Patent EP-2123619-A1 (EP)
Inventor: DR LEHMANN LUTZ
IPC: C07B59/00
Filed: 2008-05-20
Abstract: Amide derivatives (I) and their diastereomers or enantiomers are new. Amide derivatives of formula (A-C(=O)-CH(R 1>)-CH(R 2>)-CH(NH 2)-C(=O)-G) (I) and their diastereomers or enantiomers are new. A : OH, 1-5C-alkoxy, hydroxy 1-5C-alkoxy, O-1-5C-alkyl-(O-1-4C-alkyl) n-O-1-4C-alkyl, N(1-5C-alkyl) 2, NH 2, N(H)-L, O-L or O-Z; G : OH, O-Z, O-1-5C-alkyl, O-2-5C-alkenyl, O-1-5C-alkyl-(O-1-4C-alkyl) nO-1-4C-alkyl, O-2-5C-alkynyl, or triphenylmethoxy; R 1>, R 2>H, 1>8>F-6-10C-alkoxy, 1>8>F-6-10C-alkyl, 1>8>F-6-10C-alkenyl, 1>8>F-6-10C-alkynyl, OH, 1-5C-alkyl or 1-5C-alkoxy; L : 1-5C-alkyl, 2-5C-alkenyl, 1-5C-alkyl-(O-1-4C-alkyl) n-O-1-4C-alkyl or 2-5C-alkynyl; Z : a metal cation equivalent; and n : 0-3. Provided that one of the substituents R 1>or R 2>contains 1>8>F isotope and the other substitution is free of 1>8>F isotope. Independent claims are included for: (1) the preparation of (I); (2) a carbonyl group containing protective compound of formula (A 1>-C(=O)-CH(R 1>)-CH(R 2>)-CH(Q)-C(=O)-G 1>) (II); (3) the preparation of (II) comprising reacting a carbonyl group containing compound of formula (A 2>-C(=O)-CH(R 3>)-CH(R 4>)-CH(Q 1>)-C(=O)-G 2>) (III) with 1>8>F; (4) the carbonyl group containing compound (III); (5) a pyrrolidine compound of formula (IV); (6) a imaging kit comprising (III) or (IV); (7) a pharmaceutical composition comprising (I)-(IV) and a carrier; (8) an amide compound of formula (A 1>-C(=O)-CH(R 8>)-CH(R 9>)-CH(NH 2)-C(=O)-G 1>) (V); (9) the preparation of (V) comprising removing the protective group of formula (A-C(=O)-CH(R 8>)-CH(R 9>)-CH(Q)-C(=O)-G) (VI); (10) the preparation of (VI) comprising reacting a carbonyl compound of formula (A 3>-C(=O)-CH(R 1>0>)-CH(R 1>1>)-CH(Q 3>)-C(=O)-G 3>) (VII); (11) the carbonyl compound (VII); (12) a pyrrolidine compound of formula (VIII); (13) a kit comprising (VII) or (VIII); and (14) a pharmaceutical composition comprising (V)-(VIII) and a suitable carrier. A 1>A; G 1>G; L 1>L; Z 1>, Z 3>Z; Q : N(H)-tert-butoxycarbonyl, N(H)-allyloxycarbonyl, N(H)-benzyloxycarbonyl, N(H)-ethoxycarbonyl, N(H)-methoxycarbonyl, N(H)-propoxycarbonyl, N(H)-2,2,2-trichloroethoxycarbonyl, N(H)-1,1-dimethylpropinyl, N(H)-1-methyl-1-phenyl-ethoxycarbonyl, N(H)-1-methyl-1-(4-biphenylyl)-ethoxycarbonyl, N(H)-cyclobutylcarbonyl, N(H)-1-methylcyclobutylcarbonyl, N(H)-vinylcarbonyl, N(H)-allylcarbonyl, N(H)-adamantylcarbonyl, N(H)-diphenylmethylcarbonyl, N(H)-cinnamylcarbonyl, N(H)-formyl, N(H)-benzoyl, N(H)-trityl, N(H)-p-methoxyphenyl-diphenylmethyl, N(H)-di-(p-methoxyphenyl)-phenylmethyl, -N=C(X 1>)(X 2>) (a) or N-(tert.butyoxycarbonyl) 2, preferably N(H)-tert-butoxycarbonyl or N(H)-trityl; A 2>1-5C-alkoxy, hydroxy 1-5C-alkoxy, O-1-5C-alkyl-(O-1-4C-alkyl) n-O-1-4C-alkyl, N(1-5C-alkyl) 2, NH 2, N(H)-L 2>or O-L 2>; A 3>1-5C-alkoxy, hydroxy 1-5C-alkoxy, O-1-5C-alkyl-(O-1-4C-alkyl) n-O-1-4C-alkyl, N(1-5C-alkyl) 2, NH 2, N(H)-L 3>or O-L 3>; G 2>O-1-5C-alkyl, O-2-5C-alkenyl, O-1-5C-alkyl-(O-1-4C-alkyl) nO-1-4C-alkyl, O-2-5C-alkynyl, or triphenylmethoxy; G 3>O-Z 3>, O-1-5C-alkyl, O-2-5C-alkenyl, O-1-5C-alkyl-(O-1-4C-alkyl) n-O-1-4C-alkyl, O-2-5C-alkynyl, or triphenylmethoxy; G 4>O-1-5C-alkyl, O-2-5C-alkenyl, O-1-5C-alkyl-(O-1-4C-alkyl) n-O-1-4C-alkyl, O-2-5C-alkynyl, or triphenylmethoxy; R 3>, R 4>H, E-6-10C-alkoxy, E-6-10C-alkyl, E-6-10C-alkenyl, E-6-10C-alkynyl, OH, 1-5C-alkyl or 1-5C-alkoxy; R 5>, R 6>H, OH, 1-5C-alkyl, 1-5C-alkoxy or R 7>-E 1>; R 1>0>, R 1>1>H, E 3>-6-10C-mono- or bicyclic aryl, E 2>-5-10C mono- or bicyclic heteroaryl, E 2>-3-6C-cycloalkyl (all optionally substituted), OH, 1-5C-alkyl or 1-5C-alkoxy; R 1>2>, R 1>3>H, OH, 1-5C-alkyl, 1-5C-alkoxy or R 1>4>-E 2>; Q 3>N(H)-tert-butoxycarbonyl, N(H)-allyloxycarbonyl, N(H)-benzyloxycarbonyl, N(H)-ethoxycarbonyl, N(H)-methoxycarbonyl, N(H)-propoxycarbonyl, N(H)-2,2,2-trichloroethoxycarbonyl, N(H)-1,1-dimethylpropinyl, N(H)-1-methyl-1-phenyl-ethoxycarbonyl, N(H)-1-methyl-1-(4-biphenylyl)-ethoxycarbonyl, N(H)-cyclobutylcarbonyl, N(H)-1-methylcyclobutylcarbonyl, N(H)-vinylcarbonyl, N(H)-allylcarbonyl, N(H)-adamantylcarbonyl, N(H)-diphenylmethylcarbonyl, N(H)-cinnamylcarbonyl, N(H)-formyl, N(H)-benzoyl, N(H)-trityl, N(H)-p-methoxyphenyl-diphenylmethyl, N(H)-di-(p-methoxyphenyl)-phenylmethyl, -N=C(X 3>)(X 4>) (a) or N-(tert.butyoxycarbonyl) 2; X 1>, X 2>, X 5>, X 6>aryl, aralkyl, or heteroaryl (all optionally substituted) or 1-5C-alkyl; G 2>, G 3>O-1-5C-alkyl, O-2-5C-alkenyl, O-1-5C-alkyl-(O-1-4C-alkyl) nO-1-4C-alkyl, O-2-5C-alkynyl, or triphenylmethoxy; R 8>, R 9> 1>8>F-6-10C mono- or bicyclic aryl, 1>8>F-5-10C-mono- or bicyclic heteroaryl (all optionally substituted), H, 1>8>F-3-6C-cyclo-alkyl, OH, 1-5C-alkyl or 1-5C-alkoxy; R 7>6-10C-alkoxy, 6-10C-alkyl, 6-10C-alkenyl, or 6-10C-alkynyl; E, E 1>Cl, Br, mesyloxy, trifluoromethylsulfonyloxy, nonafluorbutyloxy, tosyloxy, or I; E 2>Cl, Br, methanesulfonyloxy, trifluoromethylsulfonyloxy, nonafluorbutyloxy, tosyloxy, or I; R 1>4>6-10C-mono or bicyclic aryl, 5-10C-mono or bicyclic heteroaryl or 3-6C-cycloalkyl (all optionally substituted); L 2>, L 3>L; Q 1>Q; and X 3>, X 4>aryl, alkylaryl or heteroaryl (optionally substituted) or 1-5-alkyl. Provided that: one of the substituent R 3>or R 4>contains E and the other substituent is free of E; one of the substituents of R 5>or R 6>contains E 1>, and the other substituent is free of E 1>; one of the substituent R 8>or R 9>contains 1>8>F isotope and the other substituent is free of 1>8>F isotope; one of the substituent R 1>0>or R 1>1>contains E 2>and the other substituent is free of E 2>; one of the substituent R 1>2>or R 1>3>contains E 2>and the other substituent is free of E 2>. [Image].