en) 1996-07-03 1998-04-16 Japan Energy Corp Purine derivative.
AU6452098A (en) 1997-03-07 1998-09-22 Metabasis Therapeutics, Inc. Novel purine inhibitors of fructose-1,6-bisphosphatase
JP4903922B2 (en) 1997-05-14 2012-03-28 スローン − ケッタリング インスティチュート フォー キャンサー リサーチ Complex compounds that degrade selected proteins
DE69832715T2 (en) 1997-07-12 2007-01-11 Cancer Research Technology Ltd. CYCLINE-DEPENDENT KINASE INHIBITING PURE DERIVATIVES
AUPO912997A0 (en) 1997-09-11 1997-10-02 Commonwealth Scientific And Industrial Research Organisation Antiviral agents
US5968921A (en) 1997-10-24 1999-10-19 Orgegon Health Sciences University Compositions and methods for promoting nerve regeneration
CA2309350C (en) 1997-11-12 2007-04-03 Mitsubishi Chemical Corporation Purine derivatives and medicaments comprising the same as active ingredient
TW572758B (en) 1997-12-22 2004-01-21 Sumitomo Pharma Type 2 helper T cell-selective immune response inhibitors comprising purine derivatives
WO1999051223A1 (en) 1998-04-03 1999-10-14 University Of Pittsburgh Of The Commonwealth System Of Higher Education Benzoquinoid ansamycins for the treatment of cardiac arrest and stroke
JP2000072773A (en) 1998-08-28 2000-03-07 Zeria Pharmaceut Co Ltd Purine derivative
CZ27399A3 (en) 1999-01-26 2000-08-16 Ústav Experimentální Botaniky Av Čr Substituted nitrogen heterocyclic derivatives process of their preparation, the derivatives employed as medicaments, pharmaceutical composition and a compound pharmaceutical preparation in which these derivatives are comprised as well as use of these derivatives for preparing medicaments
KR20010093308A (en) 1999-02-01 2001-10-27 씨브이 쎄러퓨틱스, 인코포레이티드 PURINE INHIBITORS OF CYCLIN DEPENDENT KINASE 2 AND Iκ-Aα
FR2790702B1 (en) 1999-03-08 2001-07-20 Sidel Sa MOLDING UNIT AND EXTRUSION-BLOWING MACHINE PROVIDED WITH SUCH A UNIT
US6174875B1 (en) 1999-04-01 2001-01-16 University Of Pittsburgh Benzoquinoid ansamycins for the treatment of cardiac arrest and stroke
AU4589800A (en) 1999-05-05 2000-11-21 Darwin Discovery Limited 9-(1,2,3,4-tetrahydronaphthalen-1-yl)-1,9-dihydropurin-6-one derivatives as pde7inhibitors
US6660845B1 (en) 1999-11-23 2003-12-09 Epoch Biosciences, Inc. Non-aggregating, non-quenching oligomers comprising nucleotide analogues; methods of synthesis and use thereof
WO2002002123A1 (en) 2000-06-29 2002-01-10 Trustees Of Boston University Use of geldanamycin and related compounds for prophylaxis or treatment of fibrogenic disorders
KR20030046397A (en) 2000-07-28 2003-06-12 슬로안-케테링인스티튜트퍼캔서리서치 Methods for Treating Cell Proliferative Disorders and Viral Infections
GB0100623D0 (en) 2001-01-10 2001-02-21 Vernalis Res Ltd Chemical compounds IV
MY141789A (en) 2001-01-19 2010-06-30 Lg Chem Investment Ltd Novel acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same.
US20060079493A1 (en) 2001-03-01 2006-04-13 Lawrence Fritz Methods for treating genetically- defined proliferative disorders with hsp90 inhibitors
JP4331944B2 (en) 2001-04-17 2009-09-16 大日本住友製薬株式会社 New adenine derivatives
WO2002088079A2 (en) 2001-05-01 2002-11-07 Bristol-Myers Squibb Company Dual inhibitors of pde 7 and pde 4
EP1404871A4 (en) 2001-05-23 2006-10-04 Sloan Kettering Inst Cancer Method for treatment of cancer associated with elevated her 2 levels
PE20030008A1 (en) 2001-06-19 2003-01-22 Bristol Myers Squibb Co DUAL INHIBITORS OF PDE 7 AND PDE 4
KR20050059975A (en) 2001-06-22 2005-06-21 파마셋 인코포레이티드 β-2'- or 3'-halonucleosides
ATE301123T1 (en) 2001-06-27 2005-08-15 Cyclacel Ltd 2,6,9-SUBSTITUTED PURINE DERIVATIVES AND THEIR USE IN THE TREATMENT OF PROLIFERATIVE DISEASES
US6962991B2 (en) 2001-09-12 2005-11-08 Epoch Biosciences, Inc. Process for the synthesis of pyrazolopyrimidines
JP2005504086A (en) 2001-09-24 2005-02-10 コンフォーマ セラピューティクス コーポレーション Process for producing 17-allylaminogeldanamycin (17-AAG) and other ansamycins

Patent Citations (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4294831A (en) * 1974-09-02 1981-10-13 Burroughs Wellcome Co. Purine derivatives
US4495190A (en) * 1980-12-22 1985-01-22 Astra Lakemedel Aktiebolag Derivatives of guanine for combating herpes virus infections
US4547573A (en) * 1983-12-02 1985-10-15 Ici Pharma Process for preparing cephalosporin derivatives
US4748177A (en) * 1984-03-26 1988-05-31 Warner-Lambert Company Guanine derivatives
US4617304A (en) * 1984-04-10 1986-10-14 Merck & Co., Inc. Purine derivatives
US4774325A (en) * 1984-09-20 1988-09-27 Pierrel Spa New 8-substituted nucleoside and purine derivatives, the process for the preparation thereof and the pharmaceutical compositions containing them
US4806642A (en) * 1984-10-05 1989-02-21 Warner-Lambert Company Purine derivatives
US5217866A (en) * 1985-03-15 1993-06-08 Anti-Gene Development Group Polynucleotide assay reagent and method
US4772606A (en) * 1985-08-22 1988-09-20 Warner-Lambert Company Purine derivatives
US5002950A (en) * 1986-10-24 1991-03-26 Warner-Lambert Co. 7-deazaguanines as immunomodulators
US5110818A (en) * 1988-10-06 1992-05-05 Ciba-Geigy Corporation Anticonvulsive substituted-9-benzyl-9h-purines
US4971972A (en) * 1989-03-23 1990-11-20 Schering Corporation Phosphodiesterase inhibitors having an optionally substituted purine derivative portion and a benzo- or cyclopenta-furan portion
US5332744A (en) * 1989-05-30 1994-07-26 Merck & Co., Inc. Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
US5789394A (en) * 1992-12-23 1998-08-04 Nguyen-Ba; Nghe Anti-viral compounds
US5955610A (en) * 1992-12-23 1999-09-21 Biochem Pharma, Inc. Antiviral compounds
US5602156A (en) * 1993-09-17 1997-02-11 The United States Of America As Represented By The Department Of Health And Human Services Method for inhibiting metalloproteinase expression
US5917042A (en) * 1994-02-04 1999-06-29 Glaxo Wellcome Inc. Process for the preparation of 2,5-diamino-4,6-dichloropyrimidine
US5994361A (en) * 1994-06-22 1999-11-30 Biochem Pharma Substituted purinyl derivatives with immunomodulating activity
US6333331B1 (en) * 1994-08-01 2001-12-25 The United States Of America As Represented By The Department Of Health And Human Services Substituted O6-benzylguanines
US6723727B1 (en) * 1996-12-20 2004-04-20 Hoechst Aktiengesellschaft Substituted purine derivatives, processes for their preparation, their use, and compositions comprising them
US5861503A (en) * 1997-04-30 1999-01-19 The Regents Of The University Of California Process for producing 8-fluoropurines
US6143743A (en) * 1997-07-03 2000-11-07 Dupont Pharmaceuticals Company Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders
US6369092B1 (en) * 1998-11-23 2002-04-09 Cell Pathways, Inc. Method for treating neoplasia by exposure to substituted benzimidazole derivatives
US20020161014A1 (en) * 2000-04-25 2002-10-31 Chanchal Sadhu Inhibitors of human phosphatidylinositol 3-kinase delta
US20040102458A1 (en) * 2000-11-02 2004-05-27 Gabriela Chiosis Small molecule compositions for binding to hsp90
US7439359B2 (en) * 2000-11-02 2008-10-21 Sloan-Kettering Institute For Cancer Research Small molecule compositions for binding to hsp90
US20020156277A1 (en) * 2001-04-20 2002-10-24 Fick David B. Synthesis and methods of use of purine analogues and derivatives
US20030022864A1 (en) * 2001-04-24 2003-01-30 Ishaq Khalid S. 9-[(5-dihydroxyboryl)-pentyl] purines, useful as an inhibitor of inflammatory cytokines
US20070129334A1 (en) * 2001-10-30 2007-06-07 Conforma Therapeutics Corporation Orally Active Purine-Based Inhibitors of Heat Shock Protein 90
US7241890B2 (en) * 2001-10-30 2007-07-10 Conforma Therapeutics Corporation Purine analogs having HSP90-inhibiting activity
US7129239B2 (en) * 2002-10-28 2006-10-31 Pfizer Inc. Purine compounds and uses thereof
US7129244B2 (en) * 2003-09-18 2006-10-31 Conforma Therapeutics Corporation Triazolopyrimidines and related analogs as HSP90-inhibitors
US7138401B2 (en) * 2003-09-18 2006-11-21 Conforma Therapeutics Corporation 2-aminopurine analogs having HSP90-inhibiting activity
US7148228B2 (en) * 2003-09-18 2006-12-12 Conforma Therapeutics Corporation Pyrazolopyrimidines and related analogs as HSP90-inhibitors
US20080253965A1 (en) * 2005-02-01 2008-10-16 Sloan-Kettering Institute For Cancer Research Small-Molecule Hsp90 Inhibitors
US20070299258A1 (en) * 2006-05-12 2007-12-27 Myriad Genetics, Incorporated Therapeutic compounds and their use in cancer
US7595401B2 (en) * 2006-05-12 2009-09-29 Myriad Pharmaceuticals, Inc. Therapeutic compounds and their use in cancer

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090324551A1 (en) * 2005-08-22 2009-12-31 The Regents Of The University Of California Office Of Technology Transfer Tlr agonists
US9359360B2 (en) 2005-08-22 2016-06-07 The Regents Of The University Of California TLR agonists
US20110098294A1 (en) * 2006-05-31 2011-04-28 Carson Dennis A Purine analogs
US8846697B2 (en) 2006-05-31 2014-09-30 The Regents Of The University Of California Purine analogs
US8357374B2 (en) 2007-02-07 2013-01-22 The Regents Of The University Of California Conjugates of synthetic TLR agonists and uses therefor
US8790655B2 (en) 2007-02-07 2014-07-29 The Regents Of The University Of California Conjugates of synthetic TLR agonists and uses therefor
US9050376B2 (en) 2007-02-07 2015-06-09 The Regents Of The University Of California Conjugates of synthetic TLR agonists and uses therefor
US20090202626A1 (en) * 2008-02-07 2009-08-13 Carson Dennis A Treatment of bladder diseases with a tlr7 activator
US9066940B2 (en) 2009-02-06 2015-06-30 Telormedix, Sa Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration
US9107919B2 (en) 2009-02-06 2015-08-18 Telormedix Sa Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration
US20100210598A1 (en) * 2009-02-11 2010-08-19 Regents Of The University Of California, San Diego Toll-like receptor modulators and treatment of diseases
US8729088B2 (en) 2009-02-11 2014-05-20 The Regents Of The University Of California Toll-like receptor modulators and treatment of diseases
WO2011060253A3 (en) * 2009-11-13 2011-09-09 Myrexis, Inc. Methods of treating diseases, pharmaceutical compositions, and pharmaceutical dosage forms
WO2011060253A2 (en) * 2009-11-13 2011-05-19 Myrexis, Inc. Methods of treating diseases, pharmaceutical compositions, and pharmaceutical dosage forms
US9050319B2 (en) 2010-04-30 2015-06-09 Telormedix, Sa Phospholipid drug analogs
US9173935B2 (en) 2010-04-30 2015-11-03 Telormedix Sa Phospholipid drug analogs
US9173936B2 (en) 2010-04-30 2015-11-03 Telormedix Sa Phospholipid drug analogs
US9180183B2 (en) 2010-04-30 2015-11-10 Telormedix Sa Phospholipid drug analogs
WO2017123766A1 (en) * 2016-01-12 2017-07-20 Sperovie Biosciences, Inc. Compounds and compositions for the treatment of disease
US11697851B2 (en) 2016-05-24 2023-07-11 The Regents Of The University Of California Early ovarian cancer detection diagnostic test based on mRNA isoforms

Also Published As

Publication number Publication date
EP2336133A1 (en) 2011-06-22
WO2003037860A3 (en) 2004-03-25
EP1440072A2 (en) 2004-07-28
AU2002343604C1 (en) 2009-09-17
JP2005511565A (en) 2005-04-28
EP1440072A4 (en) 2005-02-02
US20050049263A1 (en) 2005-03-03
US7241890B2 (en) 2007-07-10
AU2002343604B2 (en) 2009-04-09
WO2003037860A2 (en) 2003-05-08
JP4397691B2 (en) 2010-01-13
CA2464031A1 (en) 2003-05-08

Similar Documents

Publication Publication Date Title
US7241890B2 (en) Purine analogs having HSP90-inhibiting activity
AU2002343604A1 (en) Purine analogs having HSP90-inhibiting activity
US7138401B2 (en) 2-aminopurine analogs having HSP90-inhibiting activity
US20070129334A1 (en) Orally Active Purine-Based Inhibitors of Heat Shock Protein 90
US20080096903A1 (en) Sulfamoyl-containing derivatives and uses thereof
US20070253896A1 (en) 7,9-Dihydro-Purin-8-One and Related Analogs as HSP90-Inhibitors
US7553979B2 (en) HSP90-inhibiting zearalanol compounds and methods of producing and using same
EP3091019B1 (en) Purine derivatives useful as hsp90 inhibitors
JP2009521446A (en) Orally active purine-based inhibitors of heat shock protein 90
CN101505762A (en) Orally active purine-based inhibitors of heat shock protein 90

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE