Prodrugs of substituted ergolines

A compound of formula (1)

• wherein
• X is selected from CO and SO2;
• Y is selected from a single chemical bond, O, S, and a C1-8 alkylene, C2-8 alkenylene, C2-4 alkynylene or O—C1-6 alkylene residue, wherein each of said alkylenes, alkenylenes or alkynylenes may be optionally substituted with C1-3 alkyl or halogen;
• Z is selected from hydrogen, halogen, cyano, C1-3 trialkylsilyl, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-12 alkoxy, C1-12 alkylthio, aryl, heterocyclyl, heteroaryl, metallocenyl, COOH, CO—C1-6 alkyl, CO—C3-7 cycloalkyl, O—CO—C1-6 alkyl, O—CO—C3-7 cycloalkyl, CO—C1-6 alkoxy or CO—C3-7 cycloalkoxy, wherein each of said alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkoxy, aryl, heterocyclyl, heteroaryl or metallocenyl may be optionally substituted with C1-5 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C1-3 haloalkyl, halogen, nitro, amino, hydroxy, oxo, COOH and CONH2;
• R2 is selected from hydrogen, C1-3 alkyl, C3-5 cycloalkyl, oxetane, C1-3 haloalkyl, C1-3 alkylthio, halogen, cyano, COOH and CONH2;
• R6 is selected from C1-4 alkyl, C3-5 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, cyano and oxetane;
• Ra and Rb are each independently selected from hydrogen, C1-6 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-7 cycloalkyl, C2-4 haloalkyl, 2-methoxyethyl and 2-ethoxyethyl;
• or Ra and Rb, together with the adjacent nitrogen atom, form a 3 to 7 membered heterocyclic ring, wherein said heterocyclic ring may be optionally substituted with C1-3 alkyl or halogen;
• and
• is a single or double bond or a cyclopropyl ring;
• provided that compounds of formula (1) having a linear C1-5 acyl group, a valeroyl group or a cyclopropylcarbonyl group, as —XYZ are excluded;
• or a pharmaceutically acceptable salt thereof.

A method for producing a compound of formula (1)

• wherein
• X is selected from CO and SO2;
• Y is selected from a single chemical bond, O, S, and a C1-8 alkylene, C2-8 alkenylene, C2-4 alkynylene or O—C1-6 alkylene residue, wherein each of said alkylenes, alkenylenes or alkynylenes may be optionally substituted with C1-3 alkyl or halogen;
• Z is selected from hydrogen, halogen, cyano, C1-3 trialkylsilyl, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-12 alkoxy, C1-12 alkylthio, aryl, heterocyclyl, heteroaryl, metallocenoyl, COOH, CO—C1-6 alkyl, CO—C3-7 cycloalkyl, O—CO—C1-6 alkyl, O—CO—C3-7 cycloalkyl, CO—C1-6 alkoxy or CO—C3-7 cycloalkoxy, wherein each of said alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkoxy, aryl, heterocyclyl, heteroaryl or metallocenoyl may be optionally substituted with C1-5 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C1-3 haloalkyl, halogen, nitro, amino, hydroxy, oxo, COOH and CONH2;
• or —XYZ together represent hydrogen;
• R2 is Br;
• R6 is selected from C1-4 alkyl, C3-5 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, cyano and oxetane;
• Ra and Rb are each independently selected from hydrogen, C1-6 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-7 cycloalkyl, C2-4 haloalkyl, 2-methoxyethyl and 2-ethoxyethyl;
• or Ra and Rb together with the adjacent nitrogen atom form a 3 to 7 membered heterocyclic ring, wherein said heterocyclic ring may be optionally substituted with C1-3 alkyl or halogen;
• and
• is a single or double bond or a cyclopropyl ring,
• or a salt thereof, said method comprises saponifying bromocriptine followed by amide-formation as shown in the following reaction scheme:
• wherein the variables are as defined above.