- Process for the preparation of mixed anhydrides
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The present invention is concerned with an improved process for the manufacture of mixed anhydrides. The process comprises adding an adjuvant base to a mixture of acid and reactive acid derivative. It is especially suitable for use in the synthesis of pep
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- Concise synthesis of sibrafiban and lamifiban, two non-peptide fibrinogen receptor (GP IIb/IIIa) antagonists
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The total synthesis of the non-peptide fibrinogen receptor antagonists, sibrafiban (1) (Ro 48-3657) and lamifiban (2) (Ro 44-9883), is described. Both contain 4-hydroxypiperidine unit and the same solid-phase synthesis method was used as a key step. Conne
- Chang, Meng-Yang,Chen, Shui-Tein
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p. 133 - 135
(2007/10/03)
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- Orally active fibrinogen receptor antagonists. 2. Amidoximes as prodrugs of amidines
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The potent and selective GP IIb-IIIa antagonist lamifiban (1, Ro 44- 9883) is currently in clinical development as an injectable antithrombotic agent for treating and preventing acute coronary syndromes. However, for secondary prevention of thrombotic occlusions, orally active inhibitors are needed. By means of a prodrug strategy, the modest oral absorption of 1 in mice was improved by a factor of 9. In addition, these studies demonstrated that an amidoxime group can serve as a prodrug functionality for an amidino group. Application of this principle to the structurally related amidino carboxylate 13 led to the amidoxime ester 18 which was absorbed approximately 20 times better, after oral administration to mice, than 13. Due to the modification of the amidino group as well as of the carboxylate group, 18 completely lost its ability to interact with purified platelet GP IIb-IIIa. After oral administration of 18 to rats, dogs, and rhesus monkeys, the bioavailability of the active derivative 13 was 26 ± 5, 25 ± 6, and 33 ± 6%, respectively, and the elimination half-life was 4.1 ± 1.7, 11.4 ± 1.1, and 5.1 ± 1.4 h, respectively. On the basis of these properties, the orally active 18 (Ro 48-3657), a double prodrug of the potent and selective non- peptide GP IIb-IIIa antagonist 13 (Ro 44-3888), was selected as clinical candidate for evaluation as a prophylactic agent in patients at high risk for arterial thrombosis.
- Weller, Thomas,Alig, Leo,Beresini, Maureen,Blackburn, Brent,Bunting, Stuart,Hadváry, Paul,Müller, Marianne Hürzeler,Knopp, Dietmar,Levet-Trafit, Bernard,Lipari, M. Terry,Modi, Nishit B.,Müller, Marcel,Refino, Canio J.,Schmitt, Monique,Sch?nholzer, Peter,Weiss, Sabine,Steiner, Beat
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p. 3139 - 3147
(2007/10/03)
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