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US 6,271,227 B1Granted
Antithrombotic Agents
AssigneeEli Lilly and Company
InventorsNickolay Y Chirgadze, Matthew J Fisher, Richard W Harper, Ho-Shen Lin, Jefferson R McCowan, Alan D Palkowitz, Michael E Richett, Daniel J Sall, Gerald F Smith, Kumiko Takeuchi, Minsheng Zhang
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Abstract
This application relates to novel compounds of formula (I) (and their pharmaceutically acceptable salts), as defined herein, processes and intermediates for their preparation, pharmaceutical formulations comprising the novel compounds of formula (I), and the use of the compounds of formula (I) as thrombin inhibitors.
Claims47
A compound of formula I (or a pharmaceutically acceptable salt thereof)
- wherein
- A is carbonyl or methylene;
- D is CH, CRd or N in which Rd is methyl or methoxy;
- E is CH, CRe or N in which Re is methyl, methoxy or halo;
- R2 and R3 are defined together such that
- A. R2 is —X2—(CH2)m—NRaRb in which X2 is a direct bond, methylene or O;
- m is 1, 2, 3, 4 or 5;
- provided that when m is 1, then X2 is a direct bond;
- and Ra and Rb are independently hydrogen or (1-3C)alkyl or the group NRaRb is pyrrolidino, piperidino, or morpholino;
- and
- R3 is —CH2—Rc, in which Rc is 2-carboxypyrrolidin-1-yl or 2-[[(1-4C)alkoxy]carbonyl]pyrrolidin-1-yl;
- or
- B. R2 is —X2—(CH2)n—Rf in which X2 is a direct bond, methylene or O;
- n is 1, 2 or 3;
- provided that when n is 1, then X2 is a direct bond;
- and Rf is 2-carboxypyrrolidin-1-yl, 2-[[(1-4C)alkoxy]carbonyl]pyrrolidin-1-yl, (carboxymethyl)amino, [[(1-4C)alkoxy]carbonylmethyl]amino, (4-carboxymethylimidazol-1-yl)amino, [4-[[(1-4C)alkoxy]-carbonylmethyl]imidazol-1-yl]amino, (4-carboxybenzyl)amino, [4-[[(1-4C)alkoxy]carbonyl]benzyl]amino, (3-amino-1,4-dioxo-4-hydroxybutyl)amino or [3-amino-1,4-dioxo-4-[(1-4C)alkoxy]-butyl]amino;
- or R2 is —X2—(CH2)n—Rf in which X2 is a direct bond;
- n is 0;
- and Rf is (3-amino-1,4-dioxo-4-hydroxybutyl)-amino, [3-amino-1,4-dioxo-4-[(1-4C)alkoxy]butyl]amino, (4-amino-l,5-dioxo-5-hydroxypentyl)amino or [4-amino-1,5-dioxo-5-[(1-4C)alkoxy]butyl]amino;
- R3 is is —X3—(CH2)s—NRgRh in which X3 is a direct bond, methylene or O;
- s is 1 or 2;
- provided that when s is 1, then X3 is a direct bond;
- and Rs and Rt are independently hydrogen or (1-3C)alkyl or the group NRsRt is pyrrolidino, piperidino, or morpholino;
- and
- R6 is hydrogen, hydroxy or methoxy.
22 more elements
Dependencies are inferred from the claim text.