New F-18-marked L-glutamic acids and L-glutamic acid derivatives (1), application thereof and method for their manufacture

摘要

Amide compounds (I) are new. Amide compounds of formula (I) 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 8F-2-5C-alkoxy, 1 8F-1-5C-alkyl, 1 8F-2-5C-alkenyl, 1 8F-2-5C-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 1or R 2contains 1 8F isotope and the other substitution is free of 1 8F isotope and R 1is not H. Independent claims are included for: (1) a carbonyl compound of formula (II); (2) the preparation of (I); (3) the preparation of (II) comprising reacting a carbonyl compound of formula (III) with F-18 fluoride; (4) the carbonyl compound (III); (5) use of a pyrrolidine compound of formula (IV) for the preparation of (I) or (II); (6) a kit comprising (III) or (IV); and (7) a pharmaceutical composition comprising (I)-(IV) and a suitable carrier. A 1 : 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 1, O-L 1; G 1 : OH, O-Z 1, 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; Q : N(H)-tert-butoxycarbonyl, N(H)-benzyloxycarbonyl, -N=C(X 1)(X 2) (all preferred), N(H)-allyloxycarbonyl, 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)-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, or N-(tert.butyoxycarbonyl) 2; L 1, L 2 : L; X 1, X 2 : aryl, aralkyl or heteroaryl (all optionally substituted) or 1-5C-alkyl; Z 1, Z 2 : a metal cation equivalent; 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)-U 1, N(H)-L 2or O-L 2; G 2 : O-Z 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; R 3, R 4 : H, E-2-5C-alkoxy, E-1-5C-alkyl, E-2-5C-alkenyl, E-2-5C-alkynyl, OH, 1-5C-alkyl, or 1-5C-alkoxy; E : Cl, Br, methanesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutyloxy, tosyloxy or I; Q 1, Q 3 : Q; 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 5, R 6 : H, OH, 1-5C-alkyl, 1-5C-alkoxy or R 7-E 1; E 1 : E; and R 7 : 2-5C-alkoxy, 1-5C-alkyl, 2-5C-alkenyl or 2-5C-alkynyl. Provided that: one of the substituent R 3or R 4contains E and the other substituent is free of E and R 3is not H; and one of the substituents of R 5or R 6contains E 1, and the other substituent is free of E 1and R 5is not H. [Image] [Image].