Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy

A pharmaceutical composition which comprises a carrier and a pyrrolidine derivative of the formula (I)

• wherein
• R1 is C1-C8-alkyl, (optionally substituted C3-C12-cycloalkyl)-C1-C4-alkyl, (optionally substituted C6-C12-aryl)-C1-C4-alkyl, (optionally substituted C3-C12-heterocyclyl)-C1-C4-alkyl, optionally substituted C3-C12-cycloalkyl, optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• R2a, R2b
• are independently hydrogen, halogen, or C1-C3-alkyl, or
• R2a, R2b
• together with the carbon atom to which they are bound may form a C═O;
• R3a
• is C3-C12-cycloalkyl, optionally substituted C6-C12-aryl, hydroxy, C1-C6-alkoxy, halogenated C1-C6-alkoxy, C3-C12-cycloalkyl-C1-C4-alkoxy, C2-C6-alkenyloxy, C6-C12-aryl-C1-C4-alkoxy, C3-C12-heterocyclyl-C1-C4-alkoxy, optionally substituted C6-C12-aryloxy, C3-C12-heterocyclyloxy, or optionally substituted C3-C12-heterocyclyl;
• or
• R3a and one of R2a or R2b
• together with the carbon atoms to which they are bound may form an optionally substituted anellated C6-C12-aryl;
• R3b is hydrogen, C1-C6-alkyl, or hydroxyl;
• or
• R3a and R3b
• together are optionally substituted C2-C5-alkylene;
• Y1 is >CR6— or >N—;
• R6 is hydrogen, C1-C6-alkyl, halogenated C1-C6-alkyl, (optionally substituted C6-C12-aryl)-C1-C4-alkyl, hydroxy-C1-C6-alkyl, C1-C4-alkoxy-C1-C6-alkyl, or hydroxyl;
• or
• R6 and R3a or R3b
• together are optionally substituted C1-C5-alkylene;
• or
• R6
• is C1-C4-alkylene that is bound to a carbon atom in R3a, and R3a is an optionally substituted C6-C12-aryl or an optionally substituted C3-C12-heterocyclyl;
• R4 is —(CR7aR7b)n1OR10, —(CR7cR7d)n2NR11aR11b, —(CR7eR7f)n3R12, optionally substituted C6-C12-aryl, —NR8a(CR9aR9b)n4R13, —NR8bCOR14, —NR8cCOOR15, —NR8dCONR16aR16b, —NR8eSO2R17, —O(CR9cR9d)n5R18, —COR19, —CONR20aR20b, —SO2R21, or optionally substi tuted C3-C12-heterocyclyl;
• R7a, R7b
• are independently hydrogen or C1-C6-alkyl,
• n1 is 1, 2, 3, or 4;
• R10 is hydrogen, optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• R7c, R7d
• are independently hydrogen or C1-C6-alkyl,
• n2 is 1, 2, 3, or 4;
• R11a is C1-C8-alkyl, (optionally substituted C3-C12-cycloalkyl)-C1-C4-alkyl, C1-C6-alkoxyC1-C6-alkyl, (optionally substituted C6-C12-aryl)-C1-C4-alkyl, (optionally substituted C3-C12-heterocyclyl)-C1-C4-alkyl, optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• R11b
• is hydrogen or C1-C6-alkyl;
• R7e, R7f
• are independently hydrogen or C1-C6-alkyl,
• n3 is 1, 2, 3, or 4;
• R12
• is optionally substituted C6-C12-aryl or optionally substituted C3-C12-heterocyclyl;
• R8a, R8b, R8c, R8d, R8e
• are independently hydrogen, C1-C6-alkyl, or C1-C6-alkylcarbonyl, or
• R6 and one of R8a, R8b, R8c, R8d, or R8e
• together are optionally substituted C1-C5-alkylene, wherein one or more —CH2— of C1-C5-alkylene may be independently replaced by a an oxygen atom or C═O;
• or
• R3a and one of R8a or R8b
• together are optionally substituted C1-C5-alkylene;
• R9a, R9b
• are independently hydrogen, halogen, C1-C6-alkyl, halogenated C1-C6-alkyl, hydroxyyl, or C1-C6-alkoxy;
• n4 is 0, 1, 2, 3, or 4;
• R13 is hydrogen, C1-C8-alkyl, halogenated C1-C6-alkyl, (optionally substituted C3-C12-cycloalkyl)-C1-C4-alkyl, C1-C6-alkoxy-C1-C6-alkyl, optionally substituted C3-C12-cycloalkyl, C2-C6-alkenyl, optionally substituted C3-C6-cycloalkenyl, optionally substituted C6-C12-aryl, hydroxy, C1-C6-alkoxy, C1-C6-alkoxy-C1-C4-alkoxy, optionally substituted C6-C12-aryloxy, optionally substituted C3-C12-heterocyclyloxy, optionally substituted C3-C12-heterocyclyl, or tri-(C1-C4-alkyl)-silyloxy;
• R14 is C1-C8-alkyl, halogenated C1-C6-alkyl, (optionally substituted C3-C12-cycloalkyl)C1-C4-alkyl, (optionally substituted C6-C12-aryl)-C1-C4-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, (optionally substituted C6-C12-aryloxy)-C1-C4-alkyl, C1-C6-alkylcarbonyl-C1-C4-alkyl, C1-C6-alkoxycarbonyl-C1-C4-alkyl, C1-C6-alkylaminocarbonyl-C1-C4-alkyl, optionally substituted (C3-C12-heterocyclyl)-C1-C4-alkyl, optionally substituted C3-C12-cycloalkyl, optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• R15 is C1-C8-alkyl, optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• R16a is (optionally substituted C6-C12-aryl)-C1-C4-alkyl, optionally substituted (C3-C12-heterocyclyl)-C1-C4-alkyl, optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• R16b is hydrogen or C1-C6-alkyl;
• R17 is (optionally substituted C6-C12-aryl)-C1-C4-alkyl, (optionally substituted C3-C12-heterocyclyl)-C1-C4-alkyl, optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• R9c, R9d
• are independently hydrogen, halogen, or C1-C6-alkyl;
• n5 is 0, 1, 2, 3, or 4;
• R18 is hydrogen, C1-C8-alkyl, optionally substituted C3-C12-cycloalkyl, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, halogenated C1-C6-alkoxycarbonyl, C6-C12-aryloxycarbonyl, C1-C6-alkylaminocarbonyl, (halogenated C1-C4-alkyl)aminocarbonyl, C6-C12-arylaminocarbonyl, optionally substituted C6-C12-aryl, C1-C6-alkylamine, (C3-C12-cycloalkyl-C1-C4-alkyl)amino, (halogenated C1-C6-alkyl)amino, (C1-C6-alkoxy-C1-C6-alkyl)amino, (C6-C12-aryl-C1-C4-alkyl)amino, C1-C6-dialkylamine, optionally substituted C6-C12-arylamine, or optionally substituted C3-C12-heterocyclyl;
• R19 is optionally substituted C6-C12-aryl or optionally substituted C3-C12-heterocyclyl;
• R20a is C1-C8-alkyl, (optionally substituted C3-C12-cycloalkyl)-C1-C4-alkyl, C1-C6-alkoxyC1-C6-alkyl, (optionally substituted C6-C12-aryl)-C1-C4-alkyl, (optionally substituted C3-C12-heterocyclyl)-C1-C4-alkyl, optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• R20b is hydrogen or C1-C8-alkyl;
• R21 is optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• and
• R5a, R5b
• are independently hydrogen, halogen, or C1-C3-alkyl, or
• R5a, R5b
• together with the carbon atom to which they are bound may form a C═O;
• or
• one of R2a or Rab and one of R5a or R5b
• together are optionally substituted C1-C5-alkylene,
• or a physiologically tolerated salt thereof.

A method for treating a neurologic or psychiatric disorder or pain in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a pyrrolidine derivative of the formula (I)

• wherein
• R1 is C1-C8-alkyl, (optionally substituted C3-C12-cycloalkyl)-C1-C4-alkyl, (optionally substituted C6-C12-aryl)-C1-C4-alkyl, (optionally substituted C3-C12-heterocyclyl)-C1-C4-alkyl, optionally substituted C3-C12-cycloalkyl, optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• R2a, R2b
• are independently hydrogen, halogen, or C1-C3-alkyl, or
• R2a, R2b
• together with the carbon atom to which they are bound may form a C═O;
• R3a
• is C3-C12-cycloalkyl, optionally substituted C6-C12-aryl, hydroxy, C1-C6-alkoxy, halogenated C1-C6-alkoxy, C3-C12-cycloalkyl-C1-C4-alkoxy, C2-C6-alkenyloxy, C6-C12-aryl-C1-C4-alkoxy, C3-C12-heterocyclyl-C1-C4-alkoxy, optionally substituted C6-C12-aryloxy, C3-C12-heterocyclyloxy, or optionally substituted C3-C12-heterocyclyl;
• or
• R3a and one of R2a or R2b
• together with the carbon atoms to which they are bound may form an optionally substituted anellated C6-C12-aryl;
• R3b is hydrogen, C1-C6-alkyl, or hydroxyl;
• or
• R3a and R3b
• together are optionally substituted C2-C5-alkylene;
• Y1 is >CR6— or >N—;
• R6 is hydrogen, C1-C6-alkyl, halogenated C1-C6-alkyl, (optionally substituted C6-C12-aryl)-C1-C4-alkyl, hydroxy-C1-C6-alkyl, C1-C4-alkoxy-C1-C6-alkyl, or hydroxyl;
• or
• R6 and R3a or R3b
• together are optionally substituted C1-C5-alkylene;
• or
• R6
• is C1-C4-alkylene that is bound to a carbon atom in R3a, and R3a is an optionally substituted C6-C12-aryl or an optionally substituted C3-C12-heterocyclyl;
• R4 is —(CR7aR7b)n1OR10, —(CR7cR7d)n2NR11aR11b, —(CR7eR7f)n3R12, optionally substituted C6-C12 aryl, —NR8a(CR9aR9b)n4R13, —NR8bCOR14, —NR8cCOOR15, —NR8dCONR16aR16b, —NR8eSO2R17, —O(CR9cR9d)n5R18, —COR19, —CONR20aR20b, —SO2R21, or optionally substi tuted C3-C12-heterocyclyl;
• R7a, R7b
• are independently hydrogen or C1-C6-alkyl,
• n1 is 1, 2, 3, or 4;
• R10 is hydrogen, optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• R7e, R7d
• are independently hydrogen or C1-C6-alkyl,
• n2 is 1, 2, 3, or 4;
• R11a is C1-C8-alkyl, (optionally substituted C3-C12-cycloalkyl)-C1-C4-alkyl, C1-C6-alkoxyC1-C6-alkyl, (optionally substituted C6-C12-aryl)-C1-C4-alkyl, (optionally substituted C3-C12-heterocyclyl)-C1-C4-alkyl, optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• R11b
• is hydrogen or C1-C6-alkyl;
• R7e, R7f
• are independently hydrogen or C1-C6-alkyl,
• n3 is 1, 2, 3, or 4;
• R12
• is optionally substituted C6-C12-aryl or optionally substituted C3-C12-heterocyclyl;
• R8a, R8b, R8c, R8d, R8e
• are independently hydrogen, C1-C6-alkyl, or C1-C6-alkylcarbonyl, or
• R6 and one of R8a, R8b, R8c, R8d, or R8e
• together are optionally substituted C1-C5-alkylene, wherein one or more —CH2— of C1-C5-alkylene may be independently replaced by a an oxygen atom or C═O;
• or
• R3a and one of R8a or R8b
• together are optionally substituted C1-C5-alkylene;
• R9a, R9b
• are independently hydrogen, halogen, C1-C6-alkyl, halogenated C1-C6-alkyl, hydroxyyl, or C1-C6-alkoxy;
• n4 is 0, 1, 2, 3, or 4;
• R13 is hydrogen, C1-C8-alkyl, halogenated C1-C6-alkyl, (optionally substituted C3-C12-cycloalkyl)-C1-C4-alkyl, C1-C6-alkoxy-C1-C6-alkyl, optionally substituted C3-C12-cycloalkyl, C2-C6-alkenyl, optionally substituted C3-C6-cycloalkenyl, optionally substituted C6-C12-aryl, hydroxy, C1-C6-alkoxy, C1-C6-alkoxy-C1-C4-alkoxy, optionally substituted C6-C12-aryloxy, optionally substituted C3-C12-heterocyclyloxy, optionally substituted C3-C12-heterocyclyl, or tri-(C1-C4-alkyl)-silyloxy;
• R14 is C1-C8-alkyl, halogenated C1-C6-alkyl, (optionally substituted C3-C12-cycloalkyl)C1-C4-alkyl, (optionally substituted C6-C12-aryl)-C1-C4-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, (optionally substituted C6-C12-aryloxy)—C1-C4-alkyl, C1-C6-alkylcarbonyl-C1-C4-alkyl, C1-C6-alkoxycarbonyl-C1-C4-alkyl, C1-C6-alkylaminocarbonyl-C1-C4-alkyl, optionally substituted (C3-C12-heterocyclyl)-C1-C4-alkyl, optionally substituted C3-C12-cycloalkyl, optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• R15 is C1-C8-alkyl, optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• R16a is (optionally substituted C6-C12-aryl)-C1-C4-alkyl, optionally substituted (C3-C12-heterocyclyl)-C1-C4-alkyl, optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• R16b is hydrogen or C1-C6-alkyl;
• R17 is (optionally substituted C6-C12-aryl)-C1-C4-alkyl, (optionally substituted C3-C12-heterocyclyl)-C1-C4-alkyl, optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• R9c, R9d
• are independently hydrogen, halogen, or C1-C6-alkyl;
• n5 is 0, 1, 2, 3, or 4;
• R18 is hydrogen, C1-C8-alkyl, optionally substituted C3-C12-cycloalkyl, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, halogenated C1-C6-alkoxycarbonyl, C6-C12-aryloxycarbonyl, C1-C6-alkylaminocarbonyl, (halogenated C1-C4-alkyl)aminocarbonyl, C6-C12-arylaminocarbonyl, optionally substituted C6-C12-aryl, C1-C6-alkylamine, (C3-C12-cycloalkyl-C1-C4-alkyl)amino, (halogenated C1-C6-alkyl)amino, (C1-C6-alkoxy-C1-C6-alkyl)amino, (C6-C12-aryl-C1-C4-alkyl)amino, C1-C6-dialkylamine, optionally substituted C6-C12-arylamine, or optionally substituted C3-C12-heterocyclyl;
• R19 is optionally substituted C6-C12-aryl or optionally substituted C3-C12-heterocyclyl;
• R20a is C1-C8-alkyl, (optionally substituted C3-C12-cycloalkyl)-C1-C4-alkyl, C1-C6-alkoxyC1-C6-alkyl, (optionally substituted C6-C12-aryl)-C1-C4-alkyl, (optionally substituted C3-C12-heterocyclyl)-C1-C4-alkyl, optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• R20b is hydrogen or C1-C8-alkyl;
• R21 is optionally substituted C6-C12-aryl, or optionally substituted C3-C12-heterocyclyl;
• and
• R5a, R5b
• are independently hydrogen, halogen, or C1-C3-alkyl, or
• R5a, R5b
• together with the carbon atom to which they are bound may form a C═O;
• or
• one of R2a or R2b and one of R5a or R5b
• together are optionally substituted C1-C5-alkylene,
• or a physiologically tolerated salt thereof.