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US 7,683,093 B2Granted
Prolinyl derivatives for the treatment of thrombosis
AssigneeMerck Patent GmbH
InventorsWerner Mederski, Christos Tsaklakidis, Dieter Dorsch, Bertram Cezanne, Johannes Gleitz
Life of this patent
Estimating the term…
Abstract
Novel compounds of the formula (I), in which R, R1, R2, R3 and R4 have the meaning indicated in Patent Claim 1, are inhibitors of coagulation factor Xa and can be employed for the prophylaxis and/or therapy of thromboembolic diseases and for the treatment of tumours.
Claims20
A compound of the formula
- N-1-[(4-chlorophenyl)]-N-2-{[4-(2{dimethylaminomethyl }phenyl)phenyl]-}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,
- N-1-[(4-ethynylphenyl)]-N-2-{[4-(2-{dimethylaminomethyl}phenyl)-phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,
- N-1-[(4-chlorophenyl)]-N-2-{[2-fluoro-4-(2-{dimethylaminomethyl}-phenyl)phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,
- N-1-[(4-ethynylphenyl)]-N-2-{[2-fluoro-4-(2-{dimethylaminomethyl}-phenyl)phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,
- N-1-[(4-chlorophenyl)]-N-2-[(4-(2-dimethylaminomethylimidazol-1-yl)-phenyl)]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,
- N-1-[(4-ethynylphenyl)]-N-2-[(4-(2-dimethylaminomethyl-imidazol-1-yl)-phenyl)]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,
- N-1-[(4-chlorophenyl)]-N-2-[(2-fluoro-4-(2-dimethylaminomethyl-imidazol -1-yl)phenyl)]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,
- N-1-[(4-ethynylphenyl)]-N-2-[(2-fluoro-4-(2-dimethylamino-methylimidazol-1-yl)phenyl)]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,
- N-1-[(4-chlorophenyl)]-N-2-[(4-(N,N-dimethylamidino)phenyl)]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,
- N-1-[(4-ethynylphenyl)]-N-2-[(4-(N,N-dimethylamidino)phenyl)]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,
- N-1-[(4-chlorophenyl)]-N-2-[(2-fluoro-4-(N,N-dimethylamidino)phenyl)]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,
- N-1-[(4-ethynylphenyl)]-N-2-[(2-fluoro-4-(N,N-dimethylamidino)phenyl)]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,
- N-1-[(4-chlorophenyl)]-N-2-[(4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl)]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,
- N-1-[(4-chlorophenyl)]-N-2-[(2-fluoro-4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl)]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,
- N-1-[(4-ethynylphenyl)]-N-2-[(4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl)]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, N-1-[(4-ethynylphenyl)]-N-2-[(2-fluoro-4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl)]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,
- or pharmaceutically usable derivatives, salts or stereoisomers thereof, including mixtures thereof in all ratios.
13 more elements
Process for the preparation of compounds of the formula I
- in which
- R denotes Hal, —C≡C—H, —C≡C-A or OA,
- R1 denotes H, ═O, Hal, A, OH, OA, A-COO—, Ph-(CH2)n—COO—, cycloalkyl-(CH2)n—COO—, A-CONH—, A-CONA-, Ph-CONA-, N3, NH2, NO2, CN, COOH, COOA, CONH2, CONHA, CON(A)2, O-allyl, O-propargyl, O-benzyl, ═N—OH, ═N—OA or ═CF2,
- R2 denotes H or A,
- Ph denotes phenyl which is unsubstituted or mono-, di- or trisub -stituted by A, OA, OH or Hal,
- R3 denotes H, Hal or A,
- R4 denotes —C6H4—(CH2)n—NR5R5′, —C(═NR5)NR5R5′,
- R5, R5 ′each, independently of one another, denote H or A,
- A denotes unbranched, branched or cyclic alkyl having 1-12 C atoms, in which, in addition, 1-7 H atoms may be replaced by F and/or chlorine,
- Hal denotes F, Cl, Br or I,
- n denotes 0, 1, 2 or 3,
- or pharmaceutically usable derivatives, salts and stereoisomers thereof, comprising reacting
- a) a compound of the formula II
- with a chloroformate derivative to give an intermediate carbamate derivative, subsequently reacting said intermediate with a compound of the formula III
- or
- b) reacting a compound of the formula III
- with a compound of the formula IV
- or
- c) reacting a compound of the formula V
- with a compound of the formula VI
- in which
- L denotes Cl, Br, I or a free or reactively functionally modified OH group
- and/or converting
- a base or acid of the formula I into one of its salts.
21 more elements
Dependencies are inferred from the claim text.