Indole derivatives and their use as 5-HT1F agonists

A pharmaceutical formulation comprising a compound of formula I:

• where;
• A—D is CH—CH2 or C═CH;
• R1 is hydrogen or C1-C4 alkyl;
• R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, or Ar—(C1-C4 alkyl);
• R3 and R4 combine, together with the 6 membered ring to which they are attached, to form a 6:5, 6:6, or 6:7 fused bicyclic ring;
• and
• Ar is an optionally substituted phenyl or optionally substituted heteroaryl, where “substituted phenyl” is taken to mean that the phenyl moiety is substituted with one substituent selected from the group consisting of halo, nitro, cyano, amino, trifluoromethyl, trifluoromethoxy, phenyl, benzoyl, C1-C6 alkyl, C1-C6 alkoxy, (C1-C4 alkyl)S(O)n, where n is 0, 1, or 2, (C1-C4 alkyl)2 amino, C1-C4 acyl, or two to three substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, C1-C4 alkyl, or C1-C4 alkoxy, and where “substituted heteroaryl” is taken to mean that the heteroaryl moiety is substituted with substituents selected from the group consisting of halo, nitro, cyano, amino, trifluoromethyl, trifluoromethoxy, phenyl, benzoyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 acyl, and (C1-C4)n amino where n is 0, 1, or 2;
• or a pharmaceutical acid addition salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

A method for activating 5-HT1F receptors in a mammal comprising administering to a mammal in need of such activation an effective amount of a compound of formula I:

• where;
• A—D is CH—CH2 or C═CH;
• R1 is hydrogen or C1-C4 alkyl;
• R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, or Ar—(C1-C4 alkyl);
• R3 and R4 combine, together with the 6 membered ring to which they are attached, to form a 6:5, 6:6, or 6:7 fused bicyclic ring;
• and
• Ar is an optionally substituted phenyl or optionally substituted heteroaryl, where “substituted phenyl” is taken to mean that the phenyl moiety is substituted with one substituent selected from the group consisting of halo, nitro, cyano, amino, trifluoromethyl, trifluoromethoxy, phenyl, benzoyl, C1-C6 alkyl, C1-C6 alkoxy, (C1-C4 alkyl)S(O)n, where n is 0, 1, or 2, (C1-C4 alkyl)2 amino, C1-C4 acyl, or two to three substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, C1-C4 alkyl, or C1-C4 alkoxy, and where “substituted heteroaryl” is taken to mean that the heteroaryl moiety is substituted with substituents selected from the group consisting of halo, nitro, cyano, amino, trifluoromethyl, trifluoromethoxy, phenyl, benzoyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 acyl, and (C1-C4)n amino where n is 0, 1, or 2;
• or a pharmaceutical acid addition salt thereof.

A method for inhibiting neuronal protein extravasation in a mammal comprising administering to a mammal in need of such inhibition an effective amount of a compound of formula I:

• where;
• A—D is CH—CH2 or C═CH;
• R1 is hydrogen or C1-C4 alkyl;
• R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, or Ar—(C1-C4 alkyl);
• R3 and R4 combine, together with the 6 membered ring to which they are attached, to form a 6:5, 6:6, or 6:7 fused bicyclic ring;
• and
• Ar is an optionally substituted phenyl or optionally substituted heteroaryl, where “substituted phenyl” is taken to mean that the phenyl moiety is substituted with one substituent selected from the group consisting of halo, nitro, cyano, amino, trifluoromethyl, trifluoromethoxy, phenyl, benzoyl, C1-C6 alkyl, C1-C6 alkoxy, (C1-C4 alkyl)S(O)n, where n is 0, 1, or 2, (C1-C4 alkyl)2 amino, C1-C4 acyl, or two to three substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, C1-C4 alkyl, or C1-C4 alkoxy, and where “substituted heteroaryl” is taken to mean that the heteroaryl moiety is substituted with substituents selected from the group consisting of halo, nitro, cyano, amino, trifluoromethyl, trifluoromethoxy, phenyl, benzoyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 acyl, and (C1-C4)n amino where n is 0, 1, or 2;
• or a pharmaceutical acid addition salt thereof.

A method for treating migraine in a mammal comprising

• administering to a mammal in need of such treatment an effective amount of a compound of formula I:
• where;
• A—D is CH—CH2 or C═CH;
• R1 is hydrogen or C1-C4 alkyl;
• R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, or Ar—(C1-C4 alkyl);
• R3 and R4 combine, together with the 6 membered ring to which they are attached, to form a 6:5, 6:6, or 6:7 fused bicyclic ring;
• and
• Ar is an optionally substituted phenyl or optionally substituted heteroaryl, were “substituted phenyl” is taken to mean that the phenyl moiety is substituted with one substituent selected from the group consisting of halo, nitro, cyano, amino, trifluoromethyl, trifluoromethoxy, phenyl, benzoyl, C1-C6 alkyl, C1-C6 alkoxy, (C1-C4 alkyl)S(O)n, where n is, 0, 1, or 2, (C1-C4 alkyl)2 amino, C1-C4 acyl, or two to three substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, C1-C4 alkyl, or C1-C4 alkoxy, and where “substituted heteroaryl” is taken to mean that the heteroaryl moiety is substituted with substituents selected from the group consist of halo, nitro, cyano, amino, trifluoromethyl, trifluoromethoxy, phenyl, benzoyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 acyl, and (C1-C4)n amino where n is 0, 1, or 2;
• or a pharmaceutical acid addition salt thereof.