TWI602567B - 磷脂醯肌醇－３－激酶（ｐｉ３ｋ）抑制劑及ｍｔｏｒ抑制劑之組合 - Google Patents
磷脂醯肌醇－３－激酶（ｐｉ３ｋ）抑制劑及ｍｔｏｒ抑制劑之組合 Download PDFInfo
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- TWI602567B TWI602567B TW101114591A TW101114591A TWI602567B TW I602567 B TWI602567 B TW I602567B TW 101114591 A TW101114591 A TW 101114591A TW 101114591 A TW101114591 A TW 101114591A TW I602567 B TWI602567 B TW I602567B
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- everolimus
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| BR9408323A (pt) | 1993-12-17 | 1997-08-19 | Sandoz Ag | Derivados de rapamicina |
| DE69624921T2 (de) | 1995-06-09 | 2003-09-11 | Novartis Ag, Basel | Rapamycinderivate |
| WO1998002441A2 (en) | 1996-07-12 | 1998-01-22 | Ariad Pharmaceuticals, Inc. | Non immunosuppressive antifungal rapalogs |
| IL147803A0 (en) | 1999-08-24 | 2002-08-14 | Ariad Gene Therapeutics Inc | 28-epirapalogs |
| AR044519A1 (es) * | 2003-05-02 | 2005-09-14 | Novartis Ag | Derivados de piridin-tiazol amina y de pirimidin-tiazol amina |
| AU2006315512B2 (en) * | 2005-11-14 | 2012-11-01 | Ariad Pharmaceuticals, Inc. | Administration of an mTOR inhibitor to treat patients with cancer |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010029082A1 (en) * | 2008-09-10 | 2010-03-18 | Novartis Ag | Organic compounds |
| WO2010049481A1 (en) * | 2008-10-31 | 2010-05-06 | Novartis Ag | Combination of a phosphatidylinositol-3-kinase (pi3k) inhibitor and a mtor inhibitor |
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