WO2015188005A1

WO2015188005A1 - Novel (r)-isometheptene compositions and uses

Info

Publication number: WO2015188005A1
Application number: PCT/US2015/034292
Authority: WO
Inventors: Seth Lederman
Original assignee: Individual
Current assignee: Individual
Priority date: 2014-06-04
Filing date: 2015-06-04
Publication date: 2015-12-10
Anticipated expiration: 2016-12-04

Abstract

The invention relates to the preparation and characterization of novel salts of (R)-isometheptene and crystalline forms thereof; moreover, the invention describes the use of the novel salts alone or in combination with other therapeutic salts for treatment of various conditions, such as hypertension or a headache, or as a sedative.

Description

Related Applications

[0001] This application claims priority to and benefit from U.S. Provisional Patent Application 62/007,454, filed June 4, 2014, and U.S. Provisional Patent Application 62/01 1 ,723, filed June 13, 2014. The contents and disclosures of each of the foregoing applications are hereby- incorporated by reference in their entirety.

Background of the Invention [0002] Racemic isometheptene (( RS)~isometheptene) is a non-ergot vasoconstrictor agent that has been used in the treatment of tension headache, vascular headache and migraine headache either alone or in a combination drug product. Racemic isometheptene is believed to be a cerebrovascular constrictor and may act by reducing pressure on the pain producing areas surrounding blood vessels. Racemic isometheptene has been shown to increase heart, rate and diastolic blood pressure, which are properties associated with sympathomimetic agents. The heart rate increase has been shown to be blocked by propranolol, a non-selective β-adrenergic receptor antagonist, while the diastolic blood pressure increase has been shown to be blocked by prazosin, an «i -adrenergic receptor antagonist. (Vaidivia, L.F., Cenurion, D., Perusquia, M., Arulmani, U., Saxena, P.R., and Villalom, CM. "Pharmacological Analysis of the Mechanisms Involved in the Tachycardic and Vasopressor Responses to the Antimigraine Agent,

Isometheptene, in Pithed Rats" Life Sciences 74: 3223-3234 (2004)). Together these findings suggest that racemic isometheptene has sympathetic effects which are complex on heart rate and blood pressure. However, it is unknown whether isometheptene interacts with a- or β-adrenergie receptors as an agonist, and/or stimulates the release of catecholamines, and/or modulates the sensitivity of catecholamine responsive cells or systems.

[ΘΘ03] Recently we discovered that (R)-isometheptene binds to the central nervous system (CNS) moxonidine binding imidazoline-!] receptor about 60 fold more avidly than the (S)- isometheptene. The imidazoline-! i receptor has been found to be the receptor for the central hypertensive agent moxonidine. Besides central hypertension, moxonidine has been efficacious in the treatment of metabolic syndrome, which includes dyslipidemia, insulin resistance, glucose intolerance, hypertension and central obesity. Moxonidine has also been considered as a treatment for heart failure. (Reference: Edwards, L.P., Brown-Bryan, T.A., McLean, I.., and Ernsberger, P. "Pharmacological Properties of the Central Antihypertensive Agent,

Moxonidine." Cardiovasc. Ther. 30: 199-208 (2012)).

[Θ004] Moxonidine is believed to function as an agonist of the imidazoiine-Ii receptor. In addition to moxonidine, known imidazoline dmgs with a postulated high affinity to the imidazoline-I j receptor are AGN 192403, riimenidine, and clonidine. Specific ligands of the imidazoline-]] receptor are 2-BF1 and BU239. The putative natural ligand for imidazoline Ii, , and h receptors is agmatine. Idazoxan is believed to function as antagonist of the It and receptors. (Radwanska A, Dlugokecka J, Wasilewski R, aliszan R. J Physiol Pharmacol. 2009 Mar;60(l): 131-42). [0005] Furthermore, we discovered that the (S)-isometheptene isomer induced a pronounced dose-dependent increase in systolic and diastolic blood pressure similar to the racemate, while the (R)-isometheptene isomer induced lower effects, and only at higher doses, suggesting that treatment with (R)-isometheptene is associated with fewer cardiovascular side effects.

[ΘΘ06] There is still a need to develop novel isometheptene, specifically (R)-isometheptene, compositions that are effective in the prevention or treatment of disorders, such as headache and/or hypertension, and as a sedative.

Summary of the Invention

[0007] In some embodiments, the invention provides an (R)-isometheptene salt, wherein the (R)-isometheptene salt is characterized by a differential scanning caiorimetry heating curve which shows an endothermic heat flow peak between 45 °C and 145 °C, In some embodiments, the (R)-isometheptene salt is characterized by a differential scanning caiorimetry heating curve which shows an endothermic heat flow peak between 45 °C and 130 °C.

1 [0008 J In some embodiments, the invention provide an ( )-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt. In some embodiments, the (R)-isometheptene salt is a maleate salt, and the (R)- isometheptene maleate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 1 12 °C and 120 °C. In some embodiments the (R)-isometheptene maleate salt is characterized by an X-ray powder diffraction pattern with peaks at about 6.3, 19.1 , 24.2, 25.5, and 32.1 degrees two theta when measured using a Cu X-ray source, in some embodiments the (R)-isometheptene maleate salt is characterized by an X-ray powder diffraction pattern with peaks at 6.3, 19.1 , 24.2, 25.5, and 32.1 degrees two theta when measured using a Cu X-ray source. In some embodiments the (R)-isometheptene maleate salt is characterized by the X-ray powder diffraction pattern of Figure 2 when measured using a Cu X- ray source.

[0009] In some embodiments, the (R)-isometheptene salt is a L-malate salt, and the (R.)- isometheptene L-malate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 74° C and 83° C. In some embodiments, the (R)-isometheptene malate salt is characterized by an X-ray powder diffraction pattern with peaks at about 5.9, 6.1 , 14.8, 16.0, 17.1 , 18.1 , 18.3, 20.8, 21.2, and 25.4 degrees two theta when measured using a Cu X-ray source, in some embodiments, the (R)-isometheptene malate salt is characterized by an X-ray powder diffraction pattern with peaks at 5.9, 6.1 , 14.8, 16.0, 17.1 , 1 8.1 , 1 8.3, 20.8, 21 ,2, and 25.4 degrees two theta when measured using a Cu X-ray source. In some embodiments, the (R)-isometheptene malate salt is characterized by the X-ray powder diffraction pattern of Figure 4 when measured using a Cu X-ray source.

[0010] In some embodiments, the (R)-isometheptene salt is a L-tartrate salt, and the (R.)- isometheptene L-tartrate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 83 °C and 89 °C. In some embodiments, the (R)-isometheptene L-tartrate salt is characterized by an X-ray powder diffraction pattern with peaks at about 6.1 , 12.1 , 14.2, 17.3, 17.7, 22.3, 24.3, and 26.5 degrees two theta when measured using a Cu X-ray source. In some embodiments, the (R^')-isometheptene L-tartrate salt is characterized by an X-ray powder diffraction pattern with peaks at 6.1 , 12. 1 , 14.2, 17.3, 17.7, 22.3, 24.3, and 26.5 degrees two theta when measured using a Cu X-ray source. In some embodiments, the (R)-isometheptene L-tartrate salt is characterized by the X-ray powder diffraction pattern of Figure 6 when measured using a Cu X-ray source.

[001 1 ] In some embodiments, the (R)-isometheptene salt is a citrate salt, and the (R)~ isometheptene citrate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 65 °C and 75 °C. In some embodiments, the (R)-isomemeptene citrate salt is characterized by an X-ray powder diffraction pattern with peaks at about 6.5, 16.0, 19.2, 19.6, 21.0, 21.4, 26.3, and 31.3 degrees two theta when measured using a Cu X-ray source. In some embodiments, the (R)-isometheptene citrate salt is

characterized by an X-ray powder diffraction pattern with peaks at 6.5, 16.0, 19.2, 19.6, 21.0,

21 .4, 26.3, and 31.3 degrees two theta when measured using a Cu X-ray source. In some embodiments, the (R)-isometheptene citrate salt is characterized by the X-ray powder diffraction pattern of Figure 8 when measured using a Cu X-ray source.

[0012] In some embodiments, the (R)-isometheptene salt is the cyclamate salt, and the (Rj- isometheptene cyclamate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 71 °C and 81 °C. In some embodiments, the (R)-isometheptene cyclamate salt is characterized by an X-ray powder diffraction pattern with peaks at about 5.4, 5.9, 16.4, 16.9, 20.2, and 21.9 degrees two theta when measured using a Cu X-ray source. In some embodiments, the (R)-isometheptene cyclamate salt is characterized by an X-ray powder diffraction pattern with peaks at 5.4, 5.9, 16.4, 16.9, 20.2, and 21.9 degrees two theta when measured using a Cu X-ray source. In some embodiments, the (R)-isometheptene cyclamate salt is characterized by the X-ray powder diffraction pattern of Figure 10 when measured using a Cu X-ray source.

[0013] In some embodiments, the (R)-isomethept.ene salt is a fumarate salt, and the (Rj- isometheptene fumarate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 105 °C and 115 °C. In some embodiments, the (R)-isometheptene fumarate salt is characterized by an X-ray powder diffraction pattern with peaks at about 6.2, 6.3, 19.1, 20.6, 24.1, 25.2, 25.6, and 32.2 degrees two theta when measured using a Cu X-ray source. In some embodiments, the (R -isometheptene fumarate salt is characterized by an X-ray powder diffraction pattern with peaks at 6.2, 6.3, 19.1, 20.6, 24.1 , 25.2, 25.6, and 32,2 degrees two theta when measured using a Cu X-ray source. In some embodiments, the (R^')-isometheptene fumarate salt is characterized by the X-ray powder diffraction pattern of Figure 12 when measured using a Cu X-ray source. [0014] In some embodiments, the (R)-isometheptene salt is a hippurate salt, and the (R)- isometheptene hippurate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 107 °C and 117 °C. In some embodiments, the (R)-isometheptene hippurate salt is characterized by an X-ray powder diffraction pattern with peaks at about 5.2, 10.4, 15.7, 19.4, and 26.4 degrees two theta when measured using a Cu X-ray source. In some embodiments, the (R)-isometheptene hippurate salt is characterized by an X-ray powder diffraction pattern with peaks at 5.2, 10.4, 15.7, 19.4, and 26.4 degrees two theta when measured using a Cu X-ray source, in some embodiments, the ( )-isometheptene hippurate salt is characterized by the X-ray powder diffraction pattern of Figure 14 when measured using a Cu X-ray source. [0015] In some embodiments, the (R)-isometheptene salt is the phosphate salt, and the (R)- isometheptene phosphate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 123 °C and 133 °C. In some embodiments, the (R)-isometheptene phosphate salt is characterized by an X-ray powder diffraction pattern with peaks at about 7,2, 14, 4, 14.9, 20.7, 22.7, and 23.4 degrees two theta when measured using a Cu X-ray source. In some embodiments, the (R)-isometheptene phosphate salt is characterized by an X-ray powder diff action pattern with peaks at 7.2, 14.4, 14.9, 20.7, 22.7, and 23.4 degrees two theta when measured using a Cu X-ray source. In some embodiments, the (R -isometheptene phosphate salt is characterized by the X-ray powder diffraction pattern of Figure 16 when measured using a Cu X-ray source. [0016] In some embodiments, the (R)-isometheptene salt is the succinate salt, and the 01)- isometheptene succinate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 48 °C and 58 °C. in some embodiments, the (R)-isometheptene succinate salt is characterized by an X-ray powder diffraction pattern with peaks at about 6.2, 18.5, 18.7, 21.1, 22.6, 23.9, 24.7, and 25.0 degrees two theta when measured using a Cu X-ray source, in some embodiments, the (R)-isometheptene succinate salt is characterized by an X-ray powder diffraction pattern with peaks at 6,2, 18,5, 18.7, 21.1, 22.6, 23.9, 24.7, and 25,0 degrees two theta when measured using a Cu X-ray source, in some embodiments, the (R)-isometheptene succinate salt is characterized by the X-ray powder diffraction pattern of Figure 18 when measured using a Cu X-ray source,

[0017] In some embodiments, the (R)-isometbeptene salt is in a crystalline form.

[0018] In some embodiments, the invention provides a phannaceutical composition comprising an (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyciamate, fumarate, hippurate, phosphate or succinate salt, and a pharmaceutically acceptable carrier. [Θ019] In some embodiments, the invention provides a pharmaceutical composition comprising a crystalline (R)-isometheptene maleate salt.

[0020] In some embodiments, the invention provides a pharmaceutical composition comprising a crystalline (R)-isometheptene L-malate salt.

[0021] In some embodiments, the invention provides a pharmaceutical composition comprising a crystalline (R)-isometheptene L-tartrate salt.

[0022] In some embodiments, the invention provides a pharmaceutical composition comprising a crystalline (R)-isometheptene citrate salt, a crystalline (R)-isometheptene cyciamate salt, a crystalline (R)-isometheptene fumarate salt, a crystalline (R)-isometheptene hippurate salt, a crystalline (R)-isometheptene phosphate salt, or a crystalline (R)-isometheptene succinate salt. In some embodiments, the pharmaceutical composition comprises a crystalline (R)- isometheptene salt described herein, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises any one of the crystalline (R)- isometheptene salts listed in Tables 1-6 or a combination thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises any one of the crystalline (R)-isometheptene salts of Figures 1-18 or a combination thereof, and a pharmaceutically acceptable carrier. [0023 J In some embodiments, the invention provides a method for treating or preventing a condition selected from the group consisting of pain; central sensitization; centralization;

regional pain syndrome; lower back pain; visceral pain; neuropathic pain; sickle cel l pain;

nociceptive pain; post-operative pain; orthopedic injuiy pain; phantom limb pain; pain associated with cancer; pain associated with post-traumatic stress disorder (PTSD); a headache; an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; depression;

allodynia; fibromyalgia; fibromyalgia-ness; temporomandibular joint syndrome (TMJ); Gulf War syndrome; osteoarthritis; rheumatoid arthritis; and hypertension in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a (R)~

isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyciamate, fumarate, hippurate, phosphate or succinate salt, or a therapeutically effective amount of a pharmaceutical composition comprising a (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyciamate, fumarate, hippurate, phosphate or succinate salt. In some embodiments, the (R^')-isometheptene salts described herein or pharmaceutical compositions comprising the (R)-isometheptene salts described herein are used in these methods. In some embodiments, the (R)-isometheptene salt used in these methods comprises any one of the (R)~ isometheptene salts listed in Tables 1-6 or a combination thereof. In some embodiments, the (R.)-isometheptene salt used in these methods comprises any one of the (R)-isometheptene salts of Figures 1-18 or a combination thereof, in some embodiments, the (R)-isometheptene salt used in these methods is in a crystalline form. In some embodiments, the condition is a headache. In some embodiments, the condition is a migraine headache. In some embodiments, the condition is an episodic tension-type headache. In some embodiments, the condition is hypertension. In some embodiments, the salt or the pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine,

dichloralphenazone, naproxen, or sumatriptan succinate. In some embodiments, the salt or the pharmaceutical composition is used with a CYP2D6 inhibitor. In some embodiments, the subject is a human. [0024 J In some embodiments, the invention provides a method of sedating a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a (R)- isometheptene salt, wherein the salt is a maleate, L-maiate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, or a therapeutically effective amount of a pharmaceutical composition comprising a (R)-isorneiheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt. In some embodiments, the (R)-isometheptene salts described herein or pharmaceutical compositions comprising the (R)-isometheptene salts described herein are used in these methods. In some embodiments, the (R)-isometheptene salt used in these methods comprises any one of the (R)- isometheptene salts listed in Tables 1 -6 or a combination thereof. In some embodiments, the (R)-isometheptene salt used in these methods comprises any one of the (R)-isometheptene salts of Figures 1-18 or a combination thereof. In some embodiments, the (R)-isometheptene salt used in these methods is in a crystalline form. In some embodiments, the salt or the pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, dichloralphenazone, naproxen, or sumatriptan succinate. In some embodiments, the salt or the pharmaceutical composition is used with a CYP2.D6 inhibitor. In some embodiments, the subject is a human,

(0025] In some embodiments, the invention provides a method of inducing analgesia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a (R -isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, or a therapeutically effective amount of a pharmaceutical composition comprising a (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt. In some embodiments, the (R -isometheptene salts described herein or pharmaceutical compositions comprising the ( R)-isometheptene salts described herein are used in these methods. In some embodiments, the (R)-isometheptene salt used in these methods comprises any one of the (R)-isometheptene salts listed in Tables 1-6 or a combination thereof, in some embodiments, the (R)-isometheptene salt used in these methods comprises any one of the (R)-isometheptene salts of Figures 1-18 or a combination thereof. In some embodiments, the (R)-isometh.eptene salt used in these methods is in a crystalline form. In some embodiments, the salt or the pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, diciiloraiphenazone, naproxen, or sumatriptan succinate, in some embodiments, the salt or the pharmaceutical composition is used with a CYP2D6 inhibitor. In some embodiments, the subject is a human. [0026] In some embodiments, a (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, or a

pharmaceutical composition comprising a (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, is used in treating or preventing a condition selected from the group consisting of: pain; central sensitization; centralization; regional pain syndrome; lower back pain; visceral pain; neuropathic pain; sickle cell pain; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; pain associated with cancer; pain associated with post-traumatic stress disorder (PTSD); a headache; an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular,

neuro vascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; depression; allodynia; fibromyalgia; fibromyalgia-ness; temporomandibular joint syndrome (TMJ); Gulf War syndrome; osteoarthritis; rheumatoid arthritis; and hypertension. In some embodiments, the (R)-isometheptene salts described herein or pharmaceutical compositions comprising the (R)-isometheptene salts described herein are used in these uses of treatment or prevention. In some embodiments, the (R)-isometheptene salt used in these uses comprises any one of the (R)-isometheptene salts listed in Tables 1 -6 or a combination thereof. In some embodiments, the (R)-isometheptene salt used in these uses comprises any one of the (R)~isometheptene salts of Figures 1-18 or a combination thereof. In some embodiments, the (R)-isometheptene salt used in these uses is in a crystalline form. In some embodiments, the condition is a headache. In some embodiments, the condition is a migraine headache. In some embodiments, the condition is an episodic tension-type headache. In some embodiments, the condition is hypertension. In some embodiments, the (R)- isometheptene salt or the pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, diciiloraiphenazone, naproxen, or sumatriptan succinate. In some embodiments, the (R)-isometheptene salt or the pharmaceutical composition is used with a CYP2D6 inhibitor,

[ΘΘ27] In some embodiments, a (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, or a

pharmaceutical composition comprising a (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succmate salt, is used as a sedative. In some embodiments, the (R)-isometheptene salts described herein or

pharmaceutical compositions comprising the (R)-isometheptene salts described herein are used in these uses. In some embodiments, the (R)-isometheptene salt used in these uses comprises any one of the (R)-isometheptene salts listed in Tables 1-6 or a combination thereof. In some embodiments, the (R)-isometheptene salt used in these uses comprises any one of the 01)- isometheptene salts of Figures 1-18 or a combination thereof. In some embodiments, the 0)- isometheptene salt used in these uses is in a crystalline form. In some embodiments, the (R)~ isometheptene salt or the pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, dichioralphenazone, naproxen, or sumatriptan succinate. In some embodiments, the (R)-isometheptene salt or the pharmaceutical composition is used with a CYP2D6 inhibitor,

[ΘΘ28] In some embodiments, a (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, or a

pharmaceutical composition comprising a (R)-isometlieptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succmate salt, is used as an analgesic. In some embodiments, the (R)-isometheptene salts described herein or pharmaceutical compositions comprising the (R)-isometheptene salts described herein are used in these uses. In some embodiments, the (R)-isometheptene salt used in these uses comprises any one of the (R)-isometlieptene salts listed in Tables 1-6 or a combination thereof. In some embodiments, the (R)-isometheptene salt used in these uses comprises any one of the 01)- isometheptene salts of Figures 1-18 or a combination thereof. In some embodiments, the 01)- isometheptene salt used in these uses is in a crystalline form. In some embodiments, the (R)~ isometheptene salt or the pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, dichloralphenazone, naproxen, or sumatriptan succinate. In some embodiments, the (R)-isometheptene salt or the pharmaceutical composition is used with a CYP2D6 inhibitor,

[0029] In some embodiments, the invention provides for use of a (R)~isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, or a pharmaceutical composition comprising a (Rj-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, for the manufacture of a medicament for treating or preventing a condition selected from the group consisting of: pain; central sensitization; centralization;

regional pain syndrome; lower back pain; visceral pain; neuropathic pain; sickle cell pain;

nociceptive pain; post-operative pain; orthopedic injur}' pain; phantom limb pain; pain associated with cancer; pain associated with post-traumatic stress disorder (PTSD); a headache; an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; depression;

allodynia; fibromyalgia; fibromyalgia-ness; temporomandibular joint syndrome (TMJ); Gulf War syndrome; osteoarthritis; rheumatoid arthritis; and hypertension. In some embodiments, the (R)~ isometheptene salts described herein or pharmaceutical compositions comprising the (R)- isometheptene salts described herein are used in these uses. In some embodiments, the (R)~ isometheptene sal t used in these uses comprises any one of the (R)-isometheptene salts l isted in Tables 1-6 or a combination thereof. In some embodiments, the (R)-isometheptene salt used in these uses comprises any one of the (R)-isometheptene salts of Figures 1-18 or a combination thereof. In some embodiments, the (R)~isometheptene salt used in these uses is in a crystalline form. In some embodiments, the condition is a headache, in some embodiments, the condition is a migraine headache. In some embodiments, the condition is an episodic tension-type headache, in some embodiments, the condition is hypertension. In some embodiments, the (Rj- isometheptene salt or the pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, dichloralphenazone, naproxen, or sumatriptan succinate. In some embodiments, the ( Visometheptene salt is used with a CYP2D6 inhibitor.

[Θ030] In some embodiments, the invention provides for use of a (R)~isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, or a pharmaceutical composition comprising a (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, for the manufacture of a medicament for sedation. In some embodiments, the (R)-isometheptene salts described herein or pharmaceutical compositions comprising the (R -isometheptene salts described herein are used in these uses of treatment or prevention. In some embodiments, the (R)-isometheptene salt used in these uses comprises any one of the (R)-isometheptene salts listed in Tables 1 -6 or a combination thereof. In some embodiments, the (R)-isometheptene salt used in these uses comprises any one of the (R)- isometheptene salts of Figures 1 -18 or a combination thereof. In some embodiments, the (R)- isometheptene salt used in these uses is in a crystalline form. In some embodiments, the condition is a headache. In some embodiments, the condition is a migraine headache. In some embodiments, the condition is an episodic tension-type headache. In some embodiments, the condition is hypertension. In some embodiments, the (R)-isometheptene salt or the

pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, dichloralphenazone, naproxen, or sumatriptan succinate. In some embodiments, the (R)-isometheptene salt or the pharmaceutical composition is used with a CYP2D6 inhibitor.

[0031] In some embodiments, the invention provides for use of a (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, or a pharmaceutical composition comprising a (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, for the manufacture of a medicament for analgesia. In some embodiments, the (R)-isometheptene salts described herein or pharmaceutical compositions comprising the (R)-isometheptene salts described herein are used in these uses of treatment or prevention. In some embodiments, the (R)-isometheptene salt used in these uses comprises any one of the ( )-isometheptene salts listed in Tables 1 -6 or a combination thereof. In some embodiments, the (R)-isometheptene salt used in these uses comprises any one of the (R)- isometheptene salts of Figures 1 -18 or a combination thereof In some embodiments, the (R)- isometheptene salt used in these uses is in a crystalline form. In some embodiments, the condition is a headache. In some embodiments, the condition is a migraine headache. In some embodiments, the condition is an episodic tension-type headache. In some embodiments, the condition is hypertension. In some embodiments, the (R)-isometheptene salt or the

pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, dichloralplieiiazone, naproxen, or sumatriptan succinate. In some embodiments, the (R)-isometheptene salt or the pharmaceutical composition is used with a CYP2D6 inhibitor.

Brief Description of the Drawings 2] In the detailed description reference is made to the illustrative figures listed below.

Fig. 1 : Differential scanning calorimetry (DSC) heating curve of (R)-isometheptene maleate.

Fig. 2: X-ray powder diffraction (XRPD) pattern of (R)-isometheptene maleate. Fig. 3: DSC heating curve of (R)-isometheptene L-malate. Fig. 4: XRPD pattern of (R)-isometheptene L-malate. Fig. 5: DSC heating curve of (R)-isometheptene L-tartrate. [Θ038] Fig. 6: XRPD pattern of (R)-isometheptene L-tartrate.

Fig. 7: DSC heating curve of (R)-isometheptene citrate. Fig. 8: XRPD pattern of (R)-isometheptene citrate. Fig. 9: DSC heating curve of (R)-isometheptene cyclamate. [0042 J Fig. 10: XRPD pattern of (R)-isometheptene cyclamate. [0043 J Fig. 1 1 : DSC heating curve of (R)-isornetheptene fumarate. [0044 J Fig. 12: XRPD pattern of (R)-isometheptene fumarate. [0045] Fig. 13 : DSC heating curve of (R)-isometheptene hippurate. [0046] Fig. 14: XRPD pattern of (R)-isometheptene hippurate. [0047] Fig. 15 : DSC heating curve of (R)-isometheptene phosphate. [0048] Fig. 16: XRPD pattern of (R)-isometheptene phosphate. Θ049] Fig. 17: DSC heating curve of (R)-isometheptene succinate. Θ050] Fig. 18: XRPD pattern of (R)-isometheptene succinate. Detailed Description of the Invention Definitions i] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, pharmacology, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, genetics and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art.

[0052] The methods and techniques of the present invention are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. [0053 J Chemistry terms used herein are used according to conventional usage in the art, as exemplified by 'The McGraw-Hill Dictionary of Chemical Terms", Parker S., Ed., McGraw- Hill, San Francisco, C.A. (1985).

[0054] All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0055] Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer (or components) or group of integers (or components), but not the exclusion of any other integer (or components) or group of integers (or components).

[0056] The singular forms "a," "an," and "the" include the plurals, and the plurals include the singulars unless the context clearly dictates otherwise.

[0057] The term "including" is used to mean "including but not limited to." "Including" and "including but not limited to" are used interchangeably. [0058] A "patient", "subject", or "individual" are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).

[0059] "Treating" a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms associated with a disease or condition as described herein.

[0060] "Administering" or "administration of a substance, a salt or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a salt or an agent can be administered sublingual iy or intranasal!)', by inhaiation into the lung or rectaliy. Administering can also be performed, for example, once, a plurality of times, and/or over one or 20 more extended periods, in some aspects, the adm stration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a patient to self- administer a drug, or to have the drug administered by another and/or who provides a patient with a prescription for a drug is administering the drug to the patient.

[ΘΘ61] The term ''therapeutic" treatment is art-recognized and includes administration to the host of one or more of the subject compositions or salts. Treatment is therapeutic if it is administered after manifestation of the unwanted condition (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). [0062] The tenns "preventing" or "prevention" are art-recognized and include stopping a disease, disorder, or condition from occurring in a subject, which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it. Preventing a condition related to a disease includes stopping the condition from occurring after the disease has been diagnosed but before the condition has been diagnosed. [ΘΘ63] The terms "therapeutic agent", "drug", "medicament" and "bioactive substance" are art- recognized tenns and include molecules and other agents that are biologically, physiological iy, or pharmacologically active substances that act locally or systemically in a patient or subject to treat a disease or condition.

[0064] The phrase "therapeutically effective amount" or "pharmaceutically effective amount" is an art-recognized term. In some embodiments, the term refers to an amount of a therapeutic agent that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment. In some embodiments, the term refers to that amount necessary or sufficient to eliminate, reduce or maintain a target of a particular therapeutic regimen. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular composition or salt without necessitating undue experimentation. In some embodiments, a therapeutically effective amount of a therapeutic agent for in vivo use will likely depend on a number of factors, including: the identity of the agent and the mode and method of administration,

[ΘΘ65] As used herein, the term "therapeutically effective dose" refers to a dose that produces the desired effect for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

Compounds

[0066] US patent application Serial No. 14/158,735 (US Patent Application Publication No. US20140212486) describes and claims the synthesis, purification and both structural and biological characterization of the ( )-isomer of isometheptene, and in particular its mucate salt. The patent application describes the uti lity of the compound for the treatment or prevention of a headache and/or hypertension among other disorders. The above -referenced patent application is herein incorporated by reference in its entirety.

[0067] As used herein, "racemic isometheptene" refers to pharmaceutically acceptable racemic isometheptene.

[0068 J As used herein, "(R)-isometheptene" refers to pharmaceutically acceptable (R)- isometheptene. The structure of (R)-isometheptene is:

[0069] As used herein, "(S)-isometheptene" refers to pharmaceutically acceptable (S)- isometheptene. The structure of (S)-isometheptene is:

(R -Lsomeiheptene Salts

[0070 J The invention provides novel ( R)-isometheptene salts and crystal line forms thereof. The invention further provides using the novel (R)-isometheptene salts and crystalline forms thereof for the treatment or prevention of pain, a headache, depression, ailodynia, fibromyalgia, fibromyalgia-ness, central sensitization, centralization, temporomandibular joint syndrome (TMJ), Gulf War syndrome, osteoarthritis, rheumatoid arthritis, or hypertension. Examples of pain include, but are not limited to, regional pain syndrome, lower back pain, visceral pain, neuropathic pain, sickle cell pain, nociceptive pain, post-operative pain, orthopedic injury pain, phantom limb pain, pain associated with cancer, or pain associated with post-traumatic stress disorder (PTSD), Examples of headache include, but are not limited to, an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; or a headache from mild to moderate hypertension. In some embodiments, the (R)-isometheptene salts and their crystalline forms of th e invention are used as analgesics. In some embodiments, the (R)-isometheptene salts and their crystalline forms of the invention are used as sedatives.

[Θ071] In one aspect, the invention provides a novel salt formed from (R)-isometheptene and citric acid, cyclamic acid, fumaric acid, hippuric acid, hydrochloric acid, maleic acid, L-malic acid, phosphoric acid, succinic acid or L-tartaric acid. In another aspect, the invention provides a novel salt formed from (R)-isometheptene and salts that are selected from acetic acid, adipic acid, aspartic acid, benzoic acid, glutaric acid, glycolic acid, and sulfuric acid, or from

hydrobromic, sulfamic, nitric and the like; and the salts prepared from organic acids such as propionic, glycolic, stearic, lactic, tartaric (to form tartrate or bitartrate salts), ascorbic, pamoic, iiydroxymaleic, phenylacetic, glutamic, salicylic, sulfanilic, 2-acetoxybenzoic, toluenesuifonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. In some embodiments, the salts of the invention are in a crystalline form. The novel salt may be one from which a crystalline solid with a desired characteristic may be formed. For example, the salt may form a crystalline solid and may be characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 45 °C and 145 °C.

[ΘΘ72] In some embodiments, the invention provides (R)-isometheptene maleate, (R)- isornetheptene L-malate, (R)-isometheptene L-tartrate, (R)-isometheptene citrate, (R)~ isometheptene cyclamate, (R)-isometheptene fumarate, (R)-isometheptene hippurate, (R)- isometheptene phosphate or (R)-isometheptene succinate. In some embodiments, the invention provides (R)-isometheptene maleate, (R)-isometheptene L-malate, or (R)-isometheptene L- tartrate. In some embodiments, the invention provides (R)-isometheptene maleate. In some embodiments, the invention provides (R)-isometheptene L-malate. In some embodiments, the invention provides (R)-isometheptene L-tartrate.

[ΘΘ73] The salts of the invention may be equal to or greater than 0% crystalline, equal to or greater than 10% crystalline, equal to or greater than 20% crystalline, equal to or greater than 30%) crystalline, equal to or greater than 40% crystalline, equal to or greater than 50%

crystalline, equal to or greater than 60% crystalline, equal to or greater than 70% crystalline, equal to or greater than 80%) crystalline, equal to or greater than 90% crystalline or equal to 100% crystalline. For example, the salt may be 10% crystalline, 20% crystalline, 30% crystalline, 40% crystalline, 50% crystalline, 60% crystalline, 70% crystalline, 80% crystalline, 90% crystalline, or 100% crystalline. In some embodiments, (R)-isomethepteiie salts are those that form crystal line salts characterized by a differential scanning calorimetry heating curve which shows a maximum endothermic heat flow (or peak) between 45 °C and 145 °C, or between 70 °C and 145 °C, or between 90 °C and 145 °C, or between 70 °C and 125 °C, or between 90 °C and 125 °C, or between 110 °C and 145 °C, or between 45 °C and 70 °C, or between 45 °C and 90 °C, or between 45 °C and 130 °C, or between 45 °C and 125 °C, or between 45 °C and 110 °C, or between 1 12 °C and 120 °C, or between 74° C and 83° C, or between 83 °C and 89 "C, or between 65 °C and 75 °C, or between 71 °C and 81 °C, or between 105 °C and 115 °C, or between 107 °C and 117 °C, between 123 °C and 133 °C, or between 48 °C and 58 °C.

[0074 J In some embodiments, the (R)-isometheptene salt is substantial!)' free of the (S)~ isometheptene salt. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 75%, or more than 80%, or more than 85%, or more than 90%, or more than 95%, or more than 96%, or more than 97%, or more than 98%, or more than 99%, or more than 99.5%, or 100% as compared to the amount of (S)-isometheptene salt in the salt. These amounts are not meant to be limiting, and increments between the recited percentages are specifically envisioned as part of the invention. For example, if a salt contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98% of the first enantiomer and only 2% of the second enantiomer. In some embodiments, substantially free means that the (R)-isornetheptene salt makes up more than 90% as compared to the amount of (S)-isometheptene salt in the salt. In some embodiments, substantial!)' free means that the (R)- isometheptene salt makes up more than 91% as compared to the amount of (S)-isometheptene salt in the salt. In some embodiments, substantially free means that the (R^')-isometheptene salt makes up more than 92% as compared to the amount of (S)-isometheptene salt in the salt. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 93% as compared to the amount of (S)-isometheptene salt in the salt. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 94% as compared to the amount of (S)-isometheptene salt in the salt. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 95% as compared to the amount of (S)- isometheptene salt in the salt. In some embodiments, substantially free means that the (R)~ isometheptene salt makes up more than 96% as compared to the amount of (S)-isometheptene salt in the salt. In some embodiments, substantially free means that the (R^')-isometheptene salt makes up more than 97% as compared to the amount of (S)-isometheptene salt in the salt. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 98% as compared to the amount of (S)-isometheptene salt in the salt. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 99% as compared to the amount of (S)-isometheptene salt in the salt, in some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 99.5% as compared to the amount of (S)- isometheptene salt in the salt. In some embodiments, substantially free means that the (R)~ isometheptene salt makes up 100%) as compared to the amount of (S)-isometheptene salt in the salt.

[0075] In some embodiments, (R)-isometheptene may be the predominant form of

isometheptene present in the salt. For example, 100%) of the isometheptene present in the salt may be (R)-isometheptene, or 99% of the isornetheptene present in the salt may be (R)~ isometheptene, or 95% of the isornetheptene present in the salt may be (R)-isometheptene, or 90% of the isornetheptene present in the salt may be (R)-isometheptene, or 85% of the isometheptene present in the salt may be (R)-isometheptene, or 80% of the isometheptene present in the salt may be (R)-isometheptene, or 75% of the isometheptene present in the salt may be (R)-isometheptene, or 70% of the isometheptene present in the salt may be (R)- iso netheptene, or 65% of the isornetheptene present in the salt may be (R)-isome heptene, or 60% of the isometheptene present in the salt may be (R)-isometheptene, or 55% of the isometheptene present in the salt may be (R)-isometheptene, or 51% of the isometheptene present in the salt may be (R)-isometheptene. Other isometheptene forms present in the salt may include (S)-isometheptene.

[0076] In some embodiments, (R)-isometheptene of the present invention may be the nonpredominant form of isometheptene present in the salt, i.e. 50% of the isometheptene in the salt may be (R)-isometheptene, or 45%) of the isometheptene in the salt may be (R)- isometheptene, or 40% of the isometheptene in the salt may be the (R -isometheptene, or 35% of the isometheptene in the salt may be (R)-isometheptene, or 30% of the isometheptene in the salt may be (R)-isometheptene, or 25% of the isometheptene in the salt may be (R)-isometheptene, or 20% of the isometheptene in the sal t may be ( R)-isometheptene, or 15% of the isometheptene in the salt may be (R)-isometheptene, or 10% of the isometheptene in the salt may be (R)- isometheptene, or 5% of the isometheptene in the salt may be (R)-isometheptene, or 1% of the isometheptene in the salt may be (R)-isometheptene. Other isometheptene forms present in the salt may include (S)-isometheptene.

Isotopes

[0077] In some embodiments, the salts of the invention further include all pharmaceutically acceptable isotopically labelled salts (e.g., salts of (R)-isometheptene). An "isotopically" or

"radio-labeled" salt is a salt where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). For example, in some embodiments, in the salts (e.g., salts of (R)-isometheptene), hydrogen atoms are replaced or substituted by one or more deuterium or tritium (e.g., hydrogen atoms on a C_1-6 alkyl or a Ci.₆ alkoxy are replaced with deutrium, such as i¾-methoxy or l,l₅2,2-c/₄-3-methylbutyl).

[Θ078] Isotopically labeled compounds (e.g., salts of (R)-isometheptene) or their corresponding prodrugs can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed. Suitable isotopes that may be incorporated in salts described herein include but are not limited to ^ZH (also written as D for deuterium), ³H (also written as T for tritium), ⁿC, ¹³C,¹ C, ^1JN, ¹⁵N, '^''Q, ¹⁸0, ¹⁸F, ³⁵8, ·^'( : , ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ^{Ϊ 23}Ι, ⁿ% ¹²⁵I, and ^{, 3J} I. [0079] Certain isotopically labeled salts (e.g., salts of (R)-isometheptene), in the inventions, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. Ή, and carbon 14, i.e., ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection, (0080] Substitution with positron emitting isotopes, such as C, ' F, O, and 'N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0081] Substitution with heavier isotopes such as deuterium, i.e., ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be desired in some circumstances. In some embodiments, the isotopically labeled salt comprises (R)-isometheptene-N-CD₃, 6 -D₆- (R)-isometheptene, or 6,7-D₆-(Tt)-isometheptGne-N-CD₃.

Polymorphs

[0082] The (R)-isometheptene salts of the invention can also exist as various polymorphs, pseudopolymorphs, or in amorphous state. As used herein, the term "polymorph" refers to different crystalline forms of (R)-isometheptene and other solid state molecular forms including pseudo-polymorphs, such as hydrates, solvates, or salts of (R)-isometheptene. Different crystalline polymorphs have different crystal structures due to a different packing of molecules in the lattice, as a result of changes in temperature, pressure, or variations in the crystallization process. Polymorphs differ from each other in their physical properties, such as X-ray diffraction characteristics, stability, melting points, solubility, or rates of dissolution in certain solvents. Thus crystalline polymorphic forms are important aspects in the development of suitable dosage forms in pharmaceutical industry.

Methods of Preparing Isometheptene Salts

[0083] Racemic isometheptene (6-methylamino-2-methylheptene) was first prepared according to the process described in U.S. Pat. No. 2,230,753. We have previously developed methods for synthesizing either (R)-or (S) isomers substantially free of the other isomer. See, for example, US patent application Serial No. 14/158,735 (US Patent Application Publication No.

US20140212486).

[0084] The present application provides a novel method to synthesize (R)-isometheptene, wherein the (R)-isometheptene is synthesized at greater than 90% enantiomeric purity, greater than 95% enantiomeric purity, greater than 96% enantiomeric purity, greater than 97%

enantiomeric purity, greater than 98%) enantiomeric purity, greater than 99% enantiomeric purity, or at 100% enantiomeric purity. The method is described briefly as outlined:

Scheme 1:

[0085] Firstly, 6-methylhept-5-en-2-one, which is commercially available, is reduced to produce the alcohol, then the alcohol is incubated with Candida Antartica Lipase B (CALB) to generate predominantly (S)-6~methylhept~5~en~2-ol. This intermediate is reacted with mesylchloride to form the mesylate which is further reacted with an amine source to synthesize (R)~A-6-rnethyihept-5~en-2~amine. In this schematic representation, an R-IMH mucate salt is eventually formed, but any other of the R-IMH salts described herein (e.g., maleate, L-malate, L- tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate) may be formed following this scheme.

Pharmaceutical Compositions ami Modes of Administration

[0086] The present invention provides pharmaceutical composition comprising a salt formed from (Rj-isometheptene. In some embodiments, the pharmaceutical composition comprises (R)- isometheptene maleate, (R)-isometheptene L-malate, (R)-isometheptene L-tartrate, (R)- isometheptene citrate, (R)-isometheptene cyclamate, (R)-isometheptene fumarate, (R)- isometheptene hippurate, (R)-isometheptene phosphate or (R)-isometheptene succinate. In some embodiments, the pharmaceutical composition comprises (R)-isometheptene maleate, (R)- isometheptene L-malate, or (R)-isometheptene L-tartrate. In some embodiments, the

pharmaceutical composition comprises (R)-isometheptene maleate. In some embodiments, the pharmaceutical composition comprises (R)-isometheptene L-malate. In some embodiments, the pharmaceutical composition comprises (R)-isometheptene L-tartrate. In some embodiments, the pharmaceutical composition comprises any one of the (R)-isornetheptene salts described herein or a combination thereof. In some embodiments, the pharmaceutical composition comprises any one of the isometheptene salts listed in Tables 1-6 or a combination thereof. In some embodiments, the pharmaceutical composition comprises any one of the ( R)-isometheptene salts of Figures 1-18 or a combination thereof. In some embodiments, the (R)-isometheptene salt contained in these pharmaceutical compositions is in a crystalline form.

[0087] In some embodiments, the pharmaceutical composition comprising the (R)- isometheptene sal t is substantially free of the (S)-isometheptene salt. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 75%, or more than 80%, or more than 85%, or more than 90%, or more than 95%, or more than 96%. or more than 97%, or more than 98%, or more than 99%, or more than 99.5%, or 100% as compared to the amount of (S)-isometheptene salt in the composition. These amounts are not meant to be limiting, and increments between the recited percentages are specifically envisioned as part of the invention. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 90% as compared to the amount of (S)-isometheptene salt in the composition. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 91% as compared to the amount of (S)-isomet eptene salt in the composition. In some embodiments, substantially free means that the (R^')-isometheptene salt makes up more than 92% as compared to the amount of (S)-isometheptene salt in the composition. In some embodiments, substantial ly free means that the (R)-isometheptene salt makes up more than 93% as compared to the amount of (S)-isometheptene salt in the composition. In some embodiments, substantially free means that the (R)-isometheptene salt- makes up more than 94% as compared to the amount of (S)-isometheptene salt in the composition. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 95%) as compared to the amount of (S)-isometheptene salt in the composition. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 96% as compared to the amount of (S)-isometheptene salt in the composition. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 97% as compared to the amount of (S)-isometheptene salt in the composition. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 98% as compared to the amount of (S)-isometheptene salt in the composition. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 99% as compared to the amount of (S)-isometheptene salt in the composition. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 99.5% as compared to the amount of (S)-isometheptene salt in the composition. In some embodiments, substantially free means that the (R)-isometheptene salt makes up 100% as compared to the amount of (S)-isometheptene salt in the composition. Θ088] The pharmaceutical compositions of the invention are administered to a subject suffering from pain, a headache, depression, allodynia, fibromyalgia, fibromyalgia-ness, central sensitization, centralization, temporomandibular joint syndrome (TMJ), Gulf War syndrome, osteoarthritis, rheumatoid arthritis, or hypertension. Examples of pain include, but are not limited to, regional pain syndrome, lower back pain, visceral pain, neuropathic pain, sickle cell pain, nociceptive pain, post-operative pain, orthopedic injur pain, phantom limb pain, pain associated with cancer, or pain associated with post-traumatic stress disorder (PTSD). Examples of headache include, but are not limited to, an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; or a headache from mild to moderate hypertension. The pharmaceutical compositions of the invention are administered to a patient as sedatives or as analgesics.

[0089 J The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will general ly be that amount of the salt which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent. Θ090] In some embodiments, the (R)-isometheptene salt or the pharmaceutical composition comprising the (R)-isometheptene salt may be combined with one or more other pharmaceutical substances, including compounds known to relieve headaches, such as acetaminophen, ibuprofen, aspirin, caffeine, dichloralphenazone, naproxen, or sumatriptan succinate. In some embodiments, the salts or the pharmaceutical compositions are with these other pharmaceutical substances in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for eac of the therapeutic agents.

[ΘΘ91] In some embodiments, the effective daily dose of the salt or the active salt or the pharmaceutical composition comprising the salt or the active salt may be administered as one, two, three, four, five, six, or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In some embodiments of the invention, the salt or the active salt or the pharmaceutical composition comprising the salt or the active salt is administered two or three times daily. In some embodiments, the salt or the active salt or the pharmaceutical composition comprising the salt or the active salt is administered once daily. [0092] In some embodiments, the pharmaceutical compositions of the invention are in a variety of forms, including, but not limited to, a composition that is enterically coated, a composition that is a controlled release or sustained release formulation, a composition that is an immediate release formulation, a composition that is a solution, a composition that is a tablet or capsule, a composition that is a topical formulation, a composition that is a suppository, a composition that is a transdermal patch, a composition that is lyophilized, a composition that is in an inhaler, a composition that is in a prefilled syringe, a composition that is in a nasal spray device, and the like. In some embodiments, the pharmaceutical compositions of the invention are formulated for oral administration, parenteral administration, mucosal administration, nasal administration, topical administration, ocular admin stration, local admin stration, rectal administration, or intrathecal administration. If parenteral, the administration can be subcutaneous, intravenous, intradermal, intraperitoneal, intrathecal, among others. The pharmaceutical compositions of the invention may be in a packaged unit dosage or multi-unit dosage. Additional routes of administration of the pharmaceutical compositions of the invention may include, without limitation, intramuscular, intrarticular, intrabronchial, intraabdominal, intracapsular, mtracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, mtracervical, intragastric, intrahepatic, intramyocardial, intraosteal, mtrapelvic, mtrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, buccal, sublingual, intranasal, and transdermal. 10093 J The pharmaceutical compositions of the present invention may include, or may he diluted into, a pharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable carrier" as used herein means one or more compatible solid, gel, or liquid fillers, diluents or encapsulating substances which are suitable for administration to a human or other mammal such as a non-human primate, a dog, cat, horse, cow, sheep, pig, or goat. The term "carrier" denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The carriers are capable of being commingled with the compositions, salts and preparations of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy or stability. Carrier formulations suitable for oral administration, for suppositories, and for parenteral administration, among others, can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. An exemplary type of carrier may include alpha-cyclodextrin, beta cyclodextrin, hydroxyethyl-beta-cyclodextrin, and hydroxyethyl-alpha- cyclodextrin. [0094] In some embodiments, excipients for oral and sublingual formulations of isometheptene mucate, isometheptene malate, isometheptene maleate, isometheptene tartrate and other salts of isometheptene include alpha-cyclodextrin and hydroxypropyl-beta cyclodextrin. Excipients for intravenous, intramuscular and subcutaneous formulations include hydroxypropyl-beta cyclodextrin. In some embodiments, the isometheptene salt is dissolved with at least 1 molar equivalent of cyclodextrin in water or a suitable mixed aqueous solvent prior to removal of solvent to ensure complete complexation. Not to be bound by theory, in some embodiments, the cyclodextrin may increase solubility and stability of the isometheptene through complexation of the isometheptene cation inside the tube-shaped cyclodextrin molecule.

[0095] In some embodiments, excipients for oral and sublingual formulations of (R)- isometheptene mucate, (R)-isometheptene malate, (R)-isometheptene maleate, (R)- isometheptene tartrate and other salts of (R)-isometheptene include alpha-cyclodextrin and hydroxypropyl-beta cyclodextrin. Excipients for intravenous, intramuscular and subcutaneous formulations include hydroxypropyl-beta cyclodextrin. In some embodiments, the (R)- isometheptene salt is dissolved with at least 1 molar equivalent of cyclodextrin in water or a suitable mixed aqueous solvent prior to removal of solvent to ensure complete complexation. Not to be bound by theory, in some embodiments, the cyclodextrin may increase solubility and stabili ty of the (R)-isometheptene through complexation of the (R)-isometheptene cation inside the tube-shaped cyclodextrin molecule. [0096] In some embodiments, a composition of the invention is administered internally. For local internal administration, such as intra-articular administration, the compositions can be formulated as a solution or a suspension in an aqueous-based medium, such as isotonicaily buffered saline or are combined with a biocompatible support or bioadhesive intended for internal administration. [0097] In some embodiments, the pharmaceutical compositions of the invention are aqueous formulations. Such aqueous formulations may include a chelating agent, a buffering agent, an anti-oxidani and, optionally, an isotonicitv agent. Chelating agents include, for example, but are not limited to ethylenediaminetetraacetic acid (EDTA) as a free acid, salt or various

combinations and derivatives thereof, citric acid and derivatives thereof, niacinamide and derivatives thereof, sodium desoxycholate and derivatives thereof, and L-glutamic acid, N,N~ diacetic acid and derivatives thereof.

[0098] Examples of buffering agents include, but are not limited to, citric acid, sodium citrate, sodium acetate, acetic acid, sodium phosphate and phosphoric acid, sodium ascorbate, tartaric acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic acid, imidazoline, sodium bicarbonate and carbonic acid, sodium succinate and succinic acid, histidine, and sodium benzoate and benzoic acid, or combinations thereof.

[0099] Examples of antioxidants include, but are not limited to, an ascorbic acid derivative, butylated hydroxy anisole, butylated hydroxy toluene, alkyl gallate, sodium meta-bisulfite, sodium bisulfite, sodium dithionite, sodium thioglycollate acid, sodium formaldehyde sulfoxylate, tocopheral and derivatives thereof monothioglycerol, or sodium sulfite or combinations thereof. In one embodiment, the antioxidant is monothioglycerol. [0100] Examples of isotonicity agents include, but are not limited to, sodium chloride, mannitol, lactose, dextrose, glycerol, or sorbitol, or combinations thereof.

[0101] In some embodiments, the pharmaceutical compositions of the invention further comprise preservatives. Examples of preservatives that can be used with the present

compositions include without limitation benzyl alcohol, parabens, thimerosal, chlorobutanol and benzalkonium chloride. In some embodiments, the preservative is present in the pharmaceutical composition in a concentration of up to about 2% by weight. The exact concentration or weight percentage of the preservative, however, will vary depending upon the intended use and can be easily ascertained by one skil led in the art. [0102] As used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without a resulting or excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues, such as amines, alkali or organic salts of acidic residues, such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. These physiologically acceptable salts are prepared by methods known in the art, e.g., by dissolving the free amine bases with an excess of the acid in aqueous alcohol, or neutralizing a free carboxylic acid with an alkali metal base such as a hydroxide, or with an amine. Certain acidic or basic compounds of the present invention may exist as zwitterions. All forms of the compounds, including free acid, free base and zwitterions, are contemplated to be within the scope of the present invention. It is well known in the art that compounds containing bot amino and carboxyl groups often exist in equilibrium with their zwitterionie forms. Thus, any of the compounds described herein that contain, for example, both amino and carboxyl groups, also include reference to their corresponding zwitterions.

[0103] In some embodiments, a product containing a therapeutic salt(s) of the invention and, optionally, one or more other active agents can be configured as an oral dosage. The oral dosage may be a liquid, a semisolid or a solid. The oral dosage may be configured to release the therapeutic salt(s) of the invention before, after or simultaneously with the other agent. The oral dosage may be configured to have the therapeutic salt(s) of the invention and the other agents release completely in the stomach, release partially in the stomach and partially in the intestine, in the intestine, in the colon, partially in the stomach, or wholly in the colon. The oral dosage also may be configured whereby the release of the therapeutic salt(s) of the invention is confined to the stomach or intestine while the release of the other active agent is not so confined or is confined differently from the therapeutic salt(s) of the invention. For example, the therapeutic salt(s) of the invention may be an enterically coated core or pel lets contained within a pill or capsule that releases the other agent first and releases the therapeutic salt(s) of the invention only after the therapeutic salt(s) of the invention passes through the stomach and into the intestine. The therapeutic sait(s) of the invention also can be in a sustained release material, whereby the therapeutic salt(s) of the invention is released throughout the gastrointestinal tract and the other agent is released on the same or a different schedule. The same objective for therapeutic salt(s) of the invention release can be achieved with immediate release of therapeutic salt(s) of the invention combined with enteric coated therapeutic salt(s) of the invention. In these instances, the other compound or agent could be released immediately in the stomach, throughout the gastrointestinal tract or only in the intestine.

[0104] The materials useful for achieving these different release profi les are well known to those of ordinary skill in the art. Immediate release is obtainable by conventional tablets with binders which dissolve in the stomach. Coatings which dissolve at the pH of the stomach, or which dissolve at elevated temperatures, will achieve the same purpose. Release only in the intestine is achieved using conventional enteric coatings such as pH sensitive coatings which dissolve in the pH environment of the intestine (but not the stomach), or coatings that dissolve over time. Release throughout the gastrointestinal tract is achieved by using sustained-release materials and/or combinations of the immediate release systems and sustained and/or delayed intentional release systems (e.g., pellets which dissolve at different pHs).

[0105] In the event that it is desirable to release the therapeutic salt(s) of the invention first, the therapeutic salt(s) of the invention could be coated on the surface of the controlled release formulation in any pharmaceutically acceptable carrier suitable for such coatings and for permitting the release of the therapeutic sait(s) of the invention, such as in a temperature sensitive pharmaceutically acceptable carrier routinely used for controlled release. Other coatings, which dissol ve when placed in the body, are well known to those of ordinary skill in the art.

[Θ106] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s). Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogeis described by H.S. Sawhney, CP. Pathak and J.A. Hubell in Macromolecules, ( 1993) 26:581 -587, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, giutin, polyanhydrides, polyacryiic acid, alginate, chitosan, poly(methyi methacrylates), poly(ethyl methacrylates), poly(butylmethaciylate), polyfisobutyl methacrylate),

poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poiy(phenyl methacrylate), poiyimethyi acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and po ly(octadecy 1 acr late) .

[0107] In some embodiments, the therapeutic agent(s) may be contained in a controlled release formulation or controlled release systems. The term "controlled release" is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations. The term "sustained release" (also referred to as "^■extended release") is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that in some embodiments, although not necessarily, results in substantially constant blood levels of a drug over an extended time period. The term "delayed release" is used in its conventional sense to refer to a drag formulation in which there is a time del ay between administration of the formulation and the release of the drug therefrom. "Delayed release" may or may not involve gradual release of drag over an extended period of time, and thus may or may not be "sustained release." These formulations may be for any mode of administration.

{0108] Deliver}' systems specific for the gastrointestinal tract are roughly divided into three types: the first is a delayed release system designed to release a drug in response to, for example, a change in pH; the second is a timed-release system designed to release a drag after a predetermined time; and the third is a microflora enzyme system making use of the abundant enterobacteria in the lower part, of the gastrointestinal tract (e.g., in a colonic site-directed release formulation). {0109] An example of a delayed release system is one that uses an acrylic or ceilulosic coating material and dissolves on pH change. Because of ease of preparation, many reports on such "enteric coatings" have been made, in general, an enteric coating is one which passes through the stomach without releasing substantial amounts of drug in the stomach (i.e., less than 10% release, 5% release and even 1% release in the stomach) and sufficiently disintegrating in the intestinal tract (by contact with approximately neutral or alkaline intestine juices) to allow the transport (active or passive) of the active agent through the walls of the intestinal tract.

[0110] The enteric coating is typically, although not necessarily, a polymeric material. Enteric coating materials comprise bioerodible, gradually hydroiyzabie and/or gradually water-soluble polymers. The "coating weight," or relative amount of coating material per capsule, generally dictates the time interval between ingestion and drug release. Any coating should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above. It is expected that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the practice of the present invention. The selection of the specific enteric coating material will depend on the following properties: resistance to dissolution and disintegration in the stomach; impermeability to gastric fluids and drug/carrier/enzyme while in the stomach; ability to dissolve or disintegrate rapidly at the target intestine site; physical and chemical stability during storage; non-toxicity; ease of application as a coating (substrate friendly); and economical practicality. [0111] Suitable enteric coating materials include, but are not limited to: ceilulosic polymers such as cellulose acetate phthalate, cellulose acetate trirnellitate, hydroxypropylmethyl cellulose phthalate, hydroxypropyhm ethyl cellulose succinate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, formed from acrylic acid, methacryiic acid, methyl acryiate, ammonium rnethylaerylate, ethyl acryiate, methyl methacrylate and/or ethyl meth acryiate (e.g., those copolymers sold under the trade name EUDRAGIT); vinyl polymers and copolymers such as polyvinyl acetate, polyvinyl acetate phthalate, vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate copolymers; and shellac (purified lac). Combinations of different coating materials may also be used. Well known enteric coating material for use herein are those acrylic acid polymers and copolymers available under the trade name EUDRAGIT from Rohm Pharma (Germany).

[Θ112] In some embodiments, the coating can, and usually does, contain a plasticizer to prevent the formation of pores and cracks that would permit the penetration of the gastric fluids.

Suitable plasticizers include, but are not limited to, triethyl citrate (Citroflex 2), triacetin

(glyceryl triacetate), acetyl triethyl citrate (Citrofiec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, a coating comprised of an anionic carboxylic acrylic polymer will usually contain approximately 10% to 25% by weight of a plasticizer, particularly dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. The coating can also contain other coating excipients such as detackifiers, antifoaming agents, lubricants (e.g., magnesium stearate), and stabilizers (e.g., hydroxypropylcellulose, acids and bases) to solubilize or disperse the coating material, and to improve coating performance and the coated product.

[Θ113] The coating can be applied to particles of the therapeutic agent(s), tablets of the therapeutic agent(s), capsules containing the therapeutic agent(s) and the like, using conventional coating methods and equipment. For example, an enteric coating can be applied to a capsule using a coating pan, an airless spray technique, fiuidized bed coating equipment, or the like. Detailed information concerning materials, equipment and processes for preparing coated dosage forms may be found in Pharmaceutical Dosage Forms: Tablets, eds. Lieberman et al. (New York: Marcel Dekker, Inc., 1989), and in Ansel et al.. Pharmaceutical Dosage Forms and Drug

Delivery Systems, 6th Ed. (Media, PA: Williams & Wilkins, 1995). The coating thickness, as noted above, must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the lower intestinal tract is reached,

[0114] In some embodiments, the compositions, according to the present invention, also can be administered as a nasal spray, nasal drop, suspension, gel, ointment, cream or powder. The administration of a composition can also include using a nasal tampon or a nasal sponge containing or impregnated with a composition of the present invention.

[Θ115] The nasal delivery systems that can be used with the present invention can take various forms including aqueous preparations, non-aqueous preparations and combinations thereof. Aqueous preparations include, for example, aqueous gels, aqueous suspensions, aqueous liposomal dispersions, aqueous emulsions, aqueous microemulsions and combinations thereof. Non-aqueous preparations include, for example, non-aqueous gels, non-aqueous suspensions, non-aqueous liposomal dispersions, non-aqueous emulsions, non-aqueous microemulsions and combinations thereof. The various forms of the nasal deliv er}' systems can include a buffer to maintain pH, a pharmaceutically acceptable thickening agent and a humectant. The pH of the buffer can be selected to optimize the absorption of the therapeutic agent(s) across the nasal mucosa.

[0116] With respect to the non-aqueous nasal formulations, suitable forms of buffering agents can be selected such that when the formulation is delivered into the nasal cavity of a mammal, selected pH ranges are achieved therein upon contact with, e.g., a nasal mucosa. In the present invention, the pH of the compositions should be maintained from about 2.0 to about 6.0. It is desirable that the pH of the compositions is one which does not cause significant irritation to the nasal mucosa of a recipient upon administration. An aerosol or spray device may be used in conj unction with the n asal delivery systems of the invention. [0117 J The viscosity of the compositions of the present invention can be maintained at a desired level using a pharmaceutically acceptable thickening agent. Thickening agents that can be used in accordance with the present invention include methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyi cellulose, earhomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof. The concentration of the thickening agent will depend upon the agent selected and the viscosity desired. Such agents can also be used in a powder formulation discussed above.

[0118] The compositions of the present invention can also include a humectant to reduce or prevent drying of the mucus membrane and to prevent irritation thereof. Illustratively, suitable humectants that can be used in the present invention include sorbitol, mineral oil, vegetable oil and glycerol; soothing agents; membrane conditioners; sweeteners; and combinations thereof. The concentration of the humectant in the present compositions will vary depending upon the agent selected.

[0119] In some embodiments, the compositions are formulated for topical administration. A. composition formulated for topical administration may be liquid or semi-solid (including, for example, a gel, lotion, emulsion, cream, ointment, spray or aerosol) or may be provided in combination with a "finite" carrier, for example, a non-spreading material that retains its form, including, for example, a patch, bioadhesive, dressing or bandage. It may be aqueous or nonaqueous; it may be formulated as a solution, emulsion, dispersion, a suspension or any other mixture.

[0120] In some embodiments, modes of administration for topical administration include application to the skin, eyes or mucosa. Thus, typical vehicles are those suitable for

pharmaceutical or cosmetic application to body surfaces. The compositions provided herein may be applied topically or locally to various areas in the body of a patient. As noted above, topical application is intended to refer to application to the tissue of an accessible body surface, such as, for example, the skin (the outer integument or covering) and the mucosa (the mucous-producing, secreting and/or containing surfaces). Exemplar}_' mucosal surfaces include the mucosal surfaces of the eyes, mouth (such as the lips, tongue, gums, cheeks, sublingual and roof of the mouth), larynx, esophagus, bronchial, nasal passages, vagina and rectum/anus; in some embodiments, the mouth, larynx, esophagus, vagina and rectum/anus; in other embodiments, the eyes, larynx, esophagus, bronchial, nasal passages, and vagina and rectum/anus. As noted above, local application herein refers to application to a discrete intemai area of the body, such as, for example, a joint, soft tissue area (such as muscle, tendon, ligaments, intraocular or other fleshy internal areas), or other internal area of the body. Thus, as used herein, local application refers to applications to discrete areas of the body.

[0121] in some embodiments, suitably prepared solutions and suspensions may also be topically applied to the eyes. Solutions, particularly those intended for ophthalmic use, may be formulated as 0.01 %- 10% isotonic solutions, pH about 5-7, with appropriate salts, and in some embodiments, containing one or more of the salts herein at a concentration of about 0.1%, in some embodiments, greater than 1%, up to 50% or more. Suitable ophthalmic solutions are known (see, e.g., U.S. Pat. No. 5, 1 16,868, which describes typical compositions of ophthalmic irrigation solutions and solutions for topical application). Such solutions, which have a pH adjusted to about 7.4, contain, for example, 90-100 mM sodium chloride, 4-6 mM dibasic potassium phosphate, 4-6 mM dibasic sodium phosphate, 8-12 mM sodium citrate, 0.5-1.5 mM magnesium chloride, 1 .5-2.5 mM calcium chloride, 15-25 mM sodium acetate, 10-20 mM D,L~ sodium, β-hydroxybutyrate and 5-5.5 mM glucose.

[Θ122] In some embodiments, the salts or pharmaceutical compositions of the invention are formulated as a lotion. Lotions, which, for example, may be in the form of a suspension, dispersion or emulsion, contain an effective concentration of one or more of the salts. In some embodiments, the effective concentration is that which will deliver an effective amount, typically at a concentration of between about 0.1-50%, by weight, or more of one or more of the salts provided herein. The lotions also contain by weight from 1 % to 50% of an emollient and the balance water, a suitable buffer, and other agents as described above. Any emollients known to those of skill in the art as suitable for application to skin, e.g., human skin, may be used. In some embodiments, the lotions further contain, by weight, from 1% to 10%, or from 2% to 5%, of an emulsifler. The emulsifiers can be noiiioiiic, anionic or cationic. Examples of satisfactory nonionic emulsifiers include, but are not limited to, fatty alcohols having 10 to 20 carbon atoms, fatty alcohols having 10 to 20 carbon atoms condensed with 2 to 20 moles of ethylene oxide or propylene oxide, alkyl phenols with 6 to 12 carbon atoms in the alkyl chain condensed with 2 to 20 moles of ethylene oxide, mono- and di-fatty acid esters of ethylene oxide, mono- and di-fatty acid esters of ethylene glycol where the fatty acid moiety contains from 10 to 20 carbon atoms, diethylene glycol, polyethylene glycols of molecular weight 200 to 6000, propylene glycols of molecular weigh 200 to 3000, glycerol, sorbitol, sorbitan, polyoxyethylene sorbitol,

poiyoxyethyiene sorbitan and hydrophilic wax esters. Suitable anionic emulsifiers include, but are not limited to, the fatty acid soaps, e.g., sodium, potassium and triethanolamine soaps, where the fatty acid moiety contains from 10 to 20 carbon atoms. Other suitable anionic emulsifiers include, but are not limited to, the alkali metal, ammonium or substituted ammonium alkyl sulfates, alkyl arylsu!fonates, and alkyl ethoxy ether sulfonates having 10 to 30 carbon atoms in the alkyl moiety. The alkyl ethoxy ether sulfonates contain from 1 to 50 ethylene oxide units. Among satisfactory cationic emulsifiers are quaternary ammonium, rnorpholinium and pyridinium compounds. When a lotion is formulated containing such an emollient, an additional ernuisifter is not needed, though it can be included in the composition. [0123] The balance of the lotion is water or a C₂ or€ alcohol, or a mixture of water and the alcohol. The lotions are formulated by simply admixing all of the components together. In some embodiments, the salt is dissolved, suspended or otherwise uniformly dispersed in the mixture.

[Θ124] Other conventional components of such lotions may be included. One such additive is a thickening agent at a level from 1% to 10% by weight of the composition. Examples of suitable thickening agents include, but are not limited to: cross-linked carboxypolymethylene polymers, ethyl cellulose, polyethylene glycols, gum tragacanth, gum kharaya, xanthan gums and bentonite, hydroxyethyl cellulose, and hydroxypropyl cellulose.

[Θ125] In some embodiments, the salts or pharmaceutical compositions of the invention are formulated in a cream. Creams can be formulated to contain a concentration effective to deliver an effective amount of therapeutic agent(s) of the invention to the treated tissue, typically at between about 0.1% and 50%, in some embodiments at greater than 1% up to and greater than

50%), in some embodiments between about 3% and 50%, in some embodiments between about

5%) and 15% therapeutic agent(s) of the invention. The creams also contain from 5% to 50%, in some embodiments from 10% to 25%, of an emollient and the remainder is water or other suitable non-toxic carrier, such as an isotonic buffer. The emollients, as described above for the lotions, can also be used in the cream compositions. The cream may also contain a suitable emulsifier, as described above. The emu!sifier is included in the composition at a level from 3% to 50%, preferably from 5% to 20%. [0126] In some embodiments, the compositions that are formulated as solutions or suspensions may be applied to the skin, or, may be formulated as an aerosol or foam and applied to the skin as a spray-on. The aerosol compositions typically contain, by weight, from 25% to 80%, in some embodiments from 30% to 50%, of a suitable propellaiit. Examples of such propellants are the chlorinated, fluorinated and chlorofluorinated lower molecular weight hydrocarbons. Nitrous oxide, carbon dioxide, butane, and propane are also used as propellaiit gases. These propellants are used as understood in the art in a quantity and under a pressure suitable to expel the contents of the container.

[0127] in some embodiments, the salts or pharmaceutical compositions of the invention are formulated in a gel. Gel compositions can be formulated by simply admixing a suitable thickening agent to the previously described solution or suspension compositions. Examples of suitable thickening agents have been previously described with respect to the lotions.

[0128] The gelled compositions contain an effective amount of therapeutic agent(s) of the invention, typical ly at a concentration of between about 0.1-50% by weight or more of one or more of the salts provided herein.; from 5% to 75%, in some embodiments, from 10% to 50%, of an organic solvent as previously described; from 0.5% to 20%, in some embodiments, from 1 % to 10%) of the thickening agent; the balance being water or other aqueous or non-aqueous carrier, such as, for example, an organic liquid, or a mixture of carriers.

[0129] Also in some embodiments, including embodiments that involve aqueous vehicles, the compositions may also contain a glycol, that is, a compound containing two or more hydroxy groups. In some embodiments, the glycol for use in the compositions is propylene glycol. In these embodiments, the glycol is included in the compositions in a concentration of from greater than 0 to about 5 wi %, based on the total weight of the composition. In some embodiments, the compositions contain from about 0.1 to less than about 5 wt. % of a glycol. In some embodiments, the compositions contain from about 0.5 to about 2 wt. %, In some embodiments, the compositions contain about 1 wt. % of a glycol.

[Θ130] The formulations can be constructed and designed to create steady state plasma levels. Steady state plasma concentrations can be measured using HPLC techniques, as are known to those of skill in the art. Steady state is achieved when the rate of dmg availability is equal to the rate of drug elimination from the circulation. In typical therapeutic settings, the therapeutic agent(s) of the invention will be administered to patients either on a periodic dosing regimen or with a constant infusion regimen. The concentration of drug in the plasma will tend to rise immediately after the onset of administration and will tend to fall over time as the dmg is eliminated from the circulation by means of distribution into cells and tissues, by metabolism, or by excretion. Steady state will be obtained when the mean dmg concentration remains constant over time. In the case of intermittent dosing, the pattern of the drag concentration cycle is repeated identically in each interval between doses with the mean concentration remaining constant. In the case of constant infusion, the mean dmg concentration will remain constant with very little oscillation. The achievemen t of steady state is determined by means of m easurin g the concentration of drag in plasma over at least one cycle of dosing such that one can verify that the cycle is being repeated identically from dose to dose. Typically, in an intermittent dosing regimen, maintenance of stead)' state can be verified by determining dmg concentrations at the consecutive troughs of a cycle, just prior to administration of another dose. In a constant infusion regimen where oscillation in the concentration is low, steady state can be verified by any two consecutive measurements of drag concentration.

[0131] In some embodiments, the salts or pharmaceutical compositions of the invention are used in in the manufacture of a medicament. In some embodiments, the salts or pharmaceutical compositions of the invention are used in the manufacture of a medicament for the treatment of pain, a headache, depression, allodynia, fibromyalgia, fibromyalgia -ness, central sensitization, centralization, temporomandibular joint syndrome (TMJ), Gul f War syndrome, osteoarthriti s, rheumatoid arthritis, or hypertension. Examples of pain include, but are not limited to, regional pain syndrome, lower back pain, visceral pain, neuropathic pain, sickle cell pain, nociceptive pain, post-operative pain, orthopedic injury pain, phantom limb pain, pain associated with cancer, or pain associ ated with post-traumati c stress disorder (PTSD). Examples of headache include, but are not limited to, an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular,

neurovascular, or neurogenic disorder or dysfunction during a migraine episode; or a headache from mild to moderate hypertension, in some embodiments, the salts or pharmaceutical compositions the invention are used in the manufacture of a medicament for sedation or analgesia.

Therapeutic uses [0132] For any of the methods described herein, embodiments of the invention contemplate the use of any of the salts and/or compositions described throughout the application. In addition, in various embodiments of any of the methods described herein, combinations of any step or steps of one method with any step or steps from another method may be employed.

[0133] These salts or pharmaceutical compositions described herein have numerous uses, including in vitro and in vivo uses. In vivo uses include not only therapeutic uses but also diagnostic and research uses in, for example, any of the animal models described herein. By way of example, any of the salts or pharmaceutical compositions of the invention may be used as research reagents and delivered to animals to understand bioactivity, enzymatic activity, gene expression, interactions with other molecules, and impacts on animal physiology in healthy or diseased animals.

[0134] The salts or pharmaceutical compositions of the invention may be used as analgesics or to treat pain, a headache, depression, allodynia, fibromyalgia, fibromyalgia-ness, central sensitization, centralization, temporomandibular joint syndrome (TMJ), Gulf War syndrome, osteoarthritis, rheumatoid arthritis, or hypertension. Examples of pain include, but are not limited to, regional pain syndrome, lower back pain, visceral pain, neuropathic pain, sickle cell pain, nociceptive pain, post-operative pain, orthopedic injur pain, phantom limb pain, pain associated with cancer, or pain associated with post-traumatic stress disorder (PTSD). Examples of headache include, but are not limited to, an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; or a headache from mild to moderate hypertension. The salts or pharmaceutical compositions of the invention may be used as sedatives.

Analgesic

[0135] In some embodiments, the salts or pharmaceutical composi tions of the invention act as potent and selective pain inhibitors or analgesics to treat or prevent diseases or disorders, including, but not limited to, allodyiiia, fibromyalgia, migraine, and rheumatoid arthritis. Pain

[Θ136] In some embodiments, the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of pain. Pain is an unpleasant feeling triggered by the nervous system, it is often classified by the region of the body involved, the system whose dysfunction may be causing the pain, the duration and pattern of occurrence, the intensity and time since onset, and the etiology. Many types of pain exist, including, but not limited to, nociceptive pain, neuropathic pain, psychogenic pain, visceral pain, and chronic pain.

Headaches and episodic tension-type headaches

[Θ137] In some embodiments, the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of pain caused by headaches and episodic tension-type headaches. A headache is pain in any region of the head, and may occur on one or both sides of the head, be isolated to a certain location, radiate across the head from one point, or have a vise- like quality. Headaches can cause shaip pain, a throbbing sensation, or a dull ache. Primary headaches can be caused by problems with or overactivity of pain-sensitive structures in the head, and secondary headaches can be caused by diseases, such as brain cancer, glaucoma, and trigeminal neuralgia, which activate the pain-sensitive nerves in the head. [0138] A tension-type headache is classified into subtypes based on how often it occurs:

infrequent episodic tension-type headache (ETTH) (<1 day/month on average), frequent ETTH (1-14 days/month on average), or chronic TTH, or CTTH, (~ 15 days/month on average). An ETTH (infrequent or frequent) may be described as a mild to moderate constant band-like pain, tightness, or pressure around the forehead or back of the head and neck. ETTH may last from 30 minutes to several days. ETTH usually begins gradually, and often occurs in the middle of the day. The severity of a tension headache generally increases significantly with its frequency.

[Θ139] Because the symptoms of ETTH overlap with other primary headache types, diagnosis is generally made, not only by inclusion, but also of exclusion of certain symptoms such as nausea, exacerbation by physical exercise and occurrence of both photophobia and phonophobia.

Migraine

[0140] In some embodiments, the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of migraines; tension or migraine headaches due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; or tension or migraine headaches due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode. Migraine is described as a paroxysmal disorder or a recurrent, incapacitating, neurovascular disorder characterized by unilateral and throbbing headaches associated characterized by attacks of headache, nausea, vomiting, photophobia, and phonophobia. [0141] Migraine affects people of ail races and both sexes with women accounting for 79% (61% between 20 and 49 years of age) of physician visits for migraines and Caucasians for 91% of the physician visits. Migraine without aura often has a strict menstrual relationship. The pathogenesis of migraine headache involves a) the cranial blood vessels, b) the trigeminal innervation of these vessels, and c) the reflex connection of the trigeminovascular system in the cranial parasympathetic outflow.

[0142] Migraine pathophysiology is believed by genetic predisposition to involve leakage of ion channels in the brain stem such that the decreased blood flow in the brain leads to neuropeptide release from trigeminal nerves inducing dilatation of cranial extracerebral blood vessel. This condition stimulates the trigeminovascuiar system producing headache associated phonophobia and photophobia as well as nausea and vomiting.

Phantom limb pain [0143] In some embodiments, the salts or pharmaceutical compositions of the invention may^¬ be used in the treatment or prevention of phantom pain. Phantom pain is pain coming from a body part that's no longer there. This pain originates in the spinal cord and brain and may be described as shooting, stabbing, boring, squeezing, throbbing or burning.

Depression [0144 J In some embodiments, the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of depression. Depression, clinical depression, major depression, unipolar depression, unipolar disorder, or recurrent depression in the case of repeated episodes is a psychiatric diagnosis for a mood disorder characterized by episodes of all encompassing low mood accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities (anhedonia) and disturbed sleep (typically early morning awakening). The term "depression" is ambiguous and can be used to describe manic-depressive disorder, but is also used to describe other mood disorders or to lower mood states lacking clinical significance. For example, endogenous depression or the depressed phases of bipolar disorder can be associated with widespread pain or regional pain disorders. [0145] Pain experienced during depression can include, but is not limited to, psychogenic pain, psychiatric pain, psychic pain, and psychological pain. Psychogenic pain is pain that results from psychological mechanisms including traumatic experiences, em athic reactions or somatization. For example, loss of a loved friend or relative by death or other separation can result in widespread pain, regional pain, and other symptoms including reactive depression. Psychiatric pain is pain that results from conditions that are believed to have biological causes. Psychic pain and psychological pain are caused by a non-physical origin and can lead to emotional suffering and mental agony. Allodynia

[0146] In some embodiments, the salts or pharmaceut cal compositions of the invention may be used in the treatment or prevention of allodynia. Allodynia, or pain due to a stimulus that does not usually provoke pain, is a prominent symptom in patients with neuropathic pain.

Allodynia is seen in various peripheral neuropathies and central pain disorders, and affects 15— 50% of patients with neuropathic pain. Allodynia is classified according to the sensory modality (touch, pressure, pinprick, cold, and heat) that is used to elicit the sensation.

Fibromyalgia

[0147] Fibromyalgia is a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues. Research indicates that fibromyalgia amplifies painful sensations by affecting the way the brain processes pain signals. Symptoms of fibromyalgia sometimes begin after a physical trauma, surgery, infection, or significant psychological stress. In other cases, symptoms gradually accumulate over time with no single triggering event. Symptoms include: widespread pain on both sides of the body and above and below the waist, fatigue, cognitive difficulties, depression, headaches, and pain or cramping in the lower abdomen. In some embodiments, the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of fibromyalgia.

Fibromyalgia-ness

[0148] Fibromyalgia-ness is the tendency to respond to illness and psychosocial stress with fatigue and widespread pain, in some embodiments, the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of fibromyalgia-ness.

Central sensitization

[Θ149] in some embodiments, the salts or pharmaceutical compositions of the invention may be used in treatment or prevention central sensitization. Central or chronic sensitization is a condition of the nervous system that is associated with the development and maintenance of chronic pain. When central sensitization occurs, the nervous system goes through a process called "wind-up" and gets regulated in a persistent state of high reactivity. This persistent, or regulated, state of reactivity subsequently comes to maintain pain even after the initial injury might be healed.

[0150] Central sensitization has two main characteristics. Both involve a heightened sensitivity to pain and the sensation of touch. They are called 'allodynia' and 'hyperalgesia.' Allodynia occurs when a person experiences pain with things that are normally not painful. Hyperalgesia occurs when an actual painful stimulus is perceived as more painful than it should. With allodynia and hyperalgesia, the sensation of pain travels through the nervous system, which is in a persistent state of high reactivi ty, and the pain is registered in the brain as a heightened level of pain.

Centralization

[0151] In some embodiments, the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of centralization. The pathogenesis of fibromyalgia is believed to involve sensitization of the central nervous system (CNS) to perceiving painful stimuli, which is termed "central sensitization" or "centralization". Centralization leads to the perception of widespread pain. Pain of thi s type is termed, "cen tral neuropath ic pain" or "central pain". Centralization also leads and to other symptoms, including visceral pain such as irritable bowel, tension-type headache, and migraine.

Regional pain syndrome [0152] In some embodiments, the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of regional pain syndrome. Regional pain syndrome or complex regional pain syndrome (CRPS) is a chronic pain condition most often affecting one of the limbs (arms, legs, hands, or feet), usually after an injury or trauma to that limb. CRPS is believed to be caused by damage to, or malfunction of, the peripheral and central nervous systems. CRPS is characterized by prolonged or excessive pain and mild or dramatic changes in skin color, temperature, and/or swelling in the affected area. Temporomandibular joint syndrome (TM J)

[0153] In some embodiments, the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of temporomandibular joint syndrome (TMJ), TMJ disorders can cause pain in the jaw joint and in the muscles that control jaw movement. Signs and symptoms of TMJ disorders may include: pain or tenderness of the jaw, aching pain in and around the ear, difficulty chewing or discomfort while chewing, aching facial pain, locking of the jaw joint, and a clicking sound or grating sensation when opening the mouth or chewing.

Lower back pain

[0154] Lower back pain may be dull or sharp pain in the lower back. The pain may be in one small area or over a broad area and may include muscle spasms. Lower back pain may be caused by overuse, strain, or injury; aging; a herniated disc; arthritis; compression fractures; illness; a congenital spine problem; or other causes. In some embodiments, the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of lower back pain. Gulf W ar syndrome

[0155] A prominent condition affecting Gulf War Veterans is a cluster of medically unexplained chronic symptoms that can include fatigue, headaches, joint pain, indigestion, insomnia, dizziness, respiratory disorders, and memory problems. In some embodiments, the salts or compositions of the invention may be used in the treatment or prevention of Gulf War syndrome.

Visceral pain

[0156] In some embodiments, the salts or pharmaceuti cal composi tions of the invention may be used in the treatment or prevention of visceral pain. Visceral pain is caused by the acti vation of pain receptors in the chest, abdomen, or pelvic areas. Visceral pain is caused by problems with internal organs, such as the stomach, kidney, gallbladder, urinary bladder, and intestines. These problems include distension, perforation, inflammation, and impaction or constipation, which can cause associated symptoms, such as nausea, fever, malaise, and pain. Visceral pain is also caused by problems with abdominal muscles and the abdominal wall, such as spasm.

Visceral pain is vague and not well localized and is usually described as pressure-like, deep squeezing, dull, or diffuse. Neuropathic pain

[0157] Neuropathic pain is a complex, chronic pain state that usually is accompanied by tissue injury. With neuropathic pain, the nerve fibers themselves might be damaged, dysfunctional, or injured, and these damaged nerve fibers send incorrect signals to other pain centers. The impact of a nerve fiber injury includes a change in nerve function both at the site of injury and areas around the injury, in some embodiments, the sal ts or pharmaceutical compositions of the invention may be used in the treatment or prevention of neuropathic pain.

Sickle ceil pain

[0158] In some embodiments, the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of sickle ceil pain. Sickle cel l disease causes red blood cells to form into a crescent shape, like a sickle. The sickle-shaped red blood cells break apart easily, causing anemia, and the damaged sickle red blood cells clump together and stick to the wails of blood vessels, blocking blood flow. This can cause severe pain and permanent damage to the brain, heart, lungs, kidneys, liver, bones, and spleen.

Nociceptive pain [0159] Nociceptive pain is caused when special nerve endings— called nociceptors— are irritated. Nociceptors are the nerves which sense and respond to parts of the body which suffer from damage. They signal tissue irritation, impending injury, or actual injury. When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain. The pain is typically well localized, constant, and often with an aching or throbbing quality. In some embodiments, the salts or pharmaceutical compositions of the invention may be used in treatment or prevention of noci ceptive pain. Post-operative pain

[0160J Post-operative pain is pain that occurs after an operation. In some embodiments, the salts or pharmaceutical compositions of the invention may be used in treatment or prevention of post-operative pain. Orthopedic injury pain

[0161] Orthopedic injuries are conditions involving the musculoskeletal system, and can mclude musculoskeletal trauma, sports injuries, degenerative diseases, or infections. In some embodiments, pain caused by orthopedic injury may be treated or prevented by the salts or pharmaceutical compositions of the invention. Osteoarthritis

[0162] Osteoarthritis is the most common form of arthritis, affecting mil lions of people worldwide. It occurs when the protective cartilage on the ends of the bones wears down over time. Symptoms include: pain, tenderness, stiffness, loss of flexibility, grating sensation, and bone spurs. In some embodiments, the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of osteoarthritis.

Rheumatoid arthritis Θ163] In some embodiments, the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of rheumatoid arthritis. Rheumatoid arthritis is a chronic inflammatory disorder that typically affects the small joints in the hands and feet. Rheumatoid arthritis affects the lining of the joints, causing painful swelling that can eventually result in bone erosion and joint deformity. An autoimmune disorder, rheumatoid arthritis occurs when the immune system mistakenly attacks the body's own tissues. In addition to causing joint problems, rheumatoid arthritis sometimes can affect other organs of the body— such as the skin, eyes, lungs, and blood vessels. Signs and symptoms of rheumatoid arthritis may include: tender, warm, swol len joints; morning stiffness; rheumatoid nodules; and fatigue, fever, and weight loss. Pain associated with post-traumatic stress disorder (PTSD)

[0164] In some embodiments, the salts or pharmaceut cal compositions of the invention may be used in the treatment or prevention of pain associated with post-traumatic stress disorder (PTSD). PTSD is a mental health condition that's triggered by a terrifying event— either experiencing it or witnessing it. Symptoms may include chronic pain, flashbacks, nightmares, and severe anxiety, as well as uncontrollable thoughts about the event.

Pain associated with cancer

[0165] In some embodiments, the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of pain associated with cancer. Cancer pain can result from the cancer itself as the cancer grows into or destroys nearby tissues. As a tumor grows, it may put pressure on nerves, bones or organs, causing pain. Cancer pain may also not just be from the physical effect of the cancer on a region of the body, but also due to chemicals that the cancer may rel ease in the region of the tumor.

[0166] Cancer treatments, such as chemotherapy, radiation and surgery, are another potential source of cancer pain. Surgery can be painful, radiation may leave behind a burning sensation or painful scars, and chemotherapy can cause many potentially painful side effects, including mouth sores, diarrhea and nerve damage.

Sedatives

[01 7] Another aspect of the invention is the use of the isometheptene salts of the invention or the pharmaceutical compositions comprising the isometheptene salts of the invention as a sedative medication. Another aspect of the invention is the use of a phannaceutical composition comprising an (R)-isometheptene salt as a sedative medication. (R)-isometheptene, like dexmedetomidine, is an ] j agonist but also interacts with adrenergic receptor a-2. A

pharmaceutical composition, comprising one of the (R)-isometheptene salts of the invention, can be used by intensive care units and anesthesiologists, for example for sedation of critically ill or injured patients in an intensive care unit setting or for nonintubated patients requiring short-term sedation for surgery or procedures. It may also useful as an adjunct for sedation and general anesthesia in the setting of certain operations and invasive medical procedures, such as colonoscopy. In contrast to other sedatives, the (R)-isometheptene salt can be bolused for ease of admi istration.

Hypertension and headaches from mild to moderate hypertension. [0168] The salts or pharmaceutical compositions of the invention may be used in the treatment and prevention of hypertension and the symptoms of hypertension. High blood pressure is a common condition in which the force of the blood against the artery walls is high enough that it may eventually cause health problems, such as heart disease. Hypertension puts strain on the heart, possibly leading to hypertensive heart disease and coronary artery disease, and it is a major risk factor for stroke, aneurysms of the arteries, peripheral arteri al disease, and chronic ki dney disease. Symptoms of hypertension include dull headaches and dizzy spells.

[0169] As used herein, "treatment" of a migraine headache may include an improvement in any of the following symptoms or conditions associated with migraine headache (or combination thereof): pain on one side or both sides of the head, sensitivity to light and sounds, nausea and vomiting, blurred vision, allodynia, and lightheadness. "Treatment" of pain may include a reduction in the pain experienced by the patient. "Treatment" of fibromyalgia may include an improvement in any of the following symptoms or conditions associated with fibromyalgia (or combination thereof): widespread pain, fatigue, and cognitive difficulties (e.g., impaired ability to focus). "Treatment" of a headache or an episodic tension-type headache may include an improvement in any of the following symptoms or conditions associated with a headache or an episodic tension-type headache (or combination thereof): sharp pain, throbbing sensation, dull ache, and nausea. "Treatment" of phantom limb pain may include an improvement in any of the following symptoms or conditions associated with phantom limb pain (or combination thereof): shooting, stabbing, or squeezing pain coming from the body part that is no longer there.

"Treatment" of depression may include an improvement in any of the following symptoms or conditions associated with depression (or combination thereof): unexplained aches and pains, concentration problems, loss of energy, and anger or irritability. "Treatment" of psychic or psychological pain may include an improvement in any of the following symptoms or conditions associated with psychic or psychological pain (or combination thereof): emotional suffering and mental agony. "Treatment" of psychiatric pain may include an improvement in any of the following symptoms or conditions associated with psychiatric pain (or combination thereof): widespread pain and regional pain. "Treatment" of allodynia may include an improvement in any of the following symptoms or conditions associated with a symptom related to allodynia (or combination thereof): pain due to a stimulus that does not usually provoke pain. "Treatment" of fibromyalgia-ness may include an improvement in any of the following symptoms or conditions associated with a symptom related to fibromyalgia-ness (or combination thereof): fatigue and widespread pain. "Treatment" of centra! sensitization may include an improvement in any of the following symptoms or conditions associated with a symptom related to central sensitization (or combination thereof}: allodynia and hyperalgesia. "Treatment" of centralization may include an improvement in any of the following symptoms or conditions associated with a symptom related to centralization (or combination thereof): irritable bowel, tension-type headache, and migraine. "Treatment" of regional pain syndrome may include an improvement in any of the following symptoms or conditions associated with a symptom related to regional pain syndrome (or combination thereof): swelling and pain in the arms, legs, hands, or feet. "Treatment" of temporomandibular joint syndrome (TMJ) may include an improvement in any of the following symptoms or conditions associated with a symptom related to I^'M J (or combination thereof): pain or tenderness of the jaw, aching pain in and around the ear, difficulty chewing or discomfort while chewing, aching facial pain, locking of the jaw joint, and a clicking sound or grating sensation when opening the mouth or chewing. "Treatment" of lower back pain may include an improvement in any of the following symptoms or conditions associated with a symptom related to lower back pain (or combination thereof): pain in the lower back and muscles spasms in the lower back. "Treatment" of Gulf War syndrome may include an improvement in any of the following symptoms or conditions associated with a symptom related to Gulf War syndrome (or combination thereof): fatigue, headaches, and joint pain. "Treatment" of visceral pain may include an improvement in any of the fol lowing symptoms or conditions associated with a symptom related to visceral pain (or combination thereof): pressure-like, deep squeezing, dull, or diffuse pain in the chest, abdomen, or pel vic areas. "Treatment" of neuropathic pain may include an improvement in any of the following symptoms or conditions associated with a symptom related to neuropathic pain (or combination thereof): shooting and burning pain, tingling, and numbness. "Treatment" of sickle celf pain may include an improvement in any of the fol lowing symptoms or conditions associated with a symptom related to sickle ceil pain (or combmation thereof): pain in the chest, abdomen, joints, and bones. "Treatment" of nociceptive pain may include an improvement in any of the following symptoms or conditions associated with a symptom related to nociceptive pain (or combmation thereof): aching or throbbing pain.

"Treatment" of post-operative pain may include an improvement in any of the following symptoms or conditions associated with a symptom related to post-operative pain (or

combination thereof): pain, swel ling, and irritation after an operation. "Treatment" of orthopedic injur}' pain may include an improvement in any of the following symptoms or conditions associated with a symptom related to orthopedic injur}' pain (or combination thereof): pain, swelling, and irritation after an orthopedic injury. "Treatment" of osteoarthritis may include an improvement in any of the following symptoms or conditions associated with a symptom related to osteoarthritis (or combination thereof): pain, tenderness, stiffness, loss of flexibility, grating sensation, and bone sp urs. "Treatment" of rheumatoid arthritis may include an improvement in any of the following symptoms or conditions associated with a symptom related to rheumatoid arthritis (or combination thereof): tender, warm, swollen joints; morning stiffness; rheumatoid nodules; and fatigue, fever and weight loss. "Treatment" of pain associated with post-traumatic stress disorder (PTSD) may include an improvement in any of the following symptoms or conditions associated with a symptom related to pain associated with post-traumatic stress disorder (PTSD) (or combination thereof): chronic pain and headaches. "Treatment" of pain associated with cancer may include an improvement in any of the following symptoms or conditions associated with a symptom related to pain associated with cancer (or combination thereot): chronic pain, nerve damage, and burning sensation. "Treatment" of hypertension may include an improvement in any of the following symptoms or conditions associated with hypertension (or combination thereof): high blood pressure, dull headaches, and dizzy spells.

[Θ170] Improvements in any of these symptoms can be readily assessed according to standard methods and techniques known in the art. Symptoms are not limited to those listed above and other symptoms may also be monitored in order to determine the effectiveness of treatment. The population of subjects treated by the method of the invention includes subjects suffering from the undesirable condition or disease, as well as subjects at risk for development of the condition or disease. Without wishing to be bound by theory, in some embodiments, administering any of the compositions or salts described herein may have any one or more of the following effects:

sedation; analgesia; al leviation of widespread pain; decrease in pain from headaches, tension- type headaches, and migraines; and relief of pain associated with PTSD, cancer, rheumatoid arthritis, allodynia, fibromyalgia, and fibromyalgia-ness. It should be noted that any of the salts or pharmaceutical compositions described above or herein may be used in any of the methods described herein. Effects are not limited to those listed above and other effects may also be noted during treatment.

Animal Models {0171 j Pain, headaches, and migraines have been modeled in animals such as mice and rats. For example, Oshinsky et al. (Oshinsky, M.L., et ai,, Spontaneous Trigeminal Allodynia in Rats: A Model of Primary Headache, Headache, 2012, 52: 1336-1349) describes spontaneous trigeminal allodynia (STA) rats with the inherited trait of spontaneously changing trigeminal von Frey thresholds. These rats are a model of spontaneous headache and can be used as a model of primary headache. Through a series of tactile sensory tests, the periorbital, hind-paw, and jaw- pressure thresholds for STA rats are determined by applying von Frey monofilaments. These determinations are made both before and after receiving treatments with compositions or salts of interest. Analgesic activity of the compositions or salts described herein can be evaluated by determining trigeminal von Frey thresholds in STA rats, {0172] Common mouse models for pain include the Formalin Test (Wheeler- Aceto, et al.,

Psychophaiiiiacology, 104, 35-44, 1991), the Hot Plate Test (Eddy and Leimbach, J. Pharmacol. Exp. Ther., 107, 385-393, 1953), and the Tail-flick Test (D'Amour and Smith, J. Pharmacol. Exp. Ther., 1 , 74-79, 1941). These methods detect analgesic activity of compositions or salts of interest. In the Formalin Test, mice are given an intraplantar injection of 5% formalin into one posterior hindpaw to induce paw licking. Test compositions or salts are given to the mice before treatment with formalin and the mice are evaluated and compared to a control group. In the Hot

Plate lest, mice are placed onto a hot metal plate maintained at 54 °C and the latency to the first foot-lick is measured. As with the Formalin test, compositions or salts of interest are given to the mice before the test and the mice are evaluated and compared to a control group. In the Tail- flick Test, a mouse's tail is heated by means of a thermal light source, and the latency before the animal withdraws its tail is measured. Test compositions or salts are administered before the test, and compared with a vehicle control group. The analgesic activity of the compositions or salts described herein can be identified using the mouse formalin, hot plate, and tail-flick tests. [0173] Stability of the salts described herein can be assessed using pharmacokinetic studies in animals such as dogs, rats, and humans. Animals are treated with varying doses of the sal ts described herein and after specified time periods, plasma samples are drawn and then analyzed for the presence of (R)- or (S)-isometheptene.

Combination therapy [0174] In some embodiments, the pharmaceutical compositions or salts of the invention can be used in combination with other therapeutics as analgesics or sedatives, in some embodiments, the pharmaceutical compositions or salts of the invention can be used in combination with other therapeutic agents to treat pain, a headache, depression, allodynia, fibromyalgia, fibromyalgia- ness, central sensitization, centralization, temporomandibular joint syndrome (TMJ), Gulf War syndrome, osteoarthritis, rheumatoid arthritis, or hypertension. Examples of pain include, but are not limited to, regional pain syndrome, lower back pain, visceral pain, neuropathic pain, sickle ceil pain, nociceptive pain, post-operative pain, orthopedic injury pain, phantom limb pain, pain associated with cancer, or pain associated with post-traumatic stress disorder (PT8D).

Examples of headache include, but are not limited to, an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; or a headache from mild to moderate hypertension.

[Θ175] in some embodiments, the phrase "combination therapy" refers to the administration of any of the pharmaceutical compositions or salts described herein and an additional therapeutic agent as part of a specific treatment regimen intended to provide a beneficial effect from the co- action of these therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). In some embodiments, "combination therapy" refers to administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time. In some embodiments, "combination therapy" refers to administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.

Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally, or by intravenous injection. In some embodiments, "combination therapy" refers to the administration of the therapeutic agents as described above in further combination with other biologically active ingredients (such as, but not limited to, a second and different therapeutic agent) and non-drug therapies (such as, but not limited to, surgery or radiation). Θ176] In some embodiments, one or more pharmaceutical compositions or salts described herein can be used as part of a therapeutic regimen combined with one or more addi tional treatment modalities. By way of example, such other treatment modalities include, but are not limited to, dietary therapy, occupational therapy, physical therapy, ventilator supportive therapy, massage, acupuncture, acupressure, mobility aids, assistance animals, speech therapy, language therapy, educational therapy, psychological therapy, occupational therapy, and the like. Θ177] In some embodiments, the combination therapy is useful for treating a mammalian disease (e.g., a human disease) including any of the conditions described herein. In other embodiments, the combination therapy is useful for veterinary treatment of companion animals, exotic and farm animals, including rodents, horses, dogs, and cats. [0178] In some embodiments, the therapeutic agents administered in combination therapy with any of the compositions or salts of the invention can comprise: acetaminophen, non-steroidal anti-inflammatory drugs ( SAJDs), ibuprofen, naprosyn, cyclooxygenase-2 inhibitors, aspirin, caffeine, dichloraiphenazone, triptans, antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRJs), or gabapentinoids, or a combination thereof.

[0179] In some embodiments, the therapeutic agents administered in combination therapy with any of the compositions or salts of the invention can comprise: anti-inflammatory agents, corticosteroids, CYP2D6 inhibitors, or TNF-alpha inhibitors, or combinations thereof

[0180] In some embodiments, the therapeutic agents administered in combination therapy with the compositions or salts of the invention can comprise one or more opiates.

[0181] Anti-inflammatory agents include, but are not limited to, non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and naprosyn (naproxen); TNF-a blockers or inhibitors such as infliximab, adalimumab, and etanercept; IL-RA; azathioprine;

cyclophosphamide; sulfasalazine; cyclooxygenase-2 inhibitors such as aspirin; caffeine;

acetaminophen; ketoprofen; dichloralphenzone, triptans such as sumatriptan succinate;

dexibuprofen; fenoprofen; dexketoprofen; flurbiprofen; oxaprozin; loxoprofen; mdomethacin; tolmetin; sulindac; droxicam; lomoxicam; isoxicam; mefenamic acid; Cortisol; corticosteroids such as cortisone, hydrocortisone, prednisone, prednisolone, fludrocortisone, methyipredinisone, dexamethasone, betamethasone, and triamcinolone; and meclofenamic acid. [0182] Gabapentinoids include, but are not limited to, gabapentin, pregabalin, gabapentin enacarbil, atagabalin, 4-methylpregabalin, and PD-217,014.

[0183] Antidepressants include, but are not limited to, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram, and escitalopram; serotonin and norepinephrine reuptake inhibitors (SNRJs) such as duioxetine, venlafaxine, desveniafaxine, tramadol, tapentadol, and levomilnacipran; norepinephrine and dopamine reuptake inhibitors (NDRJs) such as bupropion; trazodone; mirtazapine; vortioxetine; vilazodone; tricyclic antidepressants such as imipramine, nortriptyline, amitriptyline, doxepin, nimipramine, desipramine, and protriptyline; and monoamine oxidase inhibitors (MAOIs) such as tranylcypromine, phenelzine, and isocarboxazid.

[Θ184] CYP2D6 inhibitors include, but are not limited to, fluoxetine, paroxetine, bupropion, qumidme, cmaealcet, ritonavir, sertraline, duloxetine, and terbinafme. Not to be bound by theory, but in some embodiments a salt of the invention is metabolized by CYP2D6. In such embodiments, a CYP2D6 inhibitor may slow metabolism of a salt of the invention.

[0185] Opiates include, but are not limited to, codeine, thebaine, hydrocodone,

hydromorphone, morphine, oxycodone, oxymorphone, and tramadol.

[0186] Such combination products employ the pharmaceutical compositions or salts of this invention within the dosage range described herein and the other pharmaceutically active salt or salts within approved dosage ranges and/or the dosage described in the publication reference.

[0187] In some embodiments, any of the pharmaceutical compositions or salts described herein can allow the combination therapeutic agents and/or pharmaceutical compositions described herein to be administered at a low dose, that is, at a dose lower than has been conventionally used in clinical situations. For example, such low dose is a sub-therapeutic dose, which is a dose less than the therapeutic dose, that is, less than the amount/dose normally used when said therapeutic agent is administered alone (i.e., individual ly and in the absence of other therapeutic agents or compounds) for treatment of pain, a headache, depression, ailodynia, fibromyalgia, fibromyalgia-ness, central sensitization, centralization, temporomandibular joint syndrome (TMJ), Gulf War syndrome, osteoarthritis, rheumatoid arthritis, or hypertension. Examples of pain include, but are not limited to, regional pain syndrome, lower back pain, visceral pain, neuropathic pain, sickle cell pain, nociceptive pain, post-operative pain, orthopedic injury pain, phantom limb pain, pain associated with cancer, or pain associated with post-traumatic stress disorder (PTSD). Examples of headache include, but are not limited to, an episodic tension-type headache; a migraine headache: a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; or a headache from mild to moderate hypertension, [0188] Alternatively, the methods and combination of the invention can also maximize the therapeutic effect at higher doses.

[Θ189] It is to be understood that the embodiments of the present invention which have been described are merely illustrative of some of the applications of the principles of the present invention. Numerous modifications may be made by those skilled in the art based upon the teachings presented herein without departing from the true spirit and scope of the invention.

Preparation of the Salts of th e invention Θ190] In some embodiments, one or more of the salts or components to make the salts, of the invention are prepared from commercially available reagents by routine methods in synthetic organic chemistry.

Synthesis 1 of (R)-Isometheptene

O OH

NaBHd/MeOH

Heptane 100.20 1360.00 / 6.8.X 0.680

[Θ191] 200 g 6-methylhept-5-en-2-one (1) and 787 g methanol were added into a reaction vessel and cooled to 0-10 °C. 37.97 g sodium borobydri.de was added slowly and the temperature was kept below 35 °C. The reaction mixture was stirred at 20-35 °C for 1 -2 hours and then cooled to 0-10 °C. At that point, 1000 g IN hydrochloric acid were added to the reaction by dropwise addition and the mixture was kept below 35 °C

10192 J The reaction mixture was then concentrated 6 fold under vacuum and 1360 mL heptane were added and the solution stirred for 20-30 minutes. The aqueous phase was extracted twice with heptane. The combined organic phases were washed with 7% bicarbonate (5 volumes) and water (5 volumes). The organic phases were then concentrated 4.5 fold under vacuum. The purity of the (R.S)-6-methyl.hept-5-en-2-ol was -99%, and the yield was about 90-95 /

O

OH OH

I Vinyl acetate/CALB MsCi/DIPEA o" *0

\ ¹ *>^5.

J

Dichloromethane

1500.00 /

84,93 30.0X 1.325

Dimethyl 1

acetamide 160.00 / 3.2X 0.94

87.12

(DMAc)

[0193] 50 g (RS)-6-methylhept-5-en-2-ol (2) in n-heptane were added to a reaction vessel. Then 18.47 g vinyl acetate and 3.5 g CALB {Candida Antartica Lipase B (Novozymes A/S)) were added to the reaction vessel. The reaction was wanned to 30-35 °C and stirred for 3-5 hours to prepare (S)-6-methylhept-5-en-2-ol (3). HPLC showed an ee% of A > 97.0%.

[Θ1 4] The reaction mixture was filtered, and the organic phase collected and concentrated 2.5 fold under vacuum. The product was transferred to 500 g dichloromet ane in a reaction vessel and 50.40 g diisopropylethylamine were charged into the reaction vessel. The reaction was then cooled to 0-5 °C. Then, 26.80 g mesyichloride were added dropwise at 0-10 °C to the reaction vessel. The reaction was warmed to 20-25 °C and stirred for 12-15 hr to synthesize (S)-6- methylhept-5-en-2 -mesylate. HPLC showed the ratio of starting material/product as <15.0%.

[Θ195] To purify (S)-6-methylhept-5-en-2 -mesylate (4), 10 volumes water were added to the reaction mixture and stirred for 20-30 min. The organic phase was separated and washed wit 10 volumes vvater/brine (1/1) and then with 10 volumes of brine, and concentrated five fold under vacuum, 160 g dimethylacetamide were added to the reaction mixture and concentrated 5 fold under vacuum. (S)-6-methylhept-5-en-2-mesyIate (4) was present in the dimethylacetamide.

Raw Materia! List

Weight Ratio Density

Material MW. Moles

(g) (w/w) (liquid)

(S)-6-methylhept- 5-en-2-mesylate 50.00 0.2424 1.00 IX /

206.30

40% Methyl

1 88.22 2.4240 10.00 3.76X / amine (CI¾NI¾) 31.06

L-DTTA 93.65 0.2424 1 .00 1 .87X

386.35 ¹

Methyl-t-butyl

760.00 15.2X 0.76 ether (MTBE) 88.20

Acetone 1350.00 / 27.0X 0.80

58.08

[0196] 50 g (S)-6-methylhept-5-en-2 -mesylate (4) in dimethyiacetate and 188.22 g 40% methyl amine were added in the reaction vessel and warmed to 50-55 °C for 12-19 hours to synthesize (R)-N-6-methylhept-5-en-2-amme. HPLC showed a ratio of starting material/product of <2.0%.

{0197] The reaction mixture was cooled to 5-15 °C. 10 volumes of water and 10 volumes of methyl-t-butyl ether were added to the reaction mixture and stirred for 20-30 min. Following the organic phase was separated and the aqueous extracted a second time with 10 volumes methyl-t- butyl ether. The organic phases were washed with 10 volumes water twice and once with 10 volumes brine. The ee was about 90-95%.

{01 8] The product was concentrated 3 fold and dissolved in 8 fold acetone. Then the reaction was warmed to 60-65 °C. 93.68 g L-DTTA ((-)-Di-p-toluoyl-L-tartaric acid) dissolved in acetone were added to the reaction at 60-65 °C and stirred for 1 hour, then cooled to 20-25 °C over 3 hours. The reaction was stirred for an additional 1 hour at 20-25 °C, then filtered, washed with acetone (IX) and dried at 35-45 °C for 10-18 hours. The resulting product was (R)-A-6- methyihept~5~en~2~amine (2S,3S)-2,3-bis(4-methylbenzoyl)oxy)succinate (6). The observed ee% of (R)-N-6-methylhept-5-eii-2-amine was >97.0%.

[0199] 760 g methyi-i-butyl ether, water and 50 g ( )-N-6-methylhept-5-en-2-amine (2S,3S)- 2,3-bis(4~methylbenzoyi)oxy)succinate (6) were added to a reaction vessel. 40 g 30% sodium hydroxide were added dropwi.se at 20-25 °C and stirred for 40-60 minutes. The organic phase was separated and the aqueous phase was extracted with 10 volumes of methyl-t-butyl ether. The organic phases were combined and washed with 10 volumes with water and concentrated 2 fold.

[Θ200] The solvent was changed to methanol and 9.56 g mucic acid was added. The reaction was stirred at 20-25 °C for 10-15 hr, filtered, and concentrated. 265 g acetonitrile were added dropwise over 1 hour at 20-25 °C and stirred at 15-25 °C for 1-2 hours. The reaction mixture was filtered to collect solid, and the precipitate washed with acetonitrile twice. The salts were dried under vacuum at 40-50 °C for 8-12 hours to afford (R)-isometheptene mucate.

Synthesis 2 of (R)-Isometheptene

[0201 J Another synthetic route may include, but not be limited to, the following steps: (a) combining (S)-methyloxirane with 3-memyl-2-buten-l-ylmagnesium chloride in THF in the presence of copper iodide; (b) neutralizing, extracting with ether, drying with magnesium sulfate, removing solvent, and distilling the (S)-6-methyl-hept-5-en-2-ol; (c) reacting (S)-6-methyl-hept- 5-en-2~ol with methanesulfonyl chloride and DIEA in anhydrous DCM; (d) cooling the reaction mixture to about 5 °C; (e) adding mesyi chloride dropwise; (f) diluting the reaction mixture after 18 hours at room temperature; (g) washing said mixture with water, brine and drying over MgS0₄; (h) concentrating to oily product, (S)-methanesulfonic acid l,5-dimethyl-hex-4-enyI ester; (i) reacting (S)-methanesuifonic acid l,5-dimethyl-hex-4-enyl ester with N,N-dimethyl- acetamide (170 mL), and 40% methylamine in water in a sealed, heavy-walled reaction vessel at 50 °C; (k) adding diethyl ether and washing said mixture with water and brine, drying over MgSC>4 and filtering to remove the solvent; (1) removing the ether in vacuo (-25 mmHg) to yield (R)-isometheptene in the free base form; and (m) adding a pharmacologically acceptable acid.

Preparation of Isometheptene Salts

(R)-isometheptene was mixed with the following acids under different conditions to attempt to generate crystalline salts. Techniques used to analyze the samples were as follows. Different acids were selected and used to prepare a particular (R)-isometheptene salt. Exemplary methods are provided below, but these methods in no way should limit the invention. Preparation of (R)-Isometheptene Maleate

[0202 J A solution of 150.0 mg of (R)-isometheptene (1.06 mmol) and 123.4 mg of maleic acid (1.06 mmol) in 5 mL of acetone was placed in a freezer (about -20 °C) overnight, during which time crystallization occurred. The mixture was centrifuged, the mother liquor was decanted, and the solid was dried in the air to give 194.5 mg (71% yield) of (R)-isometheptene maleate.

Preparation of (R)-Isometheptene Malate

[0203] A solution of 150.0 mg of (R)-isometheptene (1.06 mmol) and 142.6 mg of L-malic acid (1.06 mmol) in 5 mL of acetone was placed in a freezer (about -20 °C) overnight, during which time crystallization occurred. The mixture was centrifuged, the mother liquor was decanted, and the solid was dried in the air to give 214.0 mg (69 % yield) of (R)-isometheptene malate.

Preparation of (R)-Isometheptene Tartrate

[0204] A solution of 150.0 mg of (R)-isometheptene (1.06 mmol) and 159.2 mg of (L)-tartaric acid (1.06 mmol ) in 13 mL of acetone was placed in an open vial at ambient temperature overnight, during which time the solvent evaporated to leave an oil. The oil was seeded with solids from a previous tartrate experiment. The oil and seeds were mixed with a spatula during which time crystallization occurred to give approximately 310 mg (100% yield) of (R)- isometheptene tartrate.

Preparation of (R)-Isometheptene Citrate Preparation A [0205] A solution of 25.0 mg of ( R)-isometheptene (0.18 mmol) and 34,0 mg of citric acid (0.18 mmol) in 2 mL of acetone was placed in a freezer (about -20 °C) overnight. No solids formed, so sample was transferred to the hood to evaporate all solvent and a gel formed after all solvent evaporated. Transferred the sample to a vacuum desiccator for 4 days, during which time crystallization occurred. The solids gave approximately 59.0 mg (100% yield) of (R)~ isometheptene citrate. Preparation of (R)-Isometheptene Citrate Preparation B

[0206 J A solution of 25.0 mg of (R)-isometheptene (0.18 mmoi) and 34.2 mg of citric acid (0.18 mmol) in 3.5 mL of ethanol was placed in a freezer (about -20 °C) overnight. No solids formed, so 3 ml. of hexanes was added to the solution. Sample was still a clear solution.

Transferred sample to the stir plate and mechanically stirred at ambient overnight, but no solids formed. The sample was transferred to the fridge overnight, but no solids formed. Transferred the sample to the freezer for 4 days, during which time crystallization occurred. The mixture was centrifuged, the mother liquor was decanted, and the solid was air dried to give

approximately 59.0 mg (100 % yield) of (R)-isometheptene citrate. Preparation of (R)-Isometheptene Cyclamate

[0207] A solution of 25.0 mg of (R)-isometheptene (0.18 mmol) and 31.6 mg of cyciamic acid (0.18 mmol) in 1 mL of ethanol was placed in a freezer (about -20 ^CC) overnight. No solids formed, so 3 mL of hexanes was added to the solution. The sample was still a clear solution. Transferred sample to the stir plate and mechanically stirred at ambient overnight, but no solids formed. The sample was transferred to the fridge overnight, but no solids formed. The sample was transferred to the freezer for 4 days, but no solids formed. All solvent was evaporated from the sample and a gel formed. Sample was then transferred to a vacuum desiccator for 1 day, during which time crystallization occurred. The solids give approximately 56.0 mg (100 % yield) of (R)-isometheptene cyclamate. Preparation of (R)-Isometheptene Fumarate

[0208] A solution of 25.0 mg of (R)-isometheptene (0.18 mmol) and 20.3 mg of fumaric acid (0.18 mmol) in 3.5 mL of ethanol was placed in a freezer (about -20 °C) overnight. No solids formed, so 3 mL of hexanes was added to the solution. The sample was still a clear solution. Transferred sample to the stir plate and mechanically stirred at ambient overnight, but no solids formed. The sample was transferred to the fridge overnight, but no solids formed. The sample was transferred to the freezer for 4 days, but no solids formed. Ail solvent was evaporated from the sample and a gel formed. The sample was then transferred to a vacuum desiccator for 1 day, during which time crystallization occurred. The solids gave approximately 45.0 mg (100 % yield) of (R)-isometheptene fumarate.

Preparation of (R)-Isometheptene Hippurate

[0209] A solution of 25.0 mg of (R)-isometheptene (0.18 mmol) and 31.9 mg of hippuric acid (0.18 mmol) in 3.5 mL of acetone was placed in a freezer (about -20 °C) overnight, but no solids formed. The sample was transferred to the hood to evaporate all solvent, during which time crystallization occurred. The solids gave approximately 57.0 mg (100% yield) of (R)~

i somethep ten e hi ppurate .

Preparation of (R)-Isometheptene Hydrochlorate [0210] A solution of 25.0 mg of (R)-isometheptene (0.18 mmol) and 6.5 mg of hydrochloric acid (0.18 mmol) in 1 mL of acetone was placed in a freezer (about -20 °C) overnight. No solids formed, so sample was transferred to the hood to evaporate all solvent. Gel formed after all solvent evaporated. Transferred the sample to a vacuum desiccator for 4 days, during which time crystallization occurred. The solids gave approximately 32.0 mg (100% yield) of (R)~ isometheptene hydrochlorate.

Preparation of (R)- Isometheptene M cate

[0211] A solution of 25.0 mg of (R)-isometheptene (0.18 mmol) and 18.4 mg of mucic acid (0.36 mmol) in 3.6 mL of acetone was placed in a freezer (about -20 °C) for 2 days, during which time crystallization occurred. The solids gave approximately 43.0 mg (100% yield) of (R)-isometheptene mucate.

Preparation of (R)-Isometheptene Phosphate

[0212] A solution of 25.0 mg of (R)-isometheptene (0.18 mmol) and 20.5 mg of phosphoric acid (0.18 mmol) in 1 mL of ethanol was placed in a freezer (about -20 °C) overnight. No solids formed, so 3 mL of hexanes was added to the solution. The sample was still a clear solution. Transferred sample to the stir plate and mechanically stirred at ambient overnight, but no solids formed. The sample was transferred to the fridge overnight, but no solids formed. The sample was transferred to the freezer for 4 days, but no solids formed. All solvent was evaporated from the sample and a gel formed. The sample was then transferred to a vacuum desiccator for 1 day, during which time crystallization occurred. The solids gave approximately 46.0 mg (100 % yield) of (R)-isometheptene phosphate. Preparation of (R)-Isometheptene Succinate

[0213] A solution of 25.0 mg of (R)-isometheptene (0.18 mmoi) and 20.8 mg of succinic acid (0.18 mmoi) in 3.5 ml. of acetone was placed in a freezer (about -20 °C) overnight. No solids formed, so sample was transferred to the hood to evaporate all solvent and a gel formed after all solvent evaporated. The sample was transferred to a vacuum desiccator for 4 days, after which the sample was still a gel. The sample in the vacuum desiccator was transferred to a 40 °C oven overnight, but the sample was still a gel. The sample was transferred to a 70 °C oven overnight, but the sample was still a gel. Triturated the sample with ethyl ether for 5 days, during which time crystallization occurred. The solids gave approximately 46.0 mg (100% yield) of (R)- isometheptene succinate. Examples

[Θ214] The following examples are set forth as being representative of the present invention. These exampies are not to be construed as limiting the scope of the invention as these and other equivalent embodiments will be apparent in view of the present disclosure, figures, and accompanying claims. Example 1

[0215] Acetic acid, adipic acid, aspartic acid, benzoic acid, citric acid, cyclamic acid, fumaric acid, glutaric acid, glycolic acid, hippuric acid, hydrochloric acid, maleic acid, L-malic acid, mucic acid, phosphoric acid, succinic acid, sulfuric acid, and L-tartaric acid salts of (R)~ isometheptene were prepared and analyzed by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), themiogravimetric (TG) analysis, dynamic vapor sorption (DVS) analysis, raman spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy. X-ray Powder Diffraction (X PD)

[0216] The Rigaku Smart-Lab X-ray diffraction system was configured for reflection Bragg- Brentano geometry using a line source X-ray beam. The X-ray source is a Cu Long Fine Focus tube that was operated, at 40 kV and 44 ma. That source provides an incident beam profile at the sample that changes from a narrow line at high angles to a broad rectangle at low angles. Beam conditioning slits are used on the line X-ray source to ensure that the maximum beam size is less than 10 mm both along the line and normal to the line. The Bragg- Brentano geometry is a para- focusing geometry controlled by passive divergence and receiving slits with the sample itself acting as the focusing component for the optics. The inherent resolution of Bragg-Brentano geometry is governed in part by the diffractometer radius and the width of the receiving slit used. Typically, the Rigaku Smart-Lab is operated to give peak widths of 0.1 °2Θ or less. The axial divergence of the X-ray beam is controlled by 5.0-degree Soiler slits in both the incident and diffracted beam paths.

[0217] Powder samples were prepared in a low background Si holder using light manual pressure to keep the sample surfaces flat and level with the reference surface of the sampl e holder. Each sample was analyzed from 2. to 40 °2Θ using a continuous scan of 6 °2Θ per minute with an effective step size of 0.02 °2f ,

Differential Scanning Calorimetry (DSC)

[0218] DSC analyses were carried out using a TA Instruments 2920 instrument. The instrument temperature calibration was performed using indium. The DSC cell was kept under a nitrogen purge of ~50 mL per minute during each analysis. Each sample was placed in a standard, crimped, aluminum pan and was heated from 20 °C to 350 ^CC at a rate of 10 °C per minute.

Thermogravimetric (TG) Analysis [Θ21 ] The TG analysis was carried out using a TA Instruments Q50 instrument. The instrument balance was calibrated using class M weights and the temperature calibration was performed using alumel. For each analysis, the nitrogen purge at the balance was -40 mL per minute, while the furnace was purged at -60 mL per minute. Each sample was placed into a pre- tared platinum pan and heated from 20 °C to 350 °C at a rate of 10 °C per minute.

Dynamic Vapor Sorption (DVS) Analysis

[0220] DVS analyses were carried out with a TA Instruments Q5000 Dynamic Vapor Sorption analyzer. The instrument was calibrated with standard weights and a sodium bromide standard for humidity. Samples were analyzed at 25 ^CC with a maximum equilibration time of 60 minutes in 10% relative humidity (RH) steps from 5 to 95% RH (adsorption cycle) and f om 95 to 5% RH (desorption cycle),

Raman Spectroscopy [0221 J Fourier transform (FT) Raman spectra were acquired on a Nicolet model 6700 spectrometer interfaced to a Nexus Raman accessory module. This instrument is configured with a Nd:YAG laser operating at 1024 nm, a CaF₂ beam splitter, and a indium gallium arsenide detector. OMNiC 8.1 software was used for control of data acquisition and processing of the spectra. Samples were packed into a 3-inch glass NMR. tube for analysis. Nuclear Magnetic Resonance (NMR) Spectroscopy

[0222] The ^¾H NMR spectra were acquired on a Bruker DRX-80Q spectrometer located at the Chemistry Department of Purdue University . Samples were prepared by dissolving material in MeQH-d4. The solutions were filtered and placed into individual 5-mm NMR tubes for subsequent spectral acquisition. The temperature controlled (296K) ^'Ή NMR spectra acquired on the DRX-8G0 utilized a 5-mm cryoprobe operating at an observing frequency of 800.13 MHz.

[0223] Samples generated and analyzed are listed in Table 1. Table 1. Sam les Generated

Put in vacuum/RT; oil.

C = cool, E = evaporate, RT = room temperature, SL = slurry

Table 1 (continued). Samples Generated

Put in vacuum/RT 1 day. and 32.2 (Fig. 12) C, acetone, RT to -20 °C; no solid. E, RT; oil. Put in vacuum/40 °C 1 day; oil. Put in 70 °C, 1 day; oil. glutar c

Triturate in ethyl ether 1 day; no solid. E, RT, oil. Put in vacuum/RT; oil.

C, acetone, RT to -20 °C; no solid. E, RT; oil. Put in

vacuum/40 °C 1 day; oil. Put in 70 °C, 1 day; oil. glutaric Triturate in ethyl ether 1 day; no solid. E, RT, oil.

Put in vacuum/RT; oil.

C, ethyl ether, RT to -20 °C; no solid. E, RT, oil. —

C, acetone, RT to -20 °C; no solid. E, RT; oil. Put in

vacuum/40 °C 1 day; oil. Put in 70 °C, 1 day; oil. glycolic

Triturate in ethyl ether 1 day; no solid. E, RT, oil. Put in vacuum/RT; oil .

C ^:::: cool, E ^::: evaporate, RT ^::: room temperature, SL ^:::: slurry- Table 1 (continued). Samples Generated

Equimoiar solution in acetone, clear solution.

Freezer overnight. Evaporation. Oil. Vacuum soft solid desiccator. Solids formed.

C, EtOH/hexanes, RT to -20 °C; no solid. E, RT; insufficient solid for hydrochloric

oil. Put in vacuum/RT 1 day. analysis

C, ethyl ether, RT to -20 °C; no solid. E, RT, oil.

—

Put in vacuum/RT, 1 day; oil.

Put salt in vacuum, RT, 2 days. soft solid

C, acetone, RT to -20 °C.

maleic C, EtOH/hexanes, RT to -20 °C; no solid. E, RT; —

oil. Put in vacuum/RT 1 day.

C, acetone, RT to -20 °C

C, acetone, RT to -20 °C; no solid. E, RT; oil. Put

L-malic

in vacuum/40 °C 1 day; oil. Put in 70 °C, 1 day; oil.

Triturate in ethyl ether 1 day.

C, acetone, RT to -20 °C.

SL, EtOH/hexanes, RT, 1 day.

mucie

C, acetone, RT to -20 °C.

—

Note: used 2: 1 API: acid ratio.

a. C = cool, E = evaporate, RT = room temperature, SL = slurry

Table 1 (continued). Samples Generated

oil. Put in vacuum/RT 1 day. 16) C, acetone, RT to -20 °C; no solid. E, RT; oil. Put

in vacuum/40 °C 1 day; oil. Put in 70 °C, 1 day; oil. Degrees 2Θ peaks: Triturate in ethyl ether 1 day; no solid. E, RT, oil. 6.2, 18.5, 18.7, 21.1, succinic

Put in vacuum/RT. 22.6, 23.9, 24.7, and

C, EtOH hexanes, RT to -20 °C; no solid. E, RT; 25.0 (Fig. 18) oil. Put in vacuum/RT 1 day.

C, acetone, RT to -20 °C; no solid. E, RT; oil. Put

in vacuum/40 °C 1 day; oil. Put in 70 °C, 1 day; oil.

—

Triturate in ethyl ether 1 day; no solid. E, RT, oil.

Put in vacuum/RT; oil.

sulfiiric

C, EtOH/hexanes, RT to -20 °C; no solid. E, RT;

oil. Put in vacuum/40 °C 1 day; oil. Put in 70 °C, 1

—

day; oil. Triturate in ethyl ether 1 day; no solid. E,

RT, oil. Put in vacuum/RT; oil.

C, ethyl ether, RT to -20 ^CC; no solid. E, RT, oil

C, acetone, RT to -20 °C; no solid. E, RT; oil. Put

in vacuum/RT 1 day.

L-tartaric C, EtOH/hexanes, RT to -20 °C; no solid. E, RT; —

oil. Put in vacuum/RT 1 day; oil. Put in

vacuum/40°C 1 day.

a. C = cool, E = evaporate, RT = room temperature, SL = slum'

[0224 J Those crystalline salts that were obtained as a single phase (no excess API or acid) were analyzed by DSC and TG (Table 2). Note that although a crystalline hydrochloride salt was observed during the screen, it was not characterized by DSC and TG due to the soft, gum-like consistency of the material . Table 2, Thermal Analyses of Crystalline Salts

Example 2

Preparation of Salts at Larger Scales

[0225] The maieate, malate, and tartrate salts (Table 3) were prepared at larger scales for characterization.

Table 3. Salts Prepared at Larger Scales

with tartrate salt, crystallized j

Characterization of the Salts 1. Maleate Salt Θ226] Characterization data are shown in Table 4. The (R)-isometheptene maleate salt has a 1 : 1 ((R)-isometheptene:maleic acid) stoichiometry and appears to be an anhydrate (no solvent of crystallization). It is non-hygroscopic. The endothermic heat flow peak observed by DSC at 118.6 °C is melting. All. samples of the maleate salt prepared exhibited the same XRPD pattern, so no evidence of polymorphism has arisen to date. DSC and XRPD are provided in Figures 1 and 2.

Table 4. Characterization Data for the Maleate Salt

2. Ma I ate Salt

[0227 J Characterization data are shown in Table 5. The (R)-isometheptene ma late salt has a 1 : 1 ((R)-isometheptene:L-malic acid) stoichiometiy and appears to be an anhydrate (no solvent of crystallization). It is moderately hygroscopic. The endo thermic heat flow peak observed by DSC at 80.4 °C is melting. All samples of the malate salt prepared exhibited the same XRPD pattern, so no evidence of polymorphism has arisen to date. DSC and XRPD are shown in Figures 3 and 4.

Table 5, Characterization Data for the Malate Salt

3. Tartrate Salt

[0228] Characterization data are shown in Table 6. The (R)-isometheptene tartrate salt has a

1 : 1 ((R)-isom.etheptene:L-tartaric acid) stoichiometiy and appears to be an anhydrate (no solvent of crystallization), it is moderately hygroscopic. The endothermic heat flow peak observed by DSC at 86,8 °C is melting. All samples of the tartrate salt prepared exhibited the same XRPD pattern, so no evidence of polymorphism has arisen to date. DSC and XRPD are shown in Figures 5 and 6.

Table 6. Characterization Data for the Tartrate Salt

Example 3

Evaluation of test salts for analgesic activity using the Formalin Test, late phase (licking score) in a mouse

[0229] The salts or pharmaceutical compositions of the invention are tested for analgesic activity in mice using the formalin test. The method, which detects anaigesic/anti-iiiflammatory activity, follows that described by Wheel er-Aceto, et ai. Psychopharmacology, 104, 35-44 (1991).

[Θ230] Mice are given an intraplantar injection of 5% formalin (25 uL) into one posterior hindpaw. This treatment induces paw licking in control animals. Mice are briefly observed at one minute intervals between 15 and 50 minutes after the injection of formalin and the number of occasions that the mice are observed licking the injected paw is recorded.

[0231 J 10 mice are studied per group. The test is performed partially blind,

[0232 J The test substances selected from (R)-isometheptene salts or pharmaceutical compositions comprising (R)-isometheptene salts are evaluated at three doses, administered p.o. 15 minutes before the test (i.e. immediately before formalin) and compared with a vehicle control group.

[0233] Morphine (32 mg/kg p.o.), administered 60 minutes before the test (i.e. 45 minutes before formalin) is used as a reference substance. Θ234] The experiment includes eight groups. Because of the number of animals, the experiment is divided into two sub-experiments (n^::::5 mice/group/day).

[0235] Inter-group comparison is performed for the test substances using a Ktuskaii-Waflls test, followed by Mann- Whitney U tests in case of significant group effect. For the reference substance, the treated group is compared with vehicle control using Mann-Whitney U test.

Example 4 Evaluation of test sal ts for anal gesic activity using the Hot Plate Test in a mouse

[0236] Salts or compositions of the invention are tested for analgesic activity in mice using a hot plate test. The method, which detects analgesic activity, follows that described by Eddy and Leimbach, J. Pharmacol. Exp. Ther., 107, 385-393, (1 953 ). [0237 J Mice are placed onto a hot metal plate maintained at 54 °C surrounded by a Plexiglas cylinder (height: 13 cm; diameter: 19 cm). The latency to the first foot-lick is measured

(maximum: 30 seconds).

[0238] 10 mice are studied per group. The test is performed partially blind . [Θ239] The test substances selected from ( )-isometheptene salts or pharmaceutical compositions comprising (R)-isometheptene salts are evaluated at three doses (10, 30 and 100 mg/kg), administered p.o. 15 minutes before the test, and compared with a vehicle control group.

[0240] Morphine (32 mg/kg p.o.) administered 60 mmutes before the test, is used as reference substance. The experiment includes 8 groups. [0241] Data with the test substance are analyzed by comparing treated groups with vehicle control using ANOVA followed by post-hoc Dunnett's tests. Data with the reference substance are analyzed using unpaired Student's t tests.

Example 5

Evaluation of test substances for analgesic activity using the Tail-flick Test in the mouse [0242J Salts or compositions of the invention are evaluated for analgesic activity in mice using the tail-flick test. The method, which detects analgesic activity, follows that described by D 'Amour and Smith, J. Pharmacol. Exp. Ther., 1 , 74-79, (1 41).

[0243] The mouse's tail is heated by means of a thermal light source (20 volts). The latency before the animal withdraws its tail is measured (maximum: 15 seconds). [0244] Ten mice are studied per group. The test is performed partial ly blind.

[0245] The test substances selected from (R)-isometheptene salts or pharmaceutical compositions comprising (R)-isometheptene salts are evaluated at three doses (10, 30, and 100 mg), administered p.o. 1 minutes before the test, and compared with a vehicle control group. [0246 J Morphine (32 mg/kg p.o.) admmister 60 mmutes before the test, is used as reference substance. The experiment includes eight groups.

[0247] Data with the test substance are analyzed by comparing treated groups with vehicle control using ANOVA followed by post-hoc Dunnett's tests. Data with the reference substance are analyzed using unpaired Student's t tests.

Example 6

Testing of salts in spontaneous trigeminal allodynia (STA) rats

[0248] Spontaneous trigeminal al lodynia (STA) rats are a model of spontaneous headache and can be used as a model of primary headache. Through a series of tactile sensor}' tests, the periorbital, hind-paw, and jaw-pressure thresholds for STA rats are determined by applying von Frey monofilaments. These determinations are made both before and after receiving treatments with salts or compositions of interest. Analgesic activity of the salts or pharmaceutical compositions described herein that is modulated through li can be evaluated by determining trigeminal von Frey thresholds in STA rats. Θ249] Spontaneous trigeminal allodynia (STA) rats are rats with the inherited trait of spontaneously changing trigeminal von Frey thresholds. Protocols for testing these rats are adapted from Oshinsky, MX., et al., Spontaneous Trigeminal Allodynia in Rats: A Model of Primary Headache, Headache, 2012, 52: 1336-1349. Oshinsky et al. describes these rats as a novel model of spontaneous headache that can be used as a model of primary headache. [0250] STA rats and litter mates without the trait are injected with test substances selected from (R)-isometheptene salts or pharmaceutical compositions comprising (R.)-isometheptene salts on days when their thresholds in spontaneous allodynia rats are 4 g or belo w for STA rats. Testing days for each of the salts are separated by at least one week. Tactile sensory thresholds are recorded prior to and following injections at 0.5 hours, 1 .5 hours, 2,5 hours, 3.5 hours, and 24 hours. Tactile sensor}' testing

[0251 J Rats are trained and acclimated to a plastic tube restraint and entered uncoaxed. This restrainer allows the rats to undergo sensory testing.

[0252] Periorbital, hind-paw, and jaw-pressure thresholds are determined by applying von Frey monofilaments (Stoelting Co., Wood Dale, IL, USA). Each monofilament is identified by manufacturer-assigned force values (26, 15, 10, 8, 6, 4, 2, 1.4, 1, 0.6, 0.4, 0.07 g). For trigeminal testing, the fi laments are tested on both the left and right sides of the face, over the rostral portion of the eye for periorbital testing, and on the skin over the masseter muscle for jaw testing. The vibrissae are not touched during testing. For the hind-paw testing, the filaments are applied to the mid-plantar region of the left and right hind paws, avoiding the less sensitive foot pads. For the hind-paw testing, the maximum value tested is 26 g; the rats that do not respond to this stimulus are assigned this value. Left and right threshold data are recorded separately. The von Frey stimuli are presented in sequential order, either ascending or descending, as necessary, to determine the threshold of response. After a positive response, a weaker stimulus is presented, and after a negative response, a stronger stimulus is presented.

[0253] Results are presented either as the threshold in grams ± standard error of the mean (SEM), or as a percent change from baseline on the side that has the lowest value. The threshold is defined as a positive response to 2 of 3, or in some cases 3 of 5 trials of a single von Frey monofilament . The value of the von Frey filament that elicited head withdrawal in 2 of 3 repetitions of the stimulus is designated as that day's threshold. Several behaviors are considered a positive head-withdrawal response, including when the rat vigorously stroked its face with the ipsilaterai forepaw and quickly recoiled its head away from the stimulus or vocalized. For the periorbital von Frey testing, rats that do not respond to the 10-g stimulus are assigned 10 g as their threshold. Example 7

Pharmacokinetic studies of salts and pharmaceutical compositions of the invention

[0254 J Stability of the salts described herein can be assessed using pharmacokinetic studies in animals such as dogs, rats, and humans. Animals are treated with varying doses of the salts described herein and after specified time periods, plasma samples are drawn and then analyzed for the presence of (R)- or (S)-isometheptene. Not wishing to be bound by theory, in some embodiments, such pharmacokinetic studies can be used to identify slow, normal, and fast metabolizers of the salts of the invention.

Studies [0255 J Pharmacokinetic (PK) studies in dogs, rats, and humans are conducted with test substances selected from (R)-isometheptene salts and compositions.

Dog studies

Dosing

[0256] For IV solutions, the vehicle is saline 0.9% NaCl for injection, USP, and for PO, the vehicle is deionized tap water. On the day of dosing, the test salts are mixed with vehicle to achieve the desired concentrations.

Test system

[0257] The animals used are beagles (dogs) from the MP] Research Colony. The dogs are at least five months of age and the males weigh 5.5 to 12.0 kg and the females weigh 5.0 to 10.0 kg at arrival, as measured within three days of arrival. The stud)' uses four males and four females. The dogs are acclimated for at least one week prior to testing and are acclimated to a sling restraint for at least three times for a period of at least 20 minutes each time. Prior to dose initiation, animals are acclimated to the oral gavage dosing procedure at least three times. A fixed dose volume of 10 mL/animal of tap water is administered on each occasion. Study design

[0258] Salts are administered via oral gavage or intravenous injection. The test salt is administered once intravenously on Day 1. After a 7-day washout period the test salt is administered once via oral gavage. For oral gavage (PO) the test salt is withdrawn from stirred formulations and dosed via oral gavage. Individual doses are based on the most recent body weights. After each dose, and prior to removal of the gavage tube, the tube is flushed with 5 to 10 mL of tap water.

{0259] For intravenous (IV), the test salt is administered via the cephalic or other suitable vein. Individual doses are based on the most recent body weights. The dose is administered by bolus injection, unless otherwise indicated. If a catheter is used for dosing, the catheter is flushed with approximately 1 mL of sterile 0.9% Sodium Chloride for Injection, USP following dosing. The intravenous route is used for pharmacodynamic studies in nonclinical species and for calculation of absolute bioavailability. Sample collection and analysis

{0260] Animals are monitored at least twice daily and observed for mortality, injury, and availability of food and water. Any animals in poor health are identified for further monitoring and possible euthanasia. Body weights are collected within three days of transfer and on the day prior to and the day following each dose.

[Θ261] 0.5 mL samples are collected from the jugular or other suitable vein. The anticoagulant used is K₂EDTA. Samples are centrifuged and the plasma stored frozen (-60 to -90 °C). The plasma is analyzed for the test salts.

Rat studies

Dosing

[0262] For IV solutions, the vehicle is saline 0.9% NaCl for Injection, IJSP, and for PO, the vehicle is deionized tap water. On the day of dosing, the test salts are mixed with vehicle to achieve the desired concentrations.

Test system

[0263] The animals used are CD* rats [Crl;CD*(SD)] from Charles River Laboratories. The rats are six weeks of age at arrival and the males weigh 130 to 210 g and the females weigh 100 to 170 g at arrival, as measured within three days of arrival. The study uses 20 males and 20 females. The rats are acclimated for at least one week prior to testing. During this acclimation period, ail animals are observed daily for any clinical signs of disease, and all animals are given a detailed clinical examination prior to selection for study.

[0264] The week prior to dose initiation, all animals (including animals potentially designated for PO and IV administration) are administered a sham dose of tap water via oral gavage on at least two occasions in the same manner and at the same volume intended for PO use during the study period.

Study design

Test salt 1

IV 5 0.2 5 5

Test salt 2 IV 0.5 5 0.1 5

Test salt I

3 PO 10 10 5

4 Test salt 2 PO 5 10 0.5

*Dose is calculated as free base.

[0265] Salts are administered via oral gavage or intravenous injection. The test salt is administered once on Day 1. For oral gavage (PO) the test salt is withdrawn from stirred formulations and dosed via oral gavage. Individual doses are based on the most recent body weights. [0266J For intravenous (IV), the test salt is administered via the tai l vein. Individual doses are based on the most recent body weights. The dose is administered by bolus injection, unless otherwise indicated. The intravenous route is used for pharmacodynamic studies in nonclinical species and for calculation of absolute bioavailability.

Sample collection and analysis [0267] Animals are monitored at least twice daily and observed for mortality, injury, and availability of food and water. Any animals in poor health are identified for further monitoring and possible euthanasia. Body weights are col lected within three days of transfer and on the day prior to and the day following each dose.

[Θ268] 0.5 mL samples are collected from the sublingual or other suitable vein. The anticoagulant used was K₂EDTA. Samples are centrifuged and the plasma stored frozen (-60 to - 90 °C). The plasma is analyzed for the test salts.

Human studies

Study design and methodology

[0269] The study is a single-center, randomized, double-blind, placebo-controlled, single ascending dose, safety and tolerability study of test salt capsules in healthy volunteers. Four successive cohorts are planned with doses of test salt capsules, 35 mg, 70 mg, 140 mg, and 280 nig, respectively. Each cohort consists of 15 subjects, and subjects are randomly assigned in a 3: 1 : 1 ratio to one of the (R)-isometheptene salts, raceniic isometheptene, or placebo capsules:

Cohort 1 : (R)-isometheptene salt, 35 mg (n 9); Racemic sometheptene, 70 mg in ?■)

Placebo (n=3)

Cohort 2: (R)-isometheptene salt, 70 mg (n~9); Racemic isometheptene, 70 mg (n=3);

Placebo (n=3)

Cohort 3: (R)-isometheptene salt, 140 mg (n=9); Racemic isometheptene, 70 mg (n=3);

Placebo (n=3)

Cohort 4: (R)-isometheptene salt, 280 mg (n=9); Racemic isometheptene, 70 mg (n=3);

Placebo (n=3)

[0270] Unless otherwise modified based on safety review following each cohort, all. subjects in Cohorts 1 , 2, and 3 take 4 capsules and subjects in Cohort 4 take 8 capsules.

{0271] All subjects are screened for eligibility. After re-confirming that subjects meet the inclusion and none of the exclusion criteria, eligible subjects are admitted on Day 1 (Visit 1) to the clinic at least 10 hours before dosing. The following morning on Day 1 after all pre-dose assessments are complete, subjects receive a single dose of study drug (4 or 8 capsules depending on the cohort). Following dosing, subjects are confined for close monitoring over 48 hours. Post-dose safety monitoring and blood collection for PK analysis occurs periodically during the 48-hour period. Once all 48-hour post-dose assessments are completed, the subject is discharged with a follow-up visit in 7 days (Day 10 ± 1 day) for their final study visit (Visit 2). incorporation by Reference

[0272] All references cited in this specification, and their references, are incorporated by reference herein in their entirety where appropriate for teachings of additional or alternative details, features, and/or technical background.

Equivalents

[0273] While the invention has been particularly shown and described with reference to particul ar embodiments, it will be appreciated that vari ations of the above-disclosed and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or applications. Also, that various presently unforeseen or unanticipated alternatives, modifications, variations or improvements therein may be subsequentiv made by those skilled in the art which are also intended to be encompassed by the following claims.

Claims

1. A (R)-isometheptene salt, wherein the (R)-isornethepteiie salt is characterized by a differential scanning ealorimetry heating curve which shows an endotherniic heat flow peak between 45 °C and 145 °C.

2. The (R)-isomeiheptene salt of claim 1 , wherein the differential scanning ealorimetry heating curve which shows an endotherniic heat flow peak between 45 °C and 130 °C.

3. The (R)-isometheptene salt of claim 1, wherein the salt is a maleate, L-malate, L- tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt.

4. The (R)-isometheptene salt of claim 3, wherein the salt is maleate, and the (R)~ isometheptene maleate salt is characterized by a differential scanning ealorimetry heating curve which shows an endotherniic heat flow peak between 112 °C and 120 °C.

5. The (R)-isometheptene salt of claim 4, wherein the (R)-isometheptene maleate salt is characterized by an X-ray powder diffraction pattern with peaks at about 6,3, 19.1 , 24.2, 25.5, and 32.1 degrees two theta when measured using a Cu X-ray source.

6. The (R)-isometheptene salt of claim 3, wherein the salt is L-malate, and the (R)~ isometheptene L-malate salt is characterized by a differential scanning ealorimetry heating curve which shows an endothermic heat flow peak between 74° C and 83° C.

7. The (R)-isometheptene salt of claim 6, wherein the (R.)-isometheptene malate salt is characterized by an X-ray powder diffraction pattern with peaks at about 5.9, 6.1, 14.8, 16.0, 17.1, 18.1, 18.3, 20.8, 21.2, and 25.4 degrees two theta when measured using a Cu X-ray source.

8. The ( )-isometheptene salt of claim 3, wherein the salt is L-tartrate, and the (R)- isometheptene L-tartrate salt is characterized by a differential scanning caiorimetry heating curve which shows an endothermic heat flow peak between 83 °C and 89 °C.

9. The (R)-isometheptene salt of claim 8, wherein the (R -isometheptene L-tartrate salt is characterized by an X-ray powder diffraction pattern with peaks at about 6.1, 12.1, 14.2, 17.3, 17.7, 22.3, 24.3, and 26.5 degrees two theta when measured using a Cu X-ray source.

10. The (R)-isonietheptene salt of claim 3, wherein the salt is citrate, and the (R)- sometheptene citrate salt is characterized by a differential scanning caiorimetry heating curve which shows an endothermic heat flow peak between 65 °C and 75 °C.

11. The (R)-isometheptene salt of claim 10, wherein the (R)-isometheptene citrate salt is characterized by an X-ray powder diffraction pattern with peaks at about 6.5, 16.0, 19.2, 19.6, 21.0, 21.4, 26.3, and 31.3 degrees two theta when measured using a Cu X-ray source.

12. The (R)-isometheptene salt of claim 3, wherein the salt is cyciamate, and the (R)~ isometheptene cyciamate salt is characterized by a differential scanning caiorimetry heating curve which shows an endothermic heat flow peak between 71 °C and 81 °C.

13. The (R)-isometheptene of claim 12, wherein the (R)-isometheptene cyciamate salt- is characterized by an X-ray powder diffraction pattern with peaks at about 5.4, 5.9, 16.4, 16.9, 20.2, and 21.9 degrees two theta when measured using a Cu X-ray source.

14. The (R)-isometheptene salt of claim 3, wherein the salt is fumarate, and the (R)- isometheptene fumarate salt is characterized by a differential scanning caiorimetry heating curve which shows an endothermic heat flow peak between 105 °C and 115 °C.

15. The ( )-isometheptene salt of claim 14, wherein the (R)-isometheptene fumarate salt is characterized by an X-ray powder diffraction pattern with peaks at about 6.2, 6.3, 19.1,

20.6, 24.1, 25.2, 25.6, and 32.2 degrees two theta when measured using a Cu X-ray source,

16. The (R)-isometheptene salt of claim 3, wherein the salt is hippurate, and the (R)~ isometheptene hippurate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 107 °C and 117 °C.

17. The (R)-isometheptene salt of claim 16, wherein the (R)-isometheptene hippurate salt is characterized by an X-ray powder diffraction pattern with peaks at about 5,2, 10.4, 15.7,

19.4, and 26.4 degrees two theta when measured using a Cu X-ray source.

18. The (R)-isometheptene salt of claim 3, wherein the salt is phosphate, and the (R)- isometheptene phosphate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 123 °C and 133 °C.

19. The (R)-isometheptene salt of claim 18, wherein the (R)-isometheptene phosphate salt is characterized by an X-ray powder diffraction pattern with peaks at about 7,2, 14,4, 14,9,

20.7, 22.7, and 23.4 degrees two theta when measured using a Cu X-ray source.

20. The (R)-isometheptene salt of claim 3, wherein the salt is succinate, and the (R)~ isometheptene succinate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 48 °C and 58 °C. 21. The (R)-isometheptene salt of claim 20, wherein the (R)-isometheptene succinate salt is characterized by an X-ray powder diffraction pattern with peaks at about 6.2, 18.5, 18.7,

21.1, 22.6, 23.9, 24,7, and 25.0 degrees two theta when measured using a Cu X-ray source.

22. The (R)-isometheptene salt of any one of claims 1-21 , wherein the (R)- isometheptene salt is in a crystalline form.

23. A pharmaceutical composition comprising a salt of any one of claims 1-22 and a pharmaceutically acceptable carrier.

24. The pharmaceutical composition of claim 23, wherein the (R)-isometheptene salt is a crystalline (R)-isomethepteiie maleate salt.

25. The pharmaceutical composition of claim 23, wherein the (R)-isometheptene salt is a crystalline (R)-isometheptene L-malate salt.

26. The pharmaceutical composition of claim 23, wherein the (R)-isometheptene salt is a crystalline (R)-isometheptene L-tartrate salt.

27. A method for treating or preventing a condition selected from the group consisting of pain; central sensitization; centralization; regional pain syndrome; lower back pain; visceral pain; neuropathic pain; sickle cell pain; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; pain associated with cancer; pain associated wit post-traumatic stress disorder (PTSD); a headache; an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; depression; allodynia; fibromyalgia; fibromyalgia-ness; temporomandibular joint syndrome (TMJ); Gulf War syndrome; osteoarthritis; rheumatoid arthritis; and hypertension in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the (R)-isometheptene salt of any one of claims 1-22, or a therapeutically effective amount of the pharmaceutical composition of any one of claims 23-26.

28. The method of claim 27, wherein the condition is a headache.

29. he method of claim 27, wherein the condition is a migraine headache.

30. The method of claim 27, wherein the condition is an episodic tension-type headache.

The method of claim 27, wherein the condition is hypertension.

32. A method of sedating a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the (R)-isometheptene salt of any one of claims 1- 22, or a therapeutical ly effective amount of the pharmaceutical composition of any one of claims 23-26.

33. A method of inducing analgesia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the (R -isometheptene salt of any one of claims 1-22, or a therapeutically effective amount of the pharmaceutical composition of any one of claims 23-26.

34. The method of any one of claims 27-33, wherein the salt or the pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, diciiloraiphenazone, naproxen, or sumatriptan succinate.

35. The method of any one of claims 27-34, wherein the salt or the pharmaceutical composition is used with a CYP2D6 inhibitor.

36. The method of any one of claims 27-35, wherein the subject is a human.

37. The (R)-isometheptene salt of any one of claims 1-22 or the pharmaceutical composition of any one of claims 23-26 for use in treating or preventing a condition selected from the group consisting of: pain; central sensitization; centralization; regional pain syndrome; lower back pain; visceral pain; neuropathic pain; sickle cell pain; nociceptive pain; post- operative pain; orthopedic injur pain; phantom limb pain; pain associated with cancer; pain associated with post-traumatic stress disorder (PTSD); a headache; an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascuiar, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascuiar, neurovasc lar, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; depression; allodynia;

fibromyalgia; fibromyalgia-ness; temporomandibular joint syndrome (TMJ); Gulf War syndrome; osteoarthritis; rheumatoid arthritis; and hypertension.

38. The ( )-isometheptene salt or the pharmaceutical composition of claim 37, wherein the condition is a headache.

39. The (R)-isometheptene salt or the pharmaceutical composition of claim 37, wherein the condition is a migraine headache.

40. The (R)-isometheptene salt or the pharmaceutical composition of claim 37, wherein the condition is an episodic tension-type headache.

41 . The ( R)-isometheptene salt or the pharmaceutical composition of claim 37, wherein the condition is hypertension,

42. The (R)-isometheptene salt of any one of claims 1-22 or the pharmaceutical composition of any one of claims 23-26 for use as a sedative.

43. The (R)-isometheptene salt of any one of claims 1-22 or the pharmaceutical composition of any one of claims 23-26 for use as an analgesic.

44. The ( R)-isometheptene salt or the pharmaceutical composition of any one of claims 37-43, wherein the salt or the pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, dichloralphenazone, naproxen, or sumatriptan succinate.

45. The (R)-isometheptene salt or the pharmaceutical composition of any one of claims 37-44, wherein the salt or the pharmaceutical composition is used with a CYP2D6 inhibitor.

46. Use of the (R)-isometheptene salt of any one of claims 1 -22 or the pharmaceutical composition of any one of claims 23-26 for the manufacture of a medicament for treating or preventing a condition selected from the group consisting of: pain; central sensitization;

centralization; regional pain syndrome; lower back pain; visceral pain; neuropathic pain; sickle cell pain; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; pain associated with cancer; pain associated with post-traumatic stress disorder (PTSD); a headache; an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension;

depression; ailodynia; fibromyalgia; fibromyalgia-ness; temporomandibular joint syndrome (TMi); Gulf War syndrome; osteoarthritis; rheumatoid arthritis; and hypertension.

47. The use of claim 46, wherein the condition is a headache.

48. The use of claim 46, wherein the condition is a migraine headache.

49. The use of claim 46, wherein the condition is an episodic tension-type headache.

50. The use of claim 46, wherein the condition is hypertension.

51. Use of the (R)-isometheptene salt of any one of claims 1-22 or the pharmaceutical composition of any one of claims 23-26 for the manufacture of a medicament for sedation.

52. Lise of the (R)-isometheptene salt of any one of claims 1-22 or the pharmaceutical composition of any one of claims 23-26 for the manufacture of a medicament for analgesia.

53. The use of any one of claims 46-52, wherein the medicament is administered simultaneously, separately, or sequentially with one or more substances selected from

acetaminophen, ibuprofen, aspirin, caffeine, dichloralphenazone, naproxen, or sumatriptan succinate.

54. The use of any one of claims 46-53, wherein the medicament is administered simultaneously, separately, or sequentially with a CYP2D6 inhibitor.