WO2010132072A1

WO2010132072A1 - Treatment or prevention of migraine by dosing at aura

Info

Publication number: WO2010132072A1
Application number: PCT/US2009/059295
Authority: WO
Inventors: John S. Andrews; Robert A. Medve
Original assignee: Neuraxon, Inc
Priority date: 2009-05-15
Filing date: 2009-10-01
Publication date: 2010-11-18

Abstract

The invention relates to methods for the treatment of migraine with aura and the prevention of pain in migraine with aura that include the administration at aura of a NOS inhibitor, e.g., substituted indole compounds that inhibit NOS (e.g., Compounds (l)-(54) and compounds described by Formulas (I), (I-A), or (1-B)). These indole compounds can also have a superior cardiovascular profile compared to triptan migraine therapeutics (e.g., sumatriptan), and these methods can be useful for migraineurs who have, or are at risk for, cardiovascular, neurological, or psychological diseases or conditions. The indole compounds described herein can also be used for the treatment or prevention of cortical spreading depression (CSD) or tactile allodynia.

Description

TREATMENT OR PREVENTION OF MIGRAINE BY DOSING AT AURA

Cross-Reference to Related Applications This application claims benefit of U.S. Provisional Application No.

61/178,871, filed May 15, 2009, which is hereby incorporated by reference.

Background of the Invention

The present invention relates to the field of treatment and prevention of migraine with aura.

The administration of NOS inhibitors or NO scavengers can be used to treat acute migraine with or without aura. The first observation by Asciano Sobrero in 1847 that small quantities of nitroglycerine, an NO releasing agent, causes severe headache led to the nitric oxide hypothesis of migraine (Olesen et al., Cephalalgia 15: 94-100, 1995). Serotonergic 5HT_JD/IB agonists such as sumatriptan (Imitrex^®), which are used clinically in the treatment of migraine, are known to prevent the cortical spreading depression (CSD) in the lissencephalic and gyrencephalic brain during migraine attack, a process resulting in widespread release of NO. It has been shown that sumatriptan modifies the artificially enhanced cortical NO levels following infusion of glyceryl trinitrate in rats (Read et al., Brain Res. 847:1-8, 1999; ibid, 870(1-2): 44-53, 2000).

Migraine with aura is experienced by approximately 15-30% of migraineurs (van de Ven et al., Arch. Neurol. 64(5):643-646, 2007, and Iadecola, Nature. Med., 8, 110-112, 2002), and aura precedes the onset of headache. Sumatriptan has been approved for the treatment of migraine with or without aura, and a patient suffering from a migraine is instructed to take sumatriptan at the first sign of headache pain. Thus, dosing a patient at the onset of pain is a common mode for treatment using triptans (5HT;_ID/IB agonists). In addition to sumatriptan, other triptans that have been approved by the U.S. Food and Drug Administration for the treatment of migraine include almotriptan (Axert^®), eletriptan (Relpax^®), frovatriptan (Frova^®), naratriptan (Amerge^®), rizatriptan (Maxalt ), and zolmitriptan (Zomig ). In the treatment of migraine with aura, however, studies indicate that triptans are ineffective when administered at aura (i.e., during the aura phase) rather than at the onset of pain (e.g., Bates et al., Neurology, 44(9): 1587-92, 1994 (sumatriptan), Dowson, Eur. Neurol 36(suppl 2): 28-31, 1996 (zolmitriptan), and Olesen et al., Eur. J. Neurol. 11(10): 617-677, 2004 (eletriptan)), despite the fact that the peak plasma level (T_max) of the drug occurs after the onset of pain. The aura in migraine also has been related to a phenomenon known as cortical spreading depression (Hadjikhani et al PNAS 98(8): 4687-4692, 2001). Sumatriptan does not completely block CSD induced in rats (Read et al., Brain Res. 89(l-2):69-77, 2001) or cats (Bradley et al., Exp. Neurol. 172(2):342-353, 2001). Moreover, patients having a history of migraine with aura may have a higher risk of cardiovascular disease or suffering major cardiovascular events such as ischemic stroke, myocardial infarction, or angina (see, for example, Kurth et al., JAMA, 296(3):283-291, 2006), and these conditions may be contraindications for triptan therapies. In addition, epilepsy is often a comorbid condition of migraine, and both share several common pathogenic mechanisms. In particular, cortical spreading depression has been found to be involved in the pathophysiology of epilepsy as well as in the generation of migraine aura (Calabresie et al, TIPS, 28(4): 188-195, 2007).

Accordingly, drugs that are effective when administered at aura would be beneficial to a patient, e.g., by allowing intervention at an earlier stage of migraine.

Summary of the Invention

The invention provides methods for the treatment of migraine with aura and the prevention of pain in migraine with aura that include the administration at aura of a NOS inhibitor, e.g., a substituted indole compound that inhibits NOS (e.g., any of Compounds (l)-(54) and compounds described by Formulas (I), (I- A), or (1-B)). The invention also provides methods for the treatment or prevention of cortical spreading depression.

In a first aspect, the invention features a method for the treatment of migraine with aura that includes administering to a patient at aura an effective amount of an indole compound having a structure according to Formula (I):

a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof, wherein,

R¹ is H, optionally substituted Cj_-6 alkyl, optionally substituted C_1-4 alkaryl, optionally substituted C_2-9 heterocyclyl, or optionally substituted Ci_-4 alkheterocyclyl; each of R² and R³ is, independently, H, Hal, optionally substituted Ci_-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-1O aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl (e.g., optionally substituted C_2-9 bridged heterocyclyl), or optionally substituted Ci_-4 alkheterocyclyl (e.g., optionally substituted Ci_-4 bridged alkheterocyclyl); each of R⁴ and R⁷ is, independently, H, F, Q_-6 alkyl, or Ci_-6 alkoxy;

R⁵ is H, R^5AC(NH)NH(CH₂)_r5 or R^5BNHC(S)NH(CH₂)_r5, wherein r5 is an integer from 0 to 2, R^5A and R^5B are each optionally substituted Ci_-6 alkyl, optionally substituted C_6-io aryl, optionally substituted Cj_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted Ci_-6 thioalkoxy, optionally substituted Ci_-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted Ci_-4 thioalkheterocyclyl; and

R⁶ is H or R^6AC(NH)NH(CH₂)_r6 or R^6BNHC(S)NH(CH₂)_r6, wherein r6 is an integer from 0 to 2, R^6A and R^6B are each optionally substituted C_)-6 alkyl, optionally substituted C_6-I0 aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted C_1-4 alkheterocyclyl, optionally substituted Ci_-6 thioalkoxy, optionally substituted C_M thioalkaryl, optionally substituted aryloyl, or optionally substituted Ci_-4 thioalkheterocyclyl; and wherein one, but not both, of R⁵ and R⁶ is H.

In a second aspect, the invention features a method for the prevention of pain in migraine with aura that includes administering to a patient at aura an effective amount of an indole compound having a structure according to Formula (I).

In another aspect, the invention features a method for the treatment or prevention of cortical spreading depression (CSD) that includes administering to a patient an effective amount of an indole compound having a structure according to Formula (I). In still another aspect, the invention features a method for the treatment of allodynia (e.g., tactile allodynia) in a patient having a migraine with aura that includes administering to the patient an effective amount of an indole compound having a structure according to Formula (I). In any of the methods described herein, R⁵ may be H, R^5AC(NH)NH(CH₂)_r5, or R^5BNHC(S)NH(CH₂)_r5, wherein r5 is an integer from 0 to 2, R^5A is optionally substituted C_6-io aryl, optionally substituted C_1-4 alkaryl, optionally substituted C₂-₉ heterocyclyl, optionally substituted C_1-4 alkheterocyclyl, optionally substituted Ci_-6 thioalkoxy, optionally substituted Cj_-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted Ci_-4 thioalkheterocyclyl; R^5B is optionally substituted Ci_-6 thioalkoxy, optionally substituted Ci_-4 thioalkaryl, or optionally substituted Ci_-4 thioalkheterocyclyl; and R⁶ is H, R^6AC(NH)NH(CH₂)_r6, or R^6BNHC(S)NH(CH₂)_r6, wherein r6 is an integer from 0 to 2, R^6Λ is optionally substituted Ci_-6 alkyl, optionally substituted C_6-I0 aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Cj_-4 alkheterocyclyl, optionally substituted Ci_-6 thioalkoxy, optionally substituted Ci_-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted Ci_-4 thioalkheterocyclyl; R^6B is optionally substituted C_6-Io ^aryl_> optionally substituted C]_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted Ci_-6 thioalkoxy, optionally substituted C]_-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted Ci_-4 thioalkheterocyclyl.

In any of the methods described herein, each of R² and R³ is, independently, H, Hal, optionally substituted Ci_-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-I0 aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, or optionally substituted Ci_-4 alkheterocyclyl; each of R⁴ and R⁷ is, independently, H, F, Ci_-6 alkyl, or C_1-6 alkoxy; R⁵ is H or R^5AC(NH)NH(CH₂)_r5, wherein r5 is an integer from 0 to 2, R^5A is optionally substituted C_6-Io aryl, optionally substituted C_1-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted Ci_-6 thioalkoxy, optionally substituted Ci_-4 thioalkaryl, or optionally substituted Ci_-4 thioalkheterocyclyl; and R⁶ is H or R^6AC(NH)NH(CH₂)_r6, wherein r6 is an integer from 0 to 2, R^6A is optionally substituted C_1-6 alkyl, optionally substituted C_6-io aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted Ci_-6thioalkoxy, optionally substituted Ci_-4 thioalkaryl, or optionally substituted Cj_-4 thioalkheterocyclyl.

In any of the methods described herein, R³ may be (CH2)_m3X³, wherein X³ is selected from the group consisting of:

, wherein each of

R^3A and R^3B is, independently, H, optionally substituted Ci_-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-I0 aryl, optionally substituted Ci_-4 alkaryl, C_2-9 heterocyclyl, or optionally substituted C_1-4 alkheterocyclyl; each of R^3C and R^3D is, independently, H, F, OH, CO₂R^3E, or NR^3FR^3G, wherein each of R^3E, R^3F, and R^3G is, independently, H, optionally substituted Ci_-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-10 aryl, optionally substituted Cj_-4 alkaryl, C_2-9 heterocyclyl, or optionally substituted C_1-4 alkheterocyclyl, or R^3C and R^3D together with the carbon they are bonded to are C=O; Z³ is NR^3H, NC(0)R^3H, NC(O)OR^3H, NC(0)NHR^3H, NC(S)R^3H, NC(S)NHR^3H, NS(O)₂R^3H, O, S, S(O), or S(O)₂, wherein R^3His H, optionally substituted Ci_-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-io aryl, optionally substituted Ci_-4 alkaryl, C_2-9 heterocyclyl, or optionally substituted Ci_-4 alkheterocyclyl; m3 is an integer of 0 to 6; n3 is an integer of 1 to 4; p3 is an integer of 0 to 2; and q3 is an integer of 0 to 5. When X³ is NR^AR^B, m3 is not 0.

In some embodiments, R¹ or R is optionally substituted C_2-9 heterocyclyl or optionally substituted C_1-4 alkheterocyclyl, where the heterocyclyl moiety is a bicyclic, nitrogen containing heterocyclyl.

In any of the methods described herein, the indole compound may have a structure according to

or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof, wherein: X is O or S; R¹ is H, optionally substituted Ci_-6 alkyl, optionally substituted Ci_-4 alkaryl, or optionally substituted Ci_-4 alkheterocyclyl; each of R and R is, independently, H, Hal, optionally substituted C]_-6 alkyl, optionally substituted C_6-10 aryl, optionally substituted Cj_-4 alkaryl, optionally substituted C_2-9 bridged heterocyclyl, optionally substituted C_1-4 bridged alkheterocyclyl, optionally substituted C_2-9 heterocyclyl, or optionally substituted Cj_-4 alkheterocyclyl; and each of R⁴ and R⁷ is, independently, H, F, Ci_-6 alkyl, or Ci_-6 alkoxy.

In any of the methods described herein, the pharmaceutically acceptable salt is the hydrochloride salt.

In any of the methods described herein, the indole compound is selected from the group consisting of:

or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof.

In some embodiments, the indole compound has the following structure:

(21) or a pharmaceutically acceptable salt, e.g., dihydrochloride, or prodrug thereof. In further embodiments, the pharmaceutically acceptable salt is the dihydrochloride salt.

In any of the methods described herein, the indole compound is a selective nNOS inhibitor.

In any of the methods described herein, administration is oral. In any of the methods described herein, 10-800 mgs of the indole compound is administered. In some embodiments, 50, 100, or 200 mgs of the indole compound is administered. In other embodiments, 400, 600, or 800 mgs of the indole compound is administered. In any of the methods described herein, the indole compound is administered at a dosage of 0.25-25 mg/kg. In some embodiments, the dosage is 0.5-5.0 mg/kg. In certain embodiments, dosage is 0.5-1.0 mg/kg, 1.0-2.0 mg/kg, or 2.0-4.0 mg/kg. In other embodiments, the dosage is 5.0-20 mg/kg. In still other embodiments, the dosage is 5.0-8.0 mg/kg, 8.0-12 mg/kg, or 1 1-16 mg/kg. In any of the methods described herein, the patient can have cardiovascular disease or can be at risk of cardiovascular disease. In some embodiments, the patient has cardiovascular disease or is at risk of cardiovascular disease.

In any of the methods described herein, the patient can have a condition that is contraindicated for triptan therapy or can be at risk of a condition that is contraindicated for triptan therapy.

By "at aura" is meant any time after the onset of aura and prior to the onset of migraine pain.

The term "acyl," as used herein, represents a hydrogen or an alkyl group (e.g., a haloalkyl group), as defined herein, that is attached to the parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, propionyl, butanoyl and the like. Exemplary unsubstituted acyl groups include from 1 to 7 carbons. In some embodiments, the alkyl group is further substituted with 1, 2, 3, or 4 substituents as described herein.

The term "alkaryl," as used herein, represents an aryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein. Exemplary unsubstituted alkaryl groups are of from 7 to 16 carbons. In some embodiments, the alkylene and the aryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups. Other groups preceded by the prefix "alk-"are defined in the same manner, where "alk" refers to a Ci_-6 alkylene, unless otherwise noted, and the attached chemical structure is as defined herein.

The term "alkcycloalkyl" represents a cycloalkyl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein (e.g., an alkylene group of 1-4, 1-6, or 1-10 carbons). In some embodiments, the alkylene and the cycloalkyl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective group.

The term "alkenyl," as used herein, represents monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 6 carbons containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl, and the like. Alkenyl groups may be optionally substituted with 1, 2, 3, or 4 substituent groups that are selected, independently, from aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.

The term "alkheteroaryl" refers to a heteroaryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein. In some embodiments, the alkylene and the heteroaryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective group. Alkheteroaryl groups are a subset of alkheterocyclyl groups.

The term "alkheterocyclyl" represents a heterocyclyl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein. Exemplary unsubstituted alkheterocyclyl groups are of from 2 to 14 carbons. In some embodiments, the alkylene and the heterocyclyl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective group.

The term "alkoxy" represents a chemical substituent of formula -OR, where R is a Ci_-6 alkyl group, unless otherwise specified. In some embodiments, the alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein.

The term "alkoxyalkyl" represents an alkyl group that is substituted with an alkoxy group. Exemplary unsubstituted alkoxyalkyl groups include between 2 to 12 carbons. In some embodiments, the alkyl and the alkoxy each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective group.

The term "alkyl," as used herein, is inclusive of both straight chain and branched chain saturated groups of from 1 to 6 carbons, unless otherwise specified. Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, neopentyl, and the like, and may be optionally substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four substituents independently selected from the group consisting of: (1) alkoxy; (2) alkylsulfinyl; (3) amino; (4) arylalkoxy; (4) azido; ((5) halo; (6) (heterocyclyl)oxy; (7) hydroxy; (8) nitro; (9) oxo (e.g., carboxyaldehyde or acyl); (10) spirocyclyl; (11) thioalkoxy; (12) thiol; (13) -CO₂R^A, where R^A is selected from the group consisting of (a) alkyl, (b) aryl, (c) hydrogen, and (d) alkaryl; (14) -C(O)NR^BR^C, where each of R^B and R^c is, independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) alkaryl; (15) -SO₂R^D, where R^D is selected from the group consisting of (a) alkyl, (b) aryl and (c) alkaryl; and (16) -SO₂NR^ER^F, where each of R^E and R^F is, independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) alkaryl. In some embodiments, each of these groups can be further substituted as described herein. For example, the alkylene group of a C₁ -alkaryl or a Q- alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.

The term "alkylene" and the prefix "alk-," as used herein, represent a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, and the like. The term "C_x-y alkylene" and the prefix "C_x-y alk-" represent alkylene groups having between x and y carbons. Exemplary values for x are 1, 2, 3, 4, 5, and 6, and exemplary values for y are 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, the alkylene can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for an alkyl group.

The term "alkylsulfinyl," as used herein, represents an alkyl group attached to the parent molecular group through an -S(O)- group. Exemplary unsubstituted alkylsulfinyl groups are of from 1 to 6 carbons. In some embodiments, the alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein.

The term "alkylsulfϊnylalkyl," as used herein, represents an alkyl group, as defined herein, substituted by an alkylsulfinyl group. Exemplary unsubstituted alkylsulfinylalkyl groups are of from 2 to 12 carbons. In some embodiments, each alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein.

The term "alkynyl," as used herein, represents monovalent straight or branched chain groups of from two to six carbon atoms containing a carbon-carbon triple bond and is exemplified by ethynyl, 1 -propynyl, and the like. Alkynyl groups may be optionally substituted with 1, 2, 3, or 4 substituent groups that are selected, independently, from aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.

The term "allodynia," as used herein, refers to a pain caused by a normally innocuous stimulus (for example, stimulus to the scalp or skin).

The term "amino," as used herein, represents -N(R^N1)₂, wherein each R^N1 is, independently, H, OH, NO₂, N(R^N2)₂, SO₂OR^N2, SO₂R^N2, SOR^N2, an iV-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkcycloalkyl, heterocyclyl (e.g., heteroaryl), alkheterocyclyl (e.g., alkheteroaryl), or two R^N1 combine to form a heterocyclyl or an iV-protecting group, and wherein each R^N2 is, independently, H, alkyl, or aryl. In a preferred embodiment, amino is -NH₂, or - NHR^N1, wherein each R^N1 is, independently, OH, NO₂, NH₂, NR^N2 ₂, SO₂OR^N2, SO₂R^N2, SOR^N2, alkyl, or aryl, and each R^N2 can be H, alkyl, or aryl.

The term "aminoalkyl," as used herein, represents an alkyl group, as defined herein, substituted by an amino group, as defined herein. The alkyl and amino each can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the respective group.

The term "aryl," as used herein, represents a mono-, bicyclic, or multicyclic carbocyclic ring system having one or two aromatic rings and is exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, and the like, and may be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of: (1) acyl (e.g., carboxyaldehyde ); (2) alkyl (e.g., alkoxyalkyl, alkylsulfinylalkyl, aminoalkyl, azidoalkyl, (carboxyaldehyde)alkyl, haloalkyl (e.g., perfluoroalkyl), hydroxyalkyl, nitroalkyl, or thioalkoxyalkyl); (3) alkoxy (e.g., perfluoroalkoxy); (4) alkylsulfinyl; (5) aryl; (6) amino; (7) alkaryl; (8) azido; (9) cycloalkyl; (10) alkcycloalkyl; (11) halo; (12) heterocyclyl (e.g., heteroaryl); (13) (heterocyclyl)oxy; (14) hydroxy; (15) nitro; (16) thioalkoxy; (17) -(CH₂)_qCO₂R^A, where q is an integer of from zero to four, and R^A is selected from the group consisting of (a) alkyl, (b) aryl, (c) hydrogen, and (d) alkaryl; (18) -(CH₂)_qCONR R , where q is an integer of from zero to four and

R C where R and R are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) alkaryl; (19) -(CH₂)_qSO₂R^D, where q is an integer of from zero to four and where R^D is selected from the group consisting of (a) alkyl, (b) aryl, and (c) alkaryl; (20) -(CH₂)_qSθ₂NR^ER^F, where q is an integer of from zero to four and where each of R^E and R^F is, independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) alkaryl; (21) thiol; (22) aryloxy; (23) cycloalkoxy; (24) arylalkoxy; and (25) alkheterocyclyl (e.g., alkheteroaryl). In some embodiments, each of these groups can be further substituted as described herein. For example, the alkylene group of a Ci -alkaryl or a Cj -alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.

The term "arylalkoxy," as used herein, represents an alkaryl group, as defined herein, attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted arylalkoxy groups are of from 7 to 16 carbons. In some embodiments, the alkaryl group can be substituted with 1, 2, 3, or 4 substituents as defined herein.

The term "aryloxy" represents a chemical substituent of formula -OR', where R' is an aryl group of 6 to 18 carbons, unless otherwise specified. In some embodiments, the aryl group can be substituted with 1, 2, 3, or 4 substituents as defined herein.

The term "aryloyl," as used herein, represents an aryl group, as defined herein, that is attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted aryloyl groups are of 7 to 11 carbons. In some embodiments, the aryl group can be substituted with 1, 2, 3, or 4 substituents as defined herein.

The term "azido" represents an N₃ group, which can also be represented as N=N=N.

The term "bridged alkheterocyclyl" represents a bridged heterocyclic compound, as described herein, attached to the parent molecular group through an alkylene group. In some embodiments, the alkylene and the bridged heterocyclyl each can be substituted with 1, 2, 3, or 4 substituents as defined herein for the respective group..

The term "bridged heterocyclyl" represents a heterocyclic compound, as otherwise described herein, having a bridged multicyclic structure in which one or more carbon atoms and/or heteroatoms bridge two non-adjacent members of a monocyclic ring. An exemplary bridged heterocyclyl group is a quinuclidinyl group. In some embodiments, the bridged heterocyclyl can be substituted with 1, 2, 3, or 4 substituents as defined herein for a heterocyclyl group. As used herein, "carbocyclic" refers to an optionally substituted C₃-C]₂ monocyclic, bicyclic, or tricyclic structure in which the rings, which may be aromatic or non-aromatic, are formed by carbon atoms. Carbocyclic structures include cycloalkyl, cycloalkenyl, and aryl groups.

As used herein, the term "carbamyl" refers to a carbamate group having the structure -NR^N1C(=O)OR or -OC(=O)N(R^N1)₂, where the meaning of each R^N1 is found in the definition of "amino" provided herein, and R is alkyl, cycloalkyl , alkcycloalkyl, aryl, alkaryl, heterocyclyl (e.g., heteroaryl), or alkheterocyclyl (e.g., alkheteroaryl), as defined herein.

The term "carbonyl," as used herein, represents a C(O) group, which can also be represented as C=O. The term "carboxyaldehyde" represents an acyl group having the structure

-CHO.

The term "cycloalkyl," as used herein represents a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon group of from three to eight carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1.]heptyl, and the like. When the cycloalkyl group includes one carbon-carbon double bond, the cycloalkyl group can be referred to as a "cycloalkenyl" group. Exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl, and the like. The cycloalkyl groups of this invention can be optionally substituted with: (1) acyl (e.g., carboxyaldehyde ); (2) alkyl (e.g., alkoxyalkyl, alkylsulfmylalkyl, aminoalkyl, azidoalkyl, (carboxyaldehyde)alkyl, haloalkyl (e.g., perfluoroalkyl), hydroxyalkyl, nitroalkyl, or thioalkoxyalkyl); (3) alkoxy (e.g., perfluoroalkoxy); (4) alkylsulfinyl; (5) aryl; (6) amino; (7) alkaryl; (8) azido; (9) cycloalkyl; (10) alkcycloalkyl; (11) halo; (12) heterocyclyl (e.g., heteroaryl); (13) (heterocyclyl)oxy; (14) hydroxy; (15) nitro; (16) thioalkoxy; (17) -(CH₂)qCO₂R^Λ, where q is an integer of from zero to four, and R^A is selected from the group consisting of (a) alkyl, (b) aryl, (c) hydrogen, and (d) alkaryl; (18) - (CH₂)_qCONR R , where q is an integer of from zero to four and where R and R are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) alkaryl; (19) -(CH₂^SO₂R⁰, where q is an integer of from zero to four and where R^D is selected from the group consisting of (a) alkyl, (b) aryl, and (c) alkaryl; (20) -(CH₂)_qSθ₂NR^ER^F, where q is an integer of from zero to four and where each of R^E and R^F is, independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) alkaryl; (21) thiol; (22) aryloxy; (23) cycloalkoxy; (24) arylalkoxy; (25) alkheterocyclyl (e.g., alkheteroaryl); and (26) oxo. In some embodiments, each of these groups can be further substituted as described herein. For example, the alkylene group of a Ci -alkaryl or a C₁ -alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.

The term "cycloalkoxy," as used herein, represents a cycloalkyl group, as defined herein, attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted cycloalkoxy groups are of from 3 to 8 carbons. In some embodiment, the cycloalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.

The term an "effective amount" of an agent, as used herein, is that amount sufficient to effect beneficial or desired results, such as clinical results, and, as such, an "effective amount" depends upon the context in which it is being applied. For example, in the context of administering an agent that is an inhibitor of NOS, an effective amount of an agent is, for example, an amount sufficient to achieve a reduction in NOS activity as compared to the response obtained without administration of the agent.

The term "hal," as used herein, represents a halogen selected from bromine, chlorine, iodine, or fluorine. The term "haloalkyl," as used herein, represents an alkyl group, as defined herein, substituted by a halogen group (i.e., F, Cl, Br, or I). A haloalkyl may be substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four halogens. Haloalkyl groups include perfluoroalkyls. In some embodiments, the haloalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.

The term "heteroalkylene," as used herein, refers to an alkylene group, as defined herein, in which 1 or 2 of the constituent carbon atoms have each been replaced by O, N, or S. In some embodiments, the heteroalkylene group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkylene groups.

The term "heteroaryl," as used herein, represents that subset of heterocyclyls, as defined herein, which are aromatic: i.e., they contain 4n+2 pi electrons within the mono- or multicyclic ring system. In some embodiment, the heteroaryl is substituted with 1, 2, 3, or 4 substituents groups as defined for a heterocyclyl group.

The term "heterocyclyl," as used herein represents a 5-, 6- or 7-membered ring, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The 5-membered ring has zero to two double bonds, and the 6- and 7-membered rings have zero to three double bonds. The term "heterocyclyl" also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and/or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group. The term "heterocyclyl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring, such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like. Examples of fused heterocyclyls include tropanes and 1,2,3,5,8,8a- hexahydroindolizine. Heterocyclics include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, isoindazoyl, triazolyl, tetrazolyl, oxadiazolyl, uricyl, thiadiazolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, benzothienyl and the like. Heterocyclic groups also include groups of the formula

where F' is selected from the group consisting of -CH₂-, -CH₂O- and -O-, and G' is selected from the group consisting of -C(O)- and -(C(R')(R"))_V-, where each of R¹ and R" is, independently, selected from the group consisting of hydrogen or alkyl of one to four carbon atoms, and v is one to three and includes groups, such as 1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl, and the like. Any of the heterocyclyl groups mentioned herein may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of: (1) acyl (e.g., carboxyaldehyde ); (2) alkyl (e.g., alkoxyalkyl, alkylsulfmylalkyl, aminoalkyl, azidoalkyl, (carboxyaldehyde)alkyl, haloalkyl (e.g., perfluoroalkyl), hydroxyalkyl, nitroalkyl, or thioalkoxyalkyl); (3) alkoxy (e.g., perfluoroalkoxy); (4) alkylsulfinyl; (5) aryl; (6) amino; (7) alkaryl; (8) azido; (9) cycloalkyl; (10) alkcycloalkyl; (11) halo; (12) heterocyclyl (e.g., heteroaryl); (13) (heterocyclyl)oxy; (14) hydroxy; (15) nitro; (16) thioalkoxy; (17) -(CH₂)_qCθ₂R^A, where q is an integer of from zero to four, and R^A is selected from the group consisting of (a) alkyl, (b) aryl, (c) hydrogen, and (d) alkaryl; (18) -(CH₂)_qCONR^BR^c, where q is an integer of from zero to four and where R and R are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) alkaryl; (19) -(CH₂)_qSO₂R^D, where q is an integer of from zero to four and where R^D is selected from the group consisting of (a) alkyl, (b) aryl, and (c) alkaryl; (20) -(CH₂)_qSO₂NR^ER^F, where q is an integer of from zero to four and where each of R^E and R^F is, independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) alkaryl; (21) thiol; (22) aryloxy; (23) cycloalkoxy; (24) arylalkoxy; (25) alkheterocyclyl (e.g., alkheteroaryl); (26) oxo; and (27) (heterocyclyl)imino. In some embodiments, each of these groups can be further substituted as described herein. For example, the alkyl ene group of a Cr alkaryl or a Q-alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.

The term "(heterocyclyl)imino," as used herein, represents a heterocyclyl group, as defined herein, attached to the parent molecular group through an imino group. In some embodiments, the heterocyclyl group can be substituted with 1, 2, 3, or 4 substituent groups as defined herein.

The term "(heterocyclyl)oxy," as used herein, represents a heterocyclyl group, as defined herein, attached to the parent molecular group through an oxygen atom. In some embodiments, the heterocyclyl group can be substituted with 1, 2, 3, or 4 substituent groups as defined herein.

The term "(heterocyclyl)oyl," as used herein, represents a heterocyclyl group, as defined herein, attached to the parent molecular group through a carbonyl group. In some embodiments, the heterocyclyl group can be substituted with 1, 2, 3, or 4 substituent groups as defined herein.

The term "hydroxy," as used herein, represents an -OH group.

The term "hydroxy alkyl," as used herein, represents an alkyl group, as defined herein, substituted by one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group and is exemplified by hydroxymethyl, dihydroxypropyl, and the like.

The term "hyperalgesia," as used herein, refers to an increased response to a painful stimulus.

The term "imino," as used herein, represents a C(NH) group, which can also be represented as C=NH.

The term "JV-protected amino," as used herein, refers to an amino group, as defined herein, to which is attached one or two JV-protecting groups, as defined herein.

The term "TV-protecting group," as used herein, represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used JV-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," 3^rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. TV-protecting groups include acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2- chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o- nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine, and the like; sulfonyl-containing groups such as benzenesulfonyl, p-toluenesulfonyl, and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyl oxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)- 1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,- trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9- methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like, alkaryl groups such as benzyl, triphenylmethyl, benzyloxymethyl, and the like and silyl groups such as trimethylsilyl, and the like. Preferred TV-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxy carbonyl (Cbz).

The term "nitro," as used herein, represents an -NO₂ group.

The term "oxo" as used herein, represents =O.

The term "perfluoroalkyl," as used herein, represents an alkyl group, as defined herein, where each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical. Perfluoroalkyl groups are exemplified by trifluoromethyl, pentafluoroethyl, and the like.

The term "perfluoroalkoxy," as used herein, represents an alkoxy group, as defined herein, where each hydrogen radical bound to the alkoxy group has been replaced by a fluoride radical.

The term "pharmaceutical composition," as used herein, represents a composition containing an indole compound described herein (e.g., any of Compounds (l)-(54) and compounds of Formulas (I), (I- A), and (1-B)), formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein.

A "pharmaceutically acceptable excipient," as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

The term "pharmaceutically acceptable prodrugs" as used herein, represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.

The term "pharmaceutically acceptable salt," as use herein, represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and CG. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the indole compounds described herein or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. The term "pharmaceutically acceptable solvate" as used herein means an indole compound as described herein wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered. For example, solvates may be prepared by crystallization, recrystallization, or precipitation from a solution that includes organic solvents, water, or a mixture thereof. Examples of suitable solvents are ethanol, water (for example, mono-, di-, and tri-hydrates), jV-methylpyrrolidinone (NMP), dimethyl sulfoxide (DMSO), ΛyV'-dimethylformamide (DMF), yV,N'-dimethylacetamide (DMAC), 1,3- dimethyl-2-imidazolidinone (DMEU), l,3-dimethyl-3,4,5,6-tetrahydro-2-(lH)- pyrimidinone (DMPU), acetonitrile (ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone, benzyl benzoate, and the like. When water is the solvent, the molecule is referred to as a "hydrate."

The term "Ph" as used herein means phenyl.

The term "prevent," as used herein, refers to prophylactic treatment or treatment that prevents one or more symptoms or conditions of a disease, disorder, or conditions described herein (e.g., pain or migraine with aura and with or without allodynia). Preventative treatment can be initiated, for example, prior to ("preexposure prophylaxis") or following ("post-exposure prophylaxis") an event that precedes the onset of the disease, disorder, or conditions (e.g., at migraine aura). Preventive treatment that includes administration of an indole compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, can be acute, short-term, or chronic. The doses administered may be varied during the course of preventative treatment. See also: Kaniecki et al., "Treatment of Primary Headache: Preventive Treatment of Migraine." In: Standards of Care for Headache Diagnosis and Treatment. Chicago (IL): National Headache Foundation; 2004, p. 40-52.

The term "prodrug," as used herein, represents compounds that are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. Prodrugs of the indole compounds described herein may be conventional esters. Some common esters that have been utilized as prodrugs are phenyl esters, aliphatic (Cj-C₈ Or C₈-C₂₄) esters, cholesterol esters, acyloxymethyl esters, carbamates, and amino acid esters. For example, an indole compound that contains an OH group may be acylated at this position in its prodrug form. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and Judkins et al., Synthetic Communications 26(23):4351- 4367, 1996, each of which is incorporated herein by reference. Preferably, prodrugs of the compounds of the present invention are suitable for use in contact with the tissues of humans and animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.

Each of the terms "selectively inhibits nNOS" or "a selective nNOS inhibitor" refers to a substance that inhibits or binds the neuronal nitric oxide synthase (nNOS) isoform more effectively than the endothelial nitric oxide synthase (eNOS) and/or the inducible nitric oxide synthase (iNOS) isoform as measured by an in vitro assay, such as, for example, those assays described herein or elsewhere in the literature (e.g., Boer et al., MoI Pharmacol, 58(5): 1026-1034, 2000). Additionally, a compound can also bind to nNOS and iNOS selectively over eNOS. Selective inhibition can be expressed in terms of an IC₅₀ value, a Kj value, or the inverse of a percent inhibition value that is lower, or conversely a higher % inhibition when the substance is tested in an nNOS assay than when tested in an eNOS and/or iNOS assay. Preferably, the IC₅₀ or K; value is 2 times lower. More preferably, the IC₅₀ or K; value is 5, 10, 50, or even more than 100 times lower.

The term "spirocyclyl," as used herein, represents an alkylene diradical, both ends of which are bonded to the same carbon atom of the parent group to form a spirocyclic group, and also a heteroalkylene diradical, both ends of which are bonded to the same atom.

The term "sulfonyl," as used herein, represents an -S(O)₂- group.

The term "thioalkaryl," as used herein, represents a chemical substituent of formula -SR, where R is an alkaryl group. In some embodiments, the alkaryl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.

The term "thioalkheterocyclyl," as used herein, represents a chemical substituent of formula -SR, where R is an alkheterocyclyl group. In some embodiments, the alkheterocyclyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein. The term "thioalkoxy," as used herein, represents a chemical substituent of formula -SR, where R is an alkyl group. In some embodiments, the alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.

The term "thiol" represents an -SH group.

As used herein, and as well understood in the art, "treatment" is an approach for obtaining beneficial or desired results, such as clinical results. Beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable. "Palliating" a disease, disorder, or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.

Other features and advantages of the invention will be apparent from the following detailed description, the drawings, and the claims. Brief Description of the Drawings

Fig. IA shows the change in headache severity score (HSS) following oral administration of a placebo or 50, 100, or 200 mgs of Compound (21) to a migraineur without a history of migraine with aura (MA). Fig. IB shows the change in HSS following oral administration of a placebo or 50, 100, or 200 mgs of Compound (21) to a migraineur with a history of MA.

Fig. 2 shows the plasma concentration (ng/mL) of Compound (21) following oral administration of -200, 400, 600, or 800 mg doses.

Fig. 3 compares the estimated probability of patients requiring a second dose of either sumatriptan or Compound (21 ), or of another migraine treatment, following the initial dose of sumatriptan or Compound (21).

Fig. 4 shows the response of human coronary arteries to sumatriptan and Compound (21) as the percent response to 60 mM KCl and a larger vasoconstrictive effect of sumatriptan compared to Compound (21). Fig. 5 shows the response of a single dose of Compound 21 in an animal model of cortical spreading depression (CSD), where the compound mitigates tactile allodynia associated with CSD.

Detailed Description The invention relates to a method for the treatment or prevention of migraine with aura that includes administering a NOS inhibitor, such as an indole compound (e.g., any of Compounds (l)-(54) or a compound of Formula (I), (I-A), or (1-B)) at aura to a patient. The indole compounds described herein can also be used for the treatment or prevention of cortical spreading depression or tactile allodynia. Other NOS inhibitors are known in the art. Preferably, the NOS inhibitor employed is a selective nNOS inhibitor.

Migraine with Aura

Aura is the second of the four possible phases of migraine (prodrome, aura, headache, and postdrome), although a migraineur does not necessarily experience all four phases. Migraine with aura is experienced by approximately 30% of migraineurs (van de Ven et al., Arch. Neurol 64(5):643-646, 2007), and guidelines for diagnosis of migraine with aura are found, for example, in Eriksen et al., European Journal of Neurology 11 :583-591, 2004 and in the International Classification of Headache Disorders, Second Edition (ICHD-II). Subtypes of migraine with aura include those set forth in the ICHD-II such as typical aura with migraine headache (IHS 1.2.1), typical aura with non-migraine headache (IHS 1.2.2), typical aura without headache (IHS 1.2.3), familial hemiplegic migraine (IHS 1.2.4), sporadic hemiplegic migraine (IHS 1.2.5), and basilar-type migraine (IHS 1.2.6). Table 1 sets forth the ICHD-II diagnostic criteria A-E for typical aura with migraine headache. The time ranges described herein may vary according to the individual. For example, aura may precede the migraine headache by 20-90 minutes (e.g., by 20-40 minutes).

Table 1

ICHD-II Diagnostic Criteria for Typical Aura with Migraine

When the patient falls asleep during migraine and wakes up without it, duration of the attack is reckoned until the time of awakening. B In children, attacks may last 1 -72 hours (although the evidence for untreated durations of less than 2 hours in children requires corroboration by prospective diary studies). c When attacks occur on >15 days/month for >3 months, code as 1.1

Migraine without aura and as 1.5.1 Chronic migraine. D Migraine headache is commonly bilateral in young children; an adult pattern of unilateral pain usually emerges in late adolescence or early adult life. E Migraine headache is usually frontotemporal. Occipital headache in children, whether unilateral or bilateral, is rare and calls for diagnostic caution; many cases are attributable to structural lesions. F Pulsating means throbbing or varying with the heartbeat. G In young children, photophobia and phonophobia may be inferred from their behaviour.

Not attributed to another disorder .

Additional loss or blurring of central vision may occur.

² History and physical and neurological examinations do not suggest any of the disorders listed in groups 5-12³, or history and/or physical and/or neurological examinations do suggest such disorder but it is ruled out by appropriate investigations, or such disorder is present but attacks do not occur for the first time in close temporal relation to the disorder.

³ The cited groups 5-12 relate to ICHD-II classifications of secondary headaches that are attributed to: head and/or neck trauma; cranial or cervical vascular disorder; non-vascular intracranial disorder; a substance or its withdrawal; infection; disorder of homoeostasis; disorder of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth or other facial or cranial structures (also includes facial pain caused by any of these disorders); or psychiatric disorder.

The aura in migraine has been related to CSD. Cortical spreading depression (CSD), a wave of neuronal depolarization that spreads across the cerebral cortex, has been shown to be in place when patients experience an aura (Hadjikhani et al., PNAS 98(8):4687-4692, 2001). The appearance of aura in migraine as resulting from CSD and the subsequent progression of the headache phase has also been substantiated by mechanistic evidence (Iadecola, Nature Med. 8(2): 110-112, 2002). Thus, CSD activates trigeminal afferents that causes inflammatory changes in pain-sensitive meninges to generate the headache (Bolay et al., Nature Med. 7:136-142, 2002). Tonabersat (SB-220453), a drug being developed for the prevention of migraine

(prophylaxis as opposed to acute treatment), blocks the duration of CSD-induced NO release in anaesthetized cats without uncoupling the cerebrovascular changes associated with spreading depression (Read et al., Cephalalgia, 20(2):92-99, 2002). In addition, Tonabersat, an inhibitor of CSD, has a significant preventive effect in migraine patients with aura (Olesen et al., Cephalalgia, 29(Suppl. 1):3, 2009; 14^th Congress of the Internal Headache Society Program Absracts) but no efficacy on non- aura attacks. In patients with severe and prolonged aura, ketamine (25 mg intranasal dose) is the only agent that has been shown to offer any beneficial effect in reducing the severity of aura resulting from hemiplegic migraine (Kaube et al., Neurology 55(1): 139-41, 2000). A study using inhaled isoproterenol at the onset of aura revealed the drug could abort the neurological and visual disturbances for migraine with aura and basilar migraine. In some cases the headache phase was unaffected and in other cases it became more severe with the use of the drug. Similar effects were observed with nitroglycerin and amyl nitrite (NO donor) where the administration of during the aura phase resulted in resolution of the neurologic symptoms in half the cases but with minimal impact on the headache phase or severity. Other agents, such as sublingual nifedipine ( 10 mg), effectively reverse focal neurologic symptoms of migraine with prolonged aura but are not effective at treating the headache of migraine when given during the aura.

Dosing at Aura

The indole compounds described herein (e.g., Compound (21)) are administered to a patient at aura (e.g., concurrent with any of the symptoms described in (B) and (C) of Table 1). Treatment according to the methods described herein may avoid undesirable cardiovascular effects (e.g., an increase in blood pressure or coronary vasoconstriction associated with non-specific NOS inhibitors or triptans, respectively). The effectiveness of this dosing scheme has been studied in patients (e.g., Examples 1-3 described herein) and compared to results obtained using other medications (e.g., sumatriptan) used for the treatment of acute migraine. Surprisingly, our data indicate that administration of an indole compound as described herein at aura results in treatment of migraine. Previous studies have shown that the administration of triptans at aura, rather than at pain, are ineffective for the treatment of migraine with aura. For example, the subcutaneous administration of sumatriptan (Imitrex^®) at aura did not affect the migraine aura or delay the onset of headache (Bates et al., Neurology, 44(9): 1587-92, 1994), Dowson, Eur. Neurol 36(suppl 2): 28- 31, 1996 (zolmitriptan), and eletriptan (Relpax ) was ineffective when administered orally at aura (Olesen et al., Eur. J. Neurol. 11(10): 617-677, 2004). The combination of abortive treatment during the aura (Myers, Headache, 39:118-124, 1999) together with abortion of the migraine headache without undesirable vascular effects (e.g., such as those resulting from treatment with non-selective NOS inhibitors such as L- NMMA (Olesen, J Pharmacol. & Therapeutics, 120: 157- 171 , 2008) provides beneficial strategy for treating migraine with aura.

Disorders and Conditions Associated with Migraine with Aura

The methods described herein can also be useful for the treatment of allodynia that occurs during migraine with aura. An agent that also successfully treats allodynia symptoms, especially those associated with migraine aura (Tietjen et al., Headache, 49:1333-1344, 2009) or is able to abort migraine once allodynia has set in (Lampl, Cephalalgia, 28:1031-1038, 2008; Burstein, Ann. Neurol. 55:27-36, 2004) can be useful in migraine therapy. Clinical studies have shown that as many as 75% of patients develop cutaneous allodynia (exaggerated skin sensitivity) during migraine attacks and that its development during migraine is detrimental to the anti-migraine action of triptan 5HT_IB/ID agonists (Burstein et al., Ann. Neurol. 47:614-624, 2000; Burstein et al., Brain, 123:1703-1709, 2000). Migraineurs with aura have a higher incidence of allodynia than migraineurs without aura (e.g., Ashkenazi et al., Cephalalgia 27(2): 111-117, 2007). For example, 65% of patients experiencing migraine with aura also reported experiencing allodynia, compared to 41% of patients experiencing migraine without aura (Lovati et al., Neuro. ScL 28:S220-S221, 2007).

Migraineurs with aura may also be at risk for other serious disorders or conditions, and methods of treatment of migraine or the prevention of pain in migraine with aura that are not contraindicated by these disorders or diseases would be useful. For example, women over 45 years old who experience migraine with aura have increased risk of cardiovascular events such as ischemic stroke, myocardial infarction, angina, coronary revascularization, or death due to cardiovascular disease whereas those who experience migraine without aura did not show any increased risk (Kurth et al., JAMA, 296(3):283-291 , 2006). The potential increased risk for cardiovascular disease associated with migraine with aura can affect the types of treatments available to a migraineur: for example, contraindications for triptan therapy (e.g., sumatriptan) include uncontrolled hypertension, ischemic heart disease, Prinzmetal's angina, cardiac arrhythmias, multiple risk factors for atherosclerotic vascular disease, primary vasculopathies, and basilar and hemiplegic migraine. Representative, exemplary contraindications for selected triptans are provided in Table 2. As can be seen from this table, the contraindications for each triptan overlap considerably. The methods described herein can be useful for migraineurs who have, or who are at risk of, any of the contraindicated conditions or diseases described herein.

Table 2

In addition to cardiovascular conditions, migraineurs with aura may be at increased risk for other neurological and/or psychological conditions and disorders. It has been shown, for example, that the co-occurrence of migraine with aura with major depression or a suicide attempt increased the risk of developing unprovoked seizure (Hesdorffer et al., Epilepsy Res. 75(2-3):220-223, 2007). Other conditions associated with migraine with aura include significantly higher markers of NO activity, increased incidence of depression, and genetic biomarker correlation for stroke substantially greater than that of the general population (Etminan et al., #MJ330(7482):63, 2005). A migraineur that has, or is at risk of, any of these conditions may take medications to treat or to manage these diseases, and these medications may adversely interact with currently used medications for the treatment of migraine with aura. As shown herein, some of these conditions are contraindications for triptan therapy (e.g., stroke and sumatriptan therapy). Moreover, the FDA issued a public health advisory in 2006 regarding serotonin syndrome, a life -threatening condition that may occur when a triptan is used together with certain anti-depressants that are serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephrine reuptake inhibitors (SNRIs). Accordingly, the methods described herein may be useful for the treatment of patients who have depression or patients who have suffered, or are at risk of, stroke.

Indole Compounds

Indole compounds useful in the methods described herein (e.g., Compounds (l)-(54) and compounds of Formulas (I), (I-A), and (1-B)), or pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions thereof, as well as procedures for the preparation of these compounds, can be found in U.S. Patent No. 7,375,219, hereby incorporated by reference in its entirety.

Compounds of Formula (I) have the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof, wherein

R¹ is H, optionally substituted Ci_-6 alkyl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, or optionally substituted Ci_-4 alkheterocyclyl; each of R² and R³ is, independently, H, Hal, optionally substituted Cj_-6 alkyl, optionally substituted C_6-I0 aryl, optionally substituted C_3-8 cycloalkyl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 bridged heterocyclyl, optionally substituted Ci_-4 bridged alkheterocyclyl, optionally substituted C_2-9 heterocyclyl, or optionally substituted Ci_-4 alkheterocyclyl; each of R⁴ and R⁷ is, independently, H, F, Ci_-6 alkyl, or Ci_-6 alkoxy;

R⁵ is H, R^5AC(NH)NH(CH₂)_r5, or R^5BNHC(S)NH(CH₂)_r5, wherein r5 is an integer from 0 to 2, R^5Λ and R^5B are each optionally substituted Ci_-6 alkyl, optionally substituted C_6-Io aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted Ci_-6 thioalkoxy, optionally substituted Cj_-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted Ci_-4 thioalkheterocyclyl; and

R⁶ is H, R^6AC(NH)NH(CH₂)r6, or R^6BNHC(S)NH(CH₂)_r6, wherein r6 is an integer from 0 to 2, R^6A and R^6B are each optionally substituted Ci_-6 alkyl, optionally substituted C_6-10 aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted Ci_-6 thioalkoxy, optionally substituted Ci_-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted Ci_-4 thioalkheterocyclyl; and wherein one, but not both, of R⁵ and R⁶ is H. Representative compounds of Formula (I) include the compounds of Table 3.

Table 3

Pharmaceutical Compositions

The compounds used in the methods described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Pharmaceutical compositions typically include an indole compound as described herein (e.g., any of Compounds (l)-(54) and compounds of Formulas (I), (I-A), and (1-B)) and a pharmaceutically acceptable excipient.

The compounds described herein can also be used in the form of the free base, in the form of salts, zwitterions, solvates, or as prodrugs, or pharmaceutical compositions thereof. All forms are within the scope of the invention. The compounds, salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions thereof, may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The indole compounds used in the methods described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration, and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

A compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets or incorporated directly with the food of the diet. For oral therapeutic administration, an indole compound described herein may also be combined with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

An indole compound described herein may also be administered parenterally. Solutions of the indole compound can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF 19), published in 1999.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it is easily administered via syringe.

Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders. Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer. Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter. The indole compounds described herein may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable excipients, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.

Dosages

The dosage of the indole compound used in the methods described herein, or pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions thereof, can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The indole compounds used in the methods described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results can be obtained when the indole compounds are administered to a human at a daily dosage of, for example, between 0.05 mg and 3000 mg (measured as the solid form). Dose ranges include, for example, between 10-1000 mg (e.g., 50-800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the indole compound is administered. Alternatively, the dosage amount can be calculated using the body weight of the patient. For example, the dose of an indole compound, or pharmaceutical composition thereof, administered to a patient may range from 0.1-50 mg/kg (e.g., 0.25-25 mg/kg). In exemplary, non-limiting embodiments, the dose may range from 0.5-5.0 mg/kg (e.g., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg/kg) or from 5.0-20 mg/kg (e.g., 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg).

Combination Therapies

Any of the indole compounds described herein can be used alone or in combination with other agents that have NO S -inhibiting activity, or in combination with other types of treatment (which may or may not inhibit NOS) to treat migraine headache with aura or to prevent pain in migraine with aura. In combination treatments, the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology, 65:S3-S6, 2005). In this case, dosages of the compounds when combined should provide a therapeutic effect. For example, the indole compounds described herein can be combined with a triptan (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and/or zolmitriptan) in certain embodiments.

Administration of glyceryl trinitrate (GTN), an NO donor, induces immediate headaches in normal individuals and results in delayed migraine attacks in migraineurs with aura (Afridi et al J Neuro Neurosurg Psychiatry 76: 158-1160, 2005) and without aura with a 4-6 hour latency period (Iversen et al., Pain 38:17-24, 1989). In patients with migraine attack, levels of CGRP (Calcitonin Gene Related Peptide), a potent vasodilator, in the carotid artery correlate with the onset and ablation of migraine attack (Durham, Curr. Opin. Investig. Drugs 5(7):731-5, 2004). Sumatriptan, an antimigraine drug having affinity at 5HT_JB, 5HT₁D, and 5HT₁F receptors, reduces GTN-induced immediate headache and in parallel contracts cerebral and extracerebral arteries (Iversen and Olesen, Cephalalgia 13(Suppl. 13): 186, 1993). The antimigraine drug rizatriptan also reduces plasma levels of CGRP following migraine pain reduction (Stepien et al., Neurol Neurochir. Pol. 37(5):1013-23, 2003). Both NO and CGRP have therefore been implicated as a cause for migraine. Serotonin 5HT_1BZi_D agonists have been shown to block NMDA receptor-evoked NO signaling in brain cortex slices (Strosznajder et al., Cephalalgia 19(10):859, 1999). These results suggest that a combination of an indole compound described herein and a selective or non-selective 5HT_{!B/I D/IF} agonist or a CGRP antagonist, such as those combinations described above, would be useful for the treatment of migraine.

The following non-limiting examples are illustrative of the present invention.

EXAMPLES Example 1: Therapeutic Effects in Subjects with and without a History of Migraine with Aura

Compound (21) can be prepared according to the procedures described in Example 11 of U.S. Patent No. 7,375,219, hereby incorporated by reference.

In a double-blind placebo-controlled trial, sixty patients were dosed at pain with a placebo or 50, 100, or 200 mg of Compound (21). Efficacy was determined using the change in baseline headache severity score (HSS) using a four point pain severity scale where 0 = none, 1 = mild, 2 = moderate, and 3 = severe. If a subject required rescue medication, the headache severity score recorded at the time of rescue was carried forward to replace all non-missing observations recorded post-rescue. Following a retrospective statistical analysis of patients without a history of migraine with aura (Figure IA) and with a history of migraine with aura (Figure IB), strong responses were observed in the latter population at, for example, two and four hours post-dosage. Pharmacokinetic studies of Compound (21) have shown plasma concentration levels observed one hour after the administration of doses larger than 400 mg (e.g., 400, 600, or 800 mg doses) are 2.5 times the plasma concentration levels observed at four hours post-dosage following administration of -200 mg of Compound (21) (Figure 2). These studies suggest that the use of higher doses of the indole compound may afford earlier relief.

Example 2: Sustained Response of Sumatriptan and Compound (21)

Figure 3 shows the estimated probability of patients not taking a second dose or other medication for migraine over the 24 hours following the initial dose of sumatriptan or of Compound (21). As can be seen from the figure, the sustained response for the treatment of migraine with aura using Compound (21) is twice that of sumatriptan for the treatment of migraine with or without aura (50% versus 25%).

Example 3: Vasoconstrictive Effects of Sumatriptan and Compound (21) The vasoconstrictive effects of sumatriptan and Compound (21) were compared by measuring the response of human coronary arteries to each compound as a percentage of the maximum response by these arteries to 60 mM KCl. Figure 4 shows the concentration effect curves for sumatriptan and Compound (21) obtained using this method and that sumatriptan has a greater vasoconstrictive effect than Compound (21).

Example 4: Effects of Compound 21 on CSD

CSD can be induced in animals by KCl application (Moskowitz et al. J Neuroscience 13(3): 1167-177, 1993). After induction of CSD, hypersensitivity can be measured in animals as shown in Figure 5, and this effect can be blocked by Compound 21.

Example 5: General Preparation of Clinical Dosage Forms.

Compound 21 dihydrochloride (Compound 21, 596 g), microcrystalline cellulose Type 102 (MC; 61.1 g), and magnesium stearate (MS; 3.3 g) were weighed and sieved through a 20 mesh screen individually. The MC and MS were added to a 1 L plastic container fixed to a V-blender and mixed for 3 minutes. This blend was emptied into a polyethylene bag. Compound 21 was introduced into the V-blender, followed by the blended MS and MC. The material was mixed for 5 minutes. The blend was emptied into a double polyethylene bag, sealed, and weighed (646 g, 97.7%). The blend was transferred to a Manual Cooper Encapsulator, which was fitted with the red size 1 , hard gelatin capsules. An analytical balance was used for adjusting the filled capsule weight (375.0 mg ± 38 mg). Individual capsules (10 each at beginning, middle and end) of the run were checked for weight to ensure all were within range. Capsules were polished as needed. The total weight of capsules produced was measured (778 g), corresponding to 2074 capsules. The capsules were packaged in 21 150cc HDPE bottles (20 containing 100 capsules, 1 containing 74 capsules). The bottles were capped, induction sealed, and labeled. The following tables show exemplary dosage formulations.

Other embodiments While the present invention has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the invention is not limited to the disclosed examples. To the contrary, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims. All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term. Other embodiments are in the claims. What is claimed is:

Claims

1. A method for the treatment of migraine with aura, comprising administering to a patient at aura an effective amount of an indole compound having the structure:

C ,7 R¹ (I), or a pharmaceutically acceptable salt or prodrug thereof, a pharmaceutical composition thereof, wherein,

R¹ is H, optionally substituted C_1-6 alkyl, optionally substituted C_1-4 alkaryl, optionally substituted C_2-9 heterocyclyl, or optionally substituted Ci_-4 alkheterocyclyl; each of R² and R³ is, independently, H, Hal, optionally substituted C_1-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-10 aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 bridged heterocyclyl, optionally substituted C_1-4 bridged alkheterocyclyl, optionally substituted C_2-9 heterocyclyl, or optionally substituted C_1-4 alkheterocyclyl; each of R⁴ and R⁷ is, independently, H, F, Ci_-6 alkyl, or Ci_-6 alkoxy;

R⁵ is H, R^5AC(NH)NH(CH₂)_r5 or R^5BNHC(S)NH(CH₂)_r5, wherein r5 is an integer from 0 to 2, R^5A and R^5B are each optionally substituted Ci_-6 alkyl, optionally substituted C_6-I0 aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted C_M alkheterocyclyl, optionally substituted Ci_-6 thioalkoxy, optionally substituted Cj_-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted C_1-4 thioalkheterocyclyl; and

R⁶ is H or R^6AC(NH)NH(CH₂)_r6 or R^6BNHC(S)NH(CH₂)_r6, wherein r6 is an integer from 0 to 2, R ^A and R ^B are each optionally substituted Ci_-6 alkyl, optionally substituted C_6-1O aryl₅ optionally substituted C_1-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted C_1-6 thioalkoxy, optionally substituted Ci_-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted C_M thioalkheterocyclyl; and wherein one, but not both, of R⁵ and R⁶ is H.

2. The method of claim 1, wherein

R⁵ is H, R^5AC(NH)NH(CH₂)_r5, or R^5BNHC(S)NH(CH₂)_r5, wherein r5 is an integer from 0 to 2, R^5A is optionally substituted C_6-1O aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C₂-₉ heterocyclyl, optionally substituted Cj_-4 alkheterocyclyl, optionally substituted Ci-_δthioalkoxy, optionally substituted C_1-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted Ci_-4 thioalkheterocyclyl; R^5B is optionally substituted Ci_-6thioalkoxy, optionally substituted Ci_-4 thioalkaryl, or optionally substituted Ci_-4 thioalkheterocyclyl; and R⁶ is H, R^6AC(NH)NH(CH₂)_r6, or R^6BNHC(S)NH(CH₂)_r6, wherein r6 is an integer from 0 to 2, R^6A is optionally substituted C]_-6alkyl, optionally substituted C₆-io aryl, optionally substituted C].₄ alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted C]_-4 alkheterocyclyl, optionally substituted Ci_-6thioalkoxy, optionally substituted Ci_-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted C_1-4 thioalkheterocyclyl; R^6B is optionally substituted C_6-I0 aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted Ci_-6thioalkoxy, optionally substituted Ci_-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted Ci_-4 thioalkheterocyclyl .

3. The method of claim 1, wherein each of R² and R³ is, independently, H, Hal, optionally substituted C]_-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-1O aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, or optionally substituted Cj_-4 alkheterocyclyl;

R⁵ is H or R^5AC(NH)NH(CH₂)_r5, wherein r5 is an integer from 0 to 2, R^5A is optionally substituted C_6-Io aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted Ci_-6thioalkoxy, optionally substituted Ci_-4 thioalkaryl, or optionally substituted Ci_-4 thioalkheterocyclyl; and

R⁶ is H or R^6AC(NH)NH(CH₂)_r6, wherein r6 is an integer from 0 to 2, R^6A is optionally substituted Cj_-6 alkyl, optionally substituted C_6-I0 aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted Ci_-6thioalkoxy, optionally substituted Ci_-4 thioalkaryl, or optionally substituted Ci_-4 thioalkheterocyclyl.

4. The method of claim 1, wherein

R³ is (CH₂)_m3X³, wherein X³ is selected from the group consisting of:

R^3B,

_wherein each of R^3A and R^3B is, independently, H, optionally substituted Cj_-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-I0 aryl, optionally substituted C_1-4 alkaryl, C_2-9 heterocyclyl, or optionally substituted Cj_-4 alkheterocyclyl; each of R^3C and R^3D is, independently, H, F, OH, CO₂R^3E, or NR^3FR^3G, wherein each of R^3E, R^3F, and R^3G is, independently, H, optionally substituted C_1-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-I0 aryl, optionally substituted Cj_-4 alkaryl, C_2-9 heterocyclyl, or optionally substituted Ci_-4 alkheterocyclyl, or R^3C and R^3D together with the carbon they are bonded to are C=O;

Z³ is NR^3H, NC(0)R^3H, NC(O)OR^3H, NC(0)NHR^3H, NC(S)R^3H, NC(S)NHR^3H, NS(O)₂R³", O, S, S(O), or S(O)₂, wherein R^3H is H, optionally substituted Ci_-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6- io aryl, optionally substituted Ci_-4 alkaryl, C_2-9 heterocyclyl, or optionally substituted C i-₄ alkheterocyclyl; m3 is an integer of O to 6; n3 is an integer of 1 to 4; p3 is an integer of 0 to 2; and q3 is an integer of 0 to 5.

5. The method of claim 1, wherein R¹ or R³ is optionally substituted C_2-9 heterocyclyl or optionally substituted C]_-4 alkheterocyclyl, wherein the heterocyclyl moiety is a bicyclic, nitrogen containing heterocyclyl.

6. The method of claim 1, wherein said indole compound has a structure according to

or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof, wherein X is O or S

7. The method of claim 6, wherein said indole compound is selected from the group consisting of:

8. The method of claim 6, wherein said indole compound has the following structure:

(21), or a pharmaceutically acceptable salt or prodrug thereof.

9. The method of claim 8, wherein said pharmaceutically acceptable salt is the dihydrochloride salt.

10. The method of claim 1, wherein said indole compound is selected from the group consisting of:

11. The method of any of claims 1-10, wherein said indole compound is a selective nNOS inhibitor.

12. The method of any of claims 1-11, wherein said administration is oral.

13. The method of any of claims 1-12, wherein 10-800 mgs of said indole compound is administered.

14. The method of claim 13, wherein 50, 100, or 200 mgs of said indole compound is administered.

15. The method of claim 14, wherein 400, 600, or 800 mgs of said indole compound is administered.

16. The method of any of claims 1-12, wherein said indole compound is administered at a dosage of 0.25-25 mg/kg.

17. The method of claim 16, wherein said dosage is 0.5-5.0 mg/kg.

18. The method of claim 17, wherein said dosage is 0.5-1.0 mg/kg, 1.0-2.0 mg/kg, or 2.0-4.0 mg/kg.

19. The method of claim 16, wherein said dosage is 5.0-20 mg/kg.

20. The method of claim 19, wherein said dosage is 5.0-8.0 mg/kg, 8.0-12 mg/kg, or 11-16 mg/kg.

21. The method of any of claims 1-20, wherein said patient has cardiovascular disease.

22. The method of any of claims 1-20, wherein said patient is at risk of cardiovascular disease.

23. The method of any of claims 1-20, wherein said patient has a condition that is a contraindication for triptan therapy.

24. The method of any of claims 1-20, wherein said patient is at risk of a condition that is a contraindication for triptan therapy.

25. A method for the prevention of pain in migraine with aura, comprising administering to a patient at aura an effective amount of an indole compound having the structure:

or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof, wherein,

R¹ is H, optionally substituted C_1-6 alkyl, optionally substituted C_]-4 alkaryl, optionally substituted C_2-9 heterocyclyl, or optionally substituted C_1-4 alkheterocyclyl; each of R² and R³ is, independently, H, Hal, optionally substituted Ci_-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-10 aryl, optionally substituted C]_-4 alkaryl, optionally substituted C_2-9 bridged heterocyclyl, optionally substituted C_1-4 bridged alkheterocyclyl, optionally substituted C_2-9 heterocyclyl, or optionally substituted Ci_-4 alkheterocyclyl; each of R⁴ and R⁷ is, independently, H, F, Ci_-6 alkyl, or Cj_-6 alkoxy;

R⁵ is H, R^5AC(NH)NH(CH₂)_r5 or R^5BNHC(S)NH(CH₂)_r5, wherein r5 is an integer from 0 to 2, R^5A and R^5B are each optionally substituted Ci_-6 alkyl, optionally substituted C_6-I0 aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted C_1-6 thioalkoxy, optionally substituted Ci_-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted Ci_-4 thioalkheterocyclyl; and

R⁶ is H or R^6AC(NH)NH(CH₂)_r6 or R^6BNHC(S)NH(CH₂)_r6, wherein r6 is an integer from 0 to 2, R^6A and R^6B are each optionally substituted C]_-6 alkyl, optionally substituted C_6-I₀ aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Cj_-4 alkheterocyclyl, optionally substituted Cj_-6 thioalkoxy, optionally substituted Ci_-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted Ci_-4 thioalkheterocyclyl; and wherein one, but not both, of R⁵ and R⁶ is H.

26. The method of claim 25, wherein

R⁵ is H, R^5AC(NH)NH(CH₂)_r5, or R^5BNHC(S)NH(CH₂)_r5, wherein r5 is an integer from 0 to 2, R^5A is optionally substituted C₆-_Io ^aryl_> optionally substituted Cj_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted Ci_-6thioalkoxy, optionally substituted Ci_-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted Ci_-4 thioalkheterocyclyl; R^5B is optionally substituted Ci_-6thioalkoxy, optionally substituted Ci_-4 thioalkaryl, or optionally substituted Ci_-4 thioalkheterocyclyl; and

R⁶ is H, R^6AC(NH)NH(CH₂)_r6, R^6BNHC(S)NH(CH₂)_r6, wherein τ^β is an integer from 0 to 2, R^6A is optionally substituted C_1-6alkyl, optionally substituted C_6-I0 aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Cj_-4 alkheterocyclyl, optionally substituted C)_-6thioalkoxy, optionally substituted C_1-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted Ci_-4 thioalkheterocyclyl; R^6B is optionally substituted C_6-I0 aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted C]_-6thioalkoxy, optionally substituted Ci_-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted Ci_-4 thioalkheterocyclyl .

27. The method of claim 25, wherein each of R² and R³ is, independently, H, Hal, optionally substituted Ci_-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C₆-io aryl, optionally substituted C_1-4 alkaryl, optionally substituted C_2-9 heterocyclyl, or optionally substituted C]_-4 alkheterocyclyl;

R⁵ is H or R^5AC(NH)NH(CH₂)_r5, wherein r5 is an integer from 0 to 2, R^5A is optionally substituted C_6-I0 aryl, optionally substituted Cj_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted Ci_-6thioalkoxy, optionally substituted Cj_-4 thioalkaryl, or optionally substituted Cj_-4 thioalkheterocyclyl; and

R⁶ is H or R^6AC(NH)NH(CH₂)_r6, wherein r6 is an integer from 0 to 2, R^6A is optionally substituted C_1-6 alkyl, optionally substituted C₆-_Io aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted C_1-4 alkheterocyclyl, optionally substituted Ci_-6thioalkoxy, optionally substituted Ci_-4 thioalkaryl, or optionally substituted Ci_-4 thioalkheterocyclyl.

28. The method of claim 25, wherein

R³ is (CH₂)_m3X³, wherein X³ is selected from the group consisting of:

, wherein each of R^3A and R^3B is, independently, H, optionally substituted Ci_-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-I0 aryl, optionally substituted Ci_-4 alkaryl, C_2-9 heterocyclyl, or optionally substituted Ci_-4 alkheterocyclyl; each of R^3C and R^3D is, independently, H, F, OH, CO₂R^3E, or NR^3FR^3G, wherein each of R^3E, R^3F, and R^3G is, independently, H, optionally substituted Ci_-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-10 aryl, optionally substituted Cj_-4 alkaryl, C_2-9 heterocyclyl, or optionally substituted Ci_-4 alkheterocyclyl, or R^3C and R^3D together with the carbon they are bonded to are C=O;

Z³ is NR^3H, NC(0)R^3H, NC(0)0R^3H, NC(O)NHR^3H, NC(S)R^3H, NC(S)NHR³", NS(O)₂R³", O, S, S(O), or S(O)₂, wherein R^3H is H, optionally substituted C_1-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6- io aryl, optionally substituted Ci_-4 alkaryl, C_2-9 heterocyclyl, or optionally substituted Cj_-4 alkheterocyclyl; m3 is an integer of O to 6; n3 is an integer of 1 to 4; p3 is an integer of 0 to 2; and q3 is an integer of 0 to 5.

29. The method of claim 25, wherein R¹ or R³ is optionally substituted C_2-9 heterocyclyl or optionally substituted Ci_-4 alkheterocyclyl, wherein the heterocyclyl moiety is a bicyclic, nitrogen containing heterocyclyl.

30. The method of claim 25, wherein said indole compound has a structure according to

or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof, wherein X is O or S.

31. The method of claim 30, wherein said indole compound is selected from the group consisting of:

32. The method of claim 30, wherein said indole compound has the following structure:

(21), or a pharmaceutically acceptable salt or prodrug thereof.

33. The method of claim 32, wherein the pharmaceutically acceptable salt is the dihydrochloride.

34. The method of claim 25, wherein said indole compound is selected from the group consisting of:

35. The method of any of claims 25-34, wherein said indole compound is a selective nNOS inhibitor.

36. The method of any of claims 25-35, wherein said administration is oral.

37. The method of any of claims 25-36, wherein 10-800 mgs of said indole compound is administered.

38. The method of claim 37, wherein 50, 100, or 200 mgs of said indole compound is administered.

39. The method of claim 37, wherein 400, 600, or 800 mgs of said indole compound is administered.

40. The method of any of claims 25-35, wherein said indole compound is administered at a dosage of 0.25-25 mg/kg.

41. The method of claim 40, wherein said dosage is 0.5-5.0 mg/kg.

42. The method of claim 41, wherein said dosage is 0.5-1.0 mg/kg, 1.0-2.0 mg/kg, or 2.0-4.0 mg/kg.

43. The method of claim 40, wherein said dosage is 5.0-20 mg/kg.

44. The method of claim 43, wherein said dosage is 5.0-8.0 mg/kg, 8.0-12 mg/kg, or 11-16 mg/kg.

45. The method of any of claims 25-44, wherein said patient has cardiovascular disease.

46. The method of any of claims 25-44, wherein said patient is at risk of cardiovascular disease.

47. The method of any of claims 25-44, wherein said patient has a condition that is a contraindication for triptan therapy.

48. The method of any of claims 25-44, wherein said patient is at risk of a condition that is a contraindication for triptan therapy.

49. A method for the treatment or prevention of cortical spreading depression, comprising administering to a patient an effective amount of an indole compound having the structure:

R¹ is H, optionally substituted C_1-6 alkyl, optionally substituted C_1-4 alkaryl, optionally substituted C_2-9 heterocyclyl, or optionally substituted C_1-4 alkheterocyclyl; each of R² and R³ is, independently, H, Hal, optionally substituted Ci_-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-I0 aryl, optionally substituted C_1-4 alkaryl, optionally substituted C_2-9 bridged heterocyclyl, optionally substituted Ci_-4 bridged alkheterocyclyl, optionally substituted C_2-9 heterocyclyl, or optionally substituted Cj_-4 alkheterocyclyl; each of R⁴ and R⁷ is, independently, H, F, Ci_-6 alkyl, or Ci_-6 alkoxy;

R⁵ is H, R^5AC(NH)NH(CH₂)_r5 or R^5BNHC(S)NH(CH₂)_r5, wherein r5 is an integer from 0 to 2, R^5A and R^5B are each optionally substituted Ci_-6 alkyl, optionally substituted C_6-I₀ aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted C_1-6 thioalkoxy, optionally substituted Ci_-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted Ci_-4 thioalkheterocyclyl; and

R⁶ is H or R^6AC(NH)NH(CH₂)_r6 or R^6BNHC(S)NH(CH₂)_r6, wherein r6 is an integer from 0 to 2, R ^A and R^6B are each optionally substituted Ci_-6 alkyl, optionally substituted C_6-I0 aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted C_1-6 thioalkoxy, optionally substituted C_1-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted Ci_-4 thioalkheterocyclyl; and wherein one, but not both, of R⁵ and R⁶ is H.

50. A method for the treatment of allodynia in a patient having a migraine with aura, comprising administering to said patient at aura an effective amount of an indole compound having the structure:

R¹ is H, optionally substituted Ci_-6 alkyl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, or optionally substituted Ci_-4 alkheterocyclyl; each of R² and R³ is, independently, H, Hal, optionally substituted Ci_-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-10 aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 bridged heterocyclyl, optionally substituted C_1-4 bridged alkheterocyclyl, optionally substituted C_2-9 heterocyclyl, or optionally substituted C_1-4 alkheterocyclyl; each of R⁴ and R⁷ is, independently, H, F, Ci_-6 alkyl, or Ci_-6 alkoxy;

R⁵ is H, R^5AC(NH)NH(CH₂)_r5 or R^5BNHC(S)NH(CH₂)_r5, wherein r5 is an integer from 0 to 2, R^5A and R^5B are each optionally substituted Ci_-6 alkyl, optionally substituted C_6-I₀ aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted Ci_-6 thioalkoxy, optionally substituted C]_-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted Cj_-4 thioalkheterocyclyl; and

R⁶ is H or R^6AC(NH)NH(CH₂)_r6 or R^6BNHC(S)NH(CH₂)_r6, wherein τ6 is an integer from 0 to 2, R^6A and R^6B are each optionally substituted Ci_-6 alkyl, optionally substituted C_6- io aryl, optionally substituted Ci_-4 alkaryl, optionally substituted C_2-9 heterocyclyl, optionally substituted Ci_-4 alkheterocyclyl, optionally substituted Ci_-6 thioalkoxy, optionally substituted Cj_-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted Cj_-4 thioalkheterocyclyl; and wherein one, but not both, of R⁵ and R⁶ is H.

51. The method of claim 50, wherein said allodynia is tactile allodynia.