- Discovery of 2-ureidophenyltriazines bearing bridged morpholines as potent and selective ATP-competitive mTOR inhibitors
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Incorporation of bridged morpholines in monocyclic triazine PI3K/mTOR inhibitors gave compounds with increased mTOR selectivity relative to the corresponding morpholine analogs. Compounds with ureidophenyl groups gave highly potent and selective mTOR inhi
- Zask, Arie,Verheijen, Jeroen C.,Richard, David J.,Kaplan, Joshua,Curran, Kevin,Toral-Barza, Lourdes,Lucas, Judy,Hollander, Irwin,Yu, Ker
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Read Online
- Synthesis of new heteroaryl substituted morpholine tagged triazines and evaluation of their cytotoxic activity
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Background: In the present study, new triazine derivatives 3, 4, 5, 6, 8 and 10 were synthesized starting from readily available cyanuric chloride 1 via nucleophilic displacement with morpholine followed by Suzuki or Stille coupling reactions and then the
- Kasturi, Sivaprasad,Surarapu, Sujatha,Uppalanchi, Srinivas,Anantaraju, Hasitha Shilpa,Dwivedi, Shubham,Yogeeswari, Perumal,Ethiraj, Krishna S.,Anireddy, Jaya Shree
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p. 181 - 192
(2018/03/21)
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- PIPERAZINOTRIAZINES AS PI3K INHIBITORS FOR USE IN THE TREATMENT ANTIPROLIFERATIVE DISORDERS
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The invention relates to compounds of formula (I) R1 is methyl, n-hexyl, aminoethyl, methylaminoethyl, ethylaminoethyl, dimethylaminoethyl, acryloylaminoethyl, methacryloylaminoethyl, methoxyethyl, ethoxyethyl, d-C4-alkyl-sulfonyl, acryloyl, or methacryloyl; or R1 is aminoethyl, acryloyl or acryloylaminoethyl carrying a linker and a tag, and R2 and R3, independently of each other, are hydrogen or CrC4-alkyl, or R2 and R3 together form a methylene or an ethylene bridge; and tautomers, solvates and pharmaceutically acceptable salts thereof. These compounds are effective in preventing or treating a disease or disorder modulated by PI3 kinases and/or mTOR, in particular treating a hyperproliferative disorder.
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Paragraph 0088; 0089
(2013/03/26)
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- Synthesis and biological evaluation of novel analogues of the pan class i phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(Difluoromethyl)-1-[4,6-di(4- morpholinyl)-1,3,5-triazin-2-yl]-1 H -benzimidazole (ZSTK474)
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A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2- yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1 -/- mice, and at a dose of 50 mg/kg given by ip injection at a qd ?- 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
- Rewcastle, Gordon W.,Gamage, Swarna A.,Flanagan, Jack U.,Frederick, Raphael,Denny, William A.,Baguley, Bruce C.,Kestell, Philip,Singh, Ripudaman,Kendall, Jackie D.,Marshall, Elaine S.,Lill, Claire L.,Lee, Woo-Jeong,Kolekar, Sharada,Buchanan, Christina M.,Jamieson, Stephen M. F.,Shepherd, Peter R.
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p. 7105 - 7126
(2011/12/04)
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- PIPERAZINOTRIAZINES AS PI3K INHIBITORS FOR USE IN THE TREATMENT ANTIPROLIFERATIVE DISORDERS
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The invention relates to compounds of formula (I) R1 is methyl, n-hexyl, aminoethyl, methylaminoethyl, ethylaminoethyl, dimethylaminoethyl, acryloylaminoethyl, methacryloylaminoethyl, methoxyethyl, ethoxyethyl, d-C4-alkyl- sulfonyl, acryloyl, or methacryloyl; or R1 is aminoethyl, acryloyl or acryloylaminoethyl carrying a linker and a tag, and R2 and R3, independently of each other, are hydrogen or CrC4-alkyl, or R2 and R3 together form a methylene or an ethylene bridge; and tautomers, solvates and pharmaceutically acceptable salts thereof. These compounds are effective in preventing or treating a disease or disorder modulated by PI3 kinases and/or mTOR, in particular treating a hyperproliferative disorder.
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Page/Page column 30
(2011/11/13)
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- Treatment of prostate cancer, melanoma or hepatic cancer
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The present application describes a method of treating prostate cancer, melanoma or hepatic cancer in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of the heterocyclic compound represented by Formula I or its pharmaceutically acceptable salt:
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Page/Page column 4
(2008/06/13)
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- IMMUNOSUPPRESSIVE AGENT AND ANTI-TUMOR AGENT COMPRISING HETEROCYCLIC COMPOUND AS ACTIVE INGREDIENT
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A novel immunosuppressive agent, more specifically an immunosuppressive agent comprising, as an active ingredient, a heterocyclic compound represented by the general formula (I) (wherein X or other variables are as defined in the specification) or a pharmaceutically acceptable salt thereof; a novel heterocyclic compound represented by the general formula (II) (wherein X or other variables are as defined in the specification) or a pharmaceutically acceptable salt thereof; and use of the compound or salt as an antitumor agent.
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Page/Page column 17
(2010/11/29)
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- HETEROCYCLIC COMPOUND AND ANTITUMOR AGENT CONTAINING THE SAME AS ACTIVE INGREDIENT
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The present invention relates to heterocyclic compounds represented by the formula I or pharmaceutically acceptable salts thereof and antitumor agents containing the heterocyclic compounds as effective components: wherein X represents nitrogen atom or CH; R1 represents CHnF3-n (wherein n is 1 or 2), hydroxy C1-C6 alkyl, NHR6 [wherein R6 represents hydrogen atom or COR (wherein R represents hydrogen atom, C1-C6 alkyl or C1-C6 alkoxy)]; R2 represents morpholino (which may be substituted with one to four C1-C6 alkyl), thiomorpholino, piperidino, pyrrolidinyl (which may be substituted with hydroxy C1-C6 alkyl), oxazolidinyl (which may be substituted with one or two C1-C6 alkyl) or tetrahydro-1,4-thiazin-1-oxo-4-yl; R3 and R4 each represent hydrogen atom or C1-C6 alkyl; and R5 represents hydrogen atom, amino or hydroxyl.
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