WO2009018367A2

WO2009018367A2 - Novel salt forms of (2s)-(4e)-n-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine

Info

Publication number: WO2009018367A2
Application number: PCT/US2008/071631
Authority: WO
Inventors: Gary Maurice Dull; Julio A. Munoz; John Genus; Balwinder Singh Bhatti; Jennifer A. Young; Merouane Bencherif; John W. James; Michael G. Williams; Kristen Jordan; Patrick M. Lippiello; Beth Fordham-Meier
Original assignee: Targacept, Inc.
Priority date: 2007-07-31
Filing date: 2008-07-30
Publication date: 2009-02-05
Also published as: WO2009018367A3

Abstract

Salts of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine, methods for their preparation, pharmaceutical compositions comprising said salts, and their use are disclosed. The salts can be administered to patients susceptible to or suffering from conditions and disorders, such as central nervous system disorders, to treat or prevent such disorders.

Description

NOVEL SALT FORMS OF (2S)-(4E)-N-METHYL-5-[3-(5-METHOXYPYRIDIN)YL]-4-

PENTEN-2-AMINE

Cross-Reference of Related Applications The present application claims benefit of U.S. Provisional Application No.

60/953,064, filed July 31 , 2007, herein incorporated by reference in its entirety.

Field of the Invention

The present invention relates to novel salt forms of (2S)-(4E)-N-methyl-5-[3- (5-methoxypyridin)yl]-4-penten-2-amine and to pharmaceutical compositions including the salt forms. The present invention also relates to methods for treating a wide variety of conditions and disorders, and particularly pain and conditions and disorders associated with dysfunction of the central and autonomic nervous systems, using the novel salt forms.

Background of the Invention

The compound (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2- amine is a neuronal nicotinic receptor (NNR) agonist with selectivity for the α4β2 nicotinic subtype over other nicotinic subtypes, for example, the α7 subtype, the ganglionic, and the muscle subtypes. (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]- 4-penten-2-amine provides benefits in the treatment or prevention of central nervous system (CNS) disorders and pain. The compound, its synthesis, and its use in methods of medical treatment, is described, for example, in published PCT application WO 99/65876 and U.S. Patent No. 7,045,538 to Caldwell et al., wherein it is referred to as (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine, the contents of each are hereby incorporated by reference in their entirety.

The commercial development of a drug candidate such as (2S)-(4E)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine involves many steps, including scaling up the chemical synthesis and purification of the compound, analyzing salt forms, and the like. As is appreciated, in the formulation of drug compositions, the drug substance should be in a form which promotes convenient handling and processing. This is of importance, not only from the point of view of obtaining a commercially-viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical formulations comprising the active compound. Further, when manufacturing drug compositions, a goal is to provide reliable, reproducible, and constant plasma concentration profiles of drug upon administration to a patient.

Chemical stability, solid state stability, and "shelf life" of active ingredients are other factors to be considered. The drug substance, and compositions containing the drug substance, should preferably be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the active component's physicochemical characteristics, including but not limited to, its chemical composition, water content, density, hygroscopicity, and solubility. Moreover, there is a preference to provide drug in a form, which is as chemically pure as possible. Acid addition salts of basic drugs can offer advantages in stability and purity, but these salts vary greatly in their ability to impart these properties.

The physical state of acid additions salts of basic drugs, such as (2S)-(4E)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine, can vary. Some salts are solids at ambient temperatures, namely, those temperatures which would typically characterize preparation, storage, and use. Other salts are liquids, including, viscous oils and gums, at ambient temperatures. There are advantages to solids, in terms of handling and stability, and solid salt forms are generally preferred for oral formulations. The skilled person will appreciate that, typically, if a drug can be readily obtained in a stable form, such as a stable crystalline form, advantages may be provided, in terms of ease of handling, ease of preparation of suitable pharmaceutical compositions, and a more reliable solubility profile.

Salt forms of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine are disclosed in published PCT applications WO 02/05798 and WO 06/053039, each of which is incorporated by reference. Nevertheless, there is a need for alternative salt forms of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine with improved properties, including purity, stability, solubility, and bioavailability. Further preferential characteristics include those that would increase the ease or efficiency of manufacture of the active ingredient and its formulation into a commercial product. Furthermore, stable polymorphic forms of these salts would allow for an increase the ease or efficiency of manufacture of the active ingredient and its formulation into a commercially product.

Summary of the Invention

The present invention includes novel forms of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine with unexpected properties. The invention also includes a scalable synthesis of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4- penten-2-amine, suitable for large scale manufacture.

One aspect of the present invention includes (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine or a pharmaceutically acceptable salt thereof in polymorphic form.

Another aspect of the present invention includes a solid acid addition salt of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine, wherein the acid is selected from hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, pamoic acid, xinafoic acid, galactaric acid, L-tartaric acid, hippuric acid, fumaric acid, citric acid, D-glucuronic acid, L-malic acid, D-gluconic acid, L-ascorbic acid, p- hydroxybenzoic acid, stearic acid, lactobionic acid, orotic acid, R-mandelic acid, S- mandelic acid, oxalic acid, or hydrobromic acid, or a hydrate or solvate thereof. In one embodiment, the salt has a stoichiometry of acid to (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine of 1 :2, 1 :1 , or 2:1. In yet another embodiment, the salt has a stoichiometry of acid to (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]- 4-penten-2-amine of 1:1.

Another aspect of the present invention includes a hydrochloric acid, maleic acid, phosphoric acid, pamoic acid, xinafoic acid, fumaric acid, galactaric acid, p- hydroxybenzoic acid, stearic acid, orotic acid, R-mandelic acid, S-mandelic acid, oxalic acid, or hydrobromic acid salt of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine, or a hydrate or solvate thereof, in substantially crystalline form.

Another aspect of the present invention includes (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine hemi-galactarate or a hydrate or solvate thereof.

Another aspect of the present invention includes (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine phosphate or a hydrate or solvate thereof.

Another aspect of the present invention includes a polymorphic form of (2S)- (4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate characterized by a powder x-ray diffraction pattern comprising at least one of the following peaks

2-Theta (deg)

10.4 + 0.5

13.1 + 0.5

15.0 + 0.5

16.2 + 0.5

17.1 + 0.5

In one embodiment, the present invention include a polymorphic form of (2S)-(4E)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate whose XRPD pattern substantially corresponds to that shown in one or more of Figures 13, 14, or 15. In still further an embodiment, the present invention includes a polymorphic form of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate whose XRPD pattern substantially corresponds to that shown in Figure 15.

Another aspect of the present invention includes Form 3 of (2S)-(4E)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate. Another aspect of the present invention includes a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable diluent, excipient, or carrier.

Another aspect of the present invention includes a compound or pharmaceutical composition according to the present invention for use in therapy. Another aspect of the present invention includes use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of a central nervous system disorder.

Another aspect of the present invention includes a method of treating or preventing a central nervous system disorder, comprising administering a compound or pharmaceutical composition of the present invention.

One embodiment of the compound, use, or method aspects of the present invention includes therapy of age-associated memory impairment, mild cognitive impairment, pre-senile dementia, early onset Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, Lewy body dementia, vascular dementia, Alzheimer's disease, stroke, AIDS dementia complex, attention deficit disorder, attention deficit hyperactivity disorder, dyslexia, schizophrenia, schizophreniform disorder, or schizoaffective disorder.

Another aspect of the present invention includes use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of pain.

Another aspect of the present invention includes a method of treating or preventing pain comprising administering a compound or pharmaceutical composition of the present invention. One embodiment of the compound, use, or method aspects of the present invention includes therapy of acute pain, persistent pain, chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, fibromyalgia, post-operative pain, pain due to medical condition, arthritis pain, temporomandibular joint disorder, burn pain, injury pain, back pain, sciatica, foot pain, headache, abdominal pain, muscle and connective tissue pain, joint pain, breakthrough pain, cancer pain, somatic pain, visceral pain, chronic fatigue syndrome, psychogenic pain, or pain disorder.

Another embodiment includes therapy wherein the neuropathic pain is trigeminal or herpetic neuralgia, diabetic neuropathy, chemotherapy-induced neuropathy, post-herpetic neuralgia, carpel-tunnel syndrome, radiculopathy, complex regional pain syndrome, causalgia, low back pain, spontaneous pain, brachial plexus avulsion, pain resulting from spinal cord injury, hyperalgesia, allodynia, parathesia, or dysthesia.

Another aspect of the present invention includes a method of making (2S)- (4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine of high chemical purity (>97%), comprising: reacting (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4- penten-2-amine with galactaric acid to make (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine hemi-galactarate.

Another aspect of the present invention includes a method of making (2S)- (4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate, comprising: (a) palladium catalyzed coupling of 3-bromo-5-methoxypyridine and a protected (2S)- N-methyl-4-penten-2-amine; (b) removing the protecting group; (c) treatment with galactaric acid to precipitate (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten- 2-amine hemi-galactarate; (d) converting (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine hemi-galactarate into (2S)-(4E)-N-methyl-5-[3- (5-methoxypyridin)yl]-4-penten-2-amine by treatment with a base and a suitable solvent; treating the (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine, in a suitable solvent, with phosphoric acid to produce (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine phosphate. One embodiment includes wherein the protected (2S)-N-methyl-4-penten-2- amine is (2S)-N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine such that the protecting group to be removed is tert-butoxycarbonyl.

One aspect of the present invention relates to the hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, L-glutamic acid, pamoic acid (4,4'- methylenebis(3-hydroxy-2-naphthoic acid), xinafoic acid (1-hydroxy-2-napthoic acid), ketoglutaric acid, L-tartaric acid, fumaric acid, galactaric acid (mucic acid), citric acid, D-glucuronic acid, L-malic acid, hippuric acid (N-benzoylglycine), D-gluconic acid, L- lactic acid, L-aspartic acid, oleic acid (9Z-octadecenoic acid), L-ascorbic acid, benzoic acid, p-hydroxybenzoic acid, succinic acid, adipic acid, acetic acid, propionic acid, stearic acid (octadecanoic acid), malonic acid, lactobionic acid (4-0-β-D- galactopyranosyl-D-gluconic acid), D-glucoheptonic acid, (+)-camphoric acid, caprylic acid (octanoic acid), orotic acid (uracil-6-carboxylic acid), R-mandelic acid, S-mandelic acid, oxalic acid and hydrobromic acid salts of (2S)-(4E)-N-methyl-5-[3- (5-methoxypyridin)yl]-4-penten-2-amine.

The present invention includes solid hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, pamoic acid, xinafoic acid, galactaric acid, L-tartaric acid, hippuric acid, fumaric acid, citric acid, D-glucuronic acid, L-malic acid, D-gluconic acid, L-ascorbic acid, p-hydroxybenzoic acid, stearic acid, lactobionic acid, orotic acid, R-mandelic acid, S-mandelic acid, oxalic acid and hydrobromic acid salts of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine. These can be obtained from (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine by mixing with the corresponding acids in appropriate solvent(s), either by precipitation from or evaporation of the solvent. The invention also includes the preparation of these salts. In one embodiment, the stoichiometric ratio of the acid to the amine base is 1 :1. In another embodiment, the stoichiometric ratio of the acid to the amine is 1 :2. In another embodiment, the stoichiometric ratio of the acid to the amine is 2:1.

The present invention includes crystalline hydrochloric acid, maleic acid, phosphoric acid, pamoic acid, xinafoic acid, fumaric acid, galactaric acid, p- hydroxybenzoic acid, stearic acid, orotic acid, R-mandelic acid, S-mandelic acid, oxalic acid and hydrobromic acid salts of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine. In one embodiment, the salt is (2S)-(4E)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate. In another embodiment, the salt is (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2- amine hemigalactarate. In yet another embodiment, the salt is (2S)-(4E)-N-methyl-5- [3-(5-methoxypyridin)yl]-4-penten-2-amine stearate. In yet another embodiment, the salt is (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine bis-orotate. In yet another embodiment, the salt is (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]- 4-penten-2-amine pamoate.

The present invention includes combinations of each of the aspects and embodiments. As noted, the present invention includes hydrates and solvates of the salts of the present invention. The present invention includes polymorphic forms of the salts, including hydrates and solvates of the salts, of the present invention. Such polymorphic forms are characterized by their x-ray powder diffraction (XRPD) patterns (diffractograms). In one embodiment, the polymorph is Form 1 , Form 2, or Form 3 of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate.

The present invention includes pharmaceutical compositions comprising a salt of the present invention, and hydrates and solvates thereof. The pharmaceutical compositions of the present invention can be used for treating or preventing a wide variety of conditions or disorders, and particularly those disorders characterized by dysfunction of nicotinic cholinergic neurotransmission or the degeneration of the nicotinic cholinergic neurons.

The present invention includes a method for treating or preventing disorders and dysfunctions, such as CNS disorders and dysfunctions, and also for treating or preventing certain conditions, for example, alleviating pain and inflammation, in mammals in need of such treatment. The methods involve administering to a subject a therapeutically effective amount of a salt, or hydrate or solvate thereof, of the present invention or a pharmaceutical composition that includes such compounds. More specifically, the present invention includes a method for the treatment or prevention of pain, inflammation, age-associated memory impairment, mild cognitive impairment, pre-senile dementia, early onset Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, Lewy body dementia, vascular dementia, Alzheimer's disease, stroke, AIDS dementia complex, attention deficit disorder, attention deficit hyperactivity disorder, dyslexia, schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive deficit in schizophrenia, and cognitive dysfunction in schizophrenia.

The present invention includes a method for alleviating pain through administration to a subject in need thereof an effective amount of a composition of the present invention. In one embodiment, the type of pain is acute pain, chronic pain, neurologic pain, neuropathic pain, female-specific pain, post-surgical pain, inflammatory pain, or cancer pain. More specifically, the present invention includes a method of treating chronic or neuropathic pain by administering the compounds of the invention. In particular embodiments, the compounds are administered to treat chronic or neuropathic pain caused by diabetes or associated with a diabetic state. In other embodiments, the compounds are administered to treat chronic or neuropathic pain caused by chemotherapeutic treatment of cancer.

The foregoing and other aspects of the present invention are explained in further detail in the detailed description and examples set forth below.

Brief Description of the Figures

Figure 1 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine hemi-galactarate.

Figure 2 shows the XRPD diffractograms of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine phosphate salts.

Figure 3 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine phosphate, Form 1.

Figure 4 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine maleate. Figure 5 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine xinafoate.

Figure 6 shows the XRPD diffractograms of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine hydrochloride salts.

Figure 7 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine di-orotate.

Figure 8 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine pamoate salts.

Figure 9 show the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine fumarate. Figure 10 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine stearate.

Figure 11 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine p-hydroxybenzoate.

Figure 12 shows the XRPD diffractogram of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine R-mandelate.

Each of Figures 13 A-E show the XRPD diffractograms of (2S)-(4E)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate, Form 1 , from various solvents.

Figure 14 shows the XRPD diffractograms of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine phosphate, Form 2, from various solvents. Figure 15 shows the XRPD diffractograms of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine phosphate, Form 3, from various solvents. Figure 16 shows the XRPD diffractograms of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine phosphate, Form 1 , under various temperature and relative humidity (RH) conditions. Figure 17 illustrates gabapentin and vehicle-treated groups tested for allodynia at 6 weeks post-STZ treatment. Gabapentin significantly reversed the allodynia (p<0.05).

Figure 18 illustrates (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten- 2-amine, specifically the hemigalatarate, and vehicle-treated groups tested for allodynia at 6 weeks post-STZ treatment. (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine demonstrated a significantly increased allodynia threshold at 2 hr post-dosing (p<0.05).

Figure 19 illustrates gabapentin and vehicle-treated groups tested for allodynia at baseline, 3 and 4 weeks post-TAXOL administration. Gabapentin significantly reversed the allodynia (p<0.001 ).

Figure 20 illustrates (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten- 2-amine and vehicle-treated groups tested for allodynia at baseline, 3 and 4 weeks post-TAXOL administration. Only the high dose of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine significantly reversed the allodynia (p<0.05) at both weeks 3 and 4. White bar indicates vehicle; very lightly shaded bar indicates 0.03 mg/kg (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine; medium shaded bar indicates 0.3 mg/kg (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine; and darkly shaded bar indicates 1 mg/kg (2S)- (4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine

Detailed Description

A scalable synthesis of and various salt forms of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine, pharmaceutical compositions including these salt forms, methods of preparing the salt forms, and methods of treatment or prevention using the salt forms, are described in detail below.

As used herein, the term "compounds" includes salt forms, preferably acid addition salts, of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine, unless, in that particular context, it is clear that the compound being referred to is the free base itself. The term "compounds" also includes hydrates and solvates of the salt forms. The compounds described herein are salts of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine, which free base has the formula:

(2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine and its salts may be prepared in a variety of ways. Approaches for preparing (2S)-(4E)-N-methyl- 5-[3-(5-methoxypyridin)yl]-4-penten-2-amine are described, for example, in U.S. patent No. 7,045,538 to Caldwell et al., herein incorporated by reference.

One embodiment of the present invention is a synthesis of (2S)-(4E)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine that is suitable for use in large scale manufacture. Thus, there is provided synthetic procedures which can be performed on a multi-kilogram scale, using standard manufacturing equipment, reagents, and protocols. As is well known to those of skill in the art of organic synthesis, particular synthetic steps vary in their amenability to scale-up. Reactions are found lacking in their ability to be scaled-up for a variety of reasons, including safety concerns, reagent expense, difficult work-up or purification, reaction energetics (thermodynamics or kinetics), and reaction yield. The synthesis of (2S)- (4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine described herein has been used to produce kilogram quantities of material, and component reactions have been carried out on multi-kilogram scale in relatively high yield. The synthetic sequences reported herein are readily scalable and avoid chromatographic purifications.

The synthesis of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2- amine typically involves performing a Heck reaction between 3-bromo-5- methoxypyridine, and a double bond-containing compound. The double bond- containing compound typically includes either a hydroxyl group, which is (subsequent to the Heck reaction) converted to an amine group to form the (2S)-(4E)-N-methyl-5- [3-(5-methoxypyridin)yl]-4-penten-2-amine, or includes a protected amine group, which is de-protected following the Heck reaction to form the (2S)-(4E)-N-methyl-5- [3-(5-methoxypyridin)yl]-4-penten-2-amine. This latter approach is exemplified in the scalable synthesis disclosed herein.

A limitation of the Heck coupling chemistry is that, while the major reaction product is the desired E (or trans) isomer, there are minor reaction products, including the Z (or cis) isomer, a coupling product wherein the double bond has migrated from the position adjacent to the pyridine ring to a non-conjugated position, and a coupling product in which the heteroaryl group is attached at the secondary (as opposed to primary) alkene carbon (i.e., a methylene compound). Thus, the Heck coupling syntheses of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten- 2-amine typically also generate minor amounts of isomeric impurities, (2S)-(4Z)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine, (2S)-(3E and 3Z)-N-methyl-5-[3- (5-methoxypyridin)yl]-3-penten-2-amine, and (2S)-N-methyl-4-[3-(5- methoxypyridin)yl]-4-penten-2-amine. It can be difficult to remove these minor reaction products, particularly on scale-up. It would be advantageous to provide new methods of preparing purified (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4- penten-2-amine substantially free, namely > 97%, from the above-described minor reaction products to assist in preparing large quantities of these compounds in a commercially reasonable manner. The present invention provides such new synthesis methods and new salt forms.

(2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine free base is a viscous oil with limited water solubility. The free base will react with both inorganic and organic acids to make certain acid addition salts that have physical properties, namely crystallinity and water solubility as well as chemical properties, namely stability toward chemical degradation, that are advantageous for the preparation of pharmaceutical compositions. Such salts are reported here. The compounds, namely salt forms, described herein are salt compositions that possess anions derived from hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, L-glutamic acid, pamoic acid (4,4'-methylenebis(3-hydroxy-2- naphthoic acid), xinafoic acid (1-hydroxy-2-napthoic acid), ketoglutaric acid, L-tartaric acid, fumaric acid, galactaric acid (mucic acid), citric acid, D-glucuronic acid, L-malic acid, hippuric acid (N-benzoylglycine), D-gluconic acid, L-lactic acid, L-aspartic acid, oleic acid (9Z-octadecenoic acid), L-ascorbic acid, benzoic acid, p-hydroxybenzoic acid, succinic acid, adipic acid, acetic acid, propionic acid, stearic acid (octadecanoic acid), malonic acid, lactobionic acid (4-O-β-D-galactopyranosyl-D-gluconic acid), D- glucoheptonic acid, (+)-camphoric acid, caprylic acid (octanoic acid), orotic acid (uracil-6-carboxylic acid), R-mandelic acid, S-mandelic acid, oxalic acid and hydrobromic acid, and cations derived from (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine. The stoichiometry of the salts comprising the present invention can vary, as discussed in the illustrations herein provided.

Phosphoric acid and citric acid each have three acidic protons of varying acid strengths, which can react with one or both of the basic amine groups present on (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine. Accordingly, the acid-base reaction can occur, for example, in a ratio of one phosphoric or citric acid molecule to one, two, or three (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4- penten-2-amine molecules, two phosphoric or citric acid molecules to one or three (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine molecules, three phosphoric or citric acid molecules to two molecules of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine. Other ratios are also possible.

Galactaric acid and maleic acid each have two acidic protons of varying acid strengths, which can react with one or both of the basic amine groups present on (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine. Accordingly, the acid-base reaction can occur, for example, in a ratio of one galactaric or maleic acid molecule to one or two (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2- amine molecules. Similarly, two molecules of either galactaric or maleic acid can react with one molecule of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2- amine. Other ratios are also possible. Orotic acid (uracil-6-carboxylic acid) and R-mandelic acid each have one acidic proton and can combine with (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4- penten-2-amine in ratios of 2:1 or 1 :1 , acid to base, for instance.

In the presently disclosed salts, it is typical that the molar ratio of acid to base ((2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine) is 1:2 or 1:1 , but other ratios, such as 3:2 and 2:1 , are possible. Depending upon the manner by which the salts described herein are formed, the salts can have crystal structures that occlude solvents that are present during salt formation. Thus, the salts can occur as hydrates and other solvates of varying stoichiometry of solvent relative to the (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine. A further aspect of the present invention comprises processes for the preparation of the salts. The precise conditions under which the salts are formed may be empirically determined. The salts may be obtained by crystallization under controlled conditions.

The method for preparing the salt forms can vary. The preparation of (2S)- (4E)-N-methyl-5-[3-(5-methoxypyridin)yl)]-4-penten-2-amine salt forms typically involves:

(i) mixing the free base, or a solution of the free base of suitably pure (2S)-(4E)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine in a suitable solvent, with any of the acids in pure form or as a solution of any of the acids in a suitable solvent, typically 0.5 to 1 equivalents of the acid,

(ii) (a) cooling the resulting salt solution if necessary to cause precipitation, or (ii) (b) adding a suitable anti-solvent to cause precipitation, or (ii) (c) evaporating the first solvent and adding and new solvent and repeating either steps (ii) (a) or step (ii) (b), and (iii) filtering and collecting the salt. The stoichiometry, solvent mix, solute concentration and temperature employed can vary. Representative solvents that can be used to prepare or recrystallize the salt forms include, without limitation, ethanol, methanol, isopropyl alcohol, isopropyl acetate, acetone, ethyl acetate, toluene, water, methyl ethyl ketone, and acetonitrile. According to a further aspect of the invention, there is provided the hydrochloric acid, maleic acid, phosphoric acid, pamoic acid, xinafoic acid, fumaric acid, galactaric acid, p-hydroxybenzoic acid, stearic acid, orotic acid, R-mandelic acid, S-mandelic acid, oxalic acid and hydrobromic acid salts of the invention in substantially crystalline form. Several of these crystalline salts demonstrated stability sufficient to establish their promise in the production of pharmaceutical preparations. Such stability can be demonstrated in a variety of ways. Propensity to gain and release atmospheric moisture can be assessed by dynamic vapor sorption (DVS), also known as gravimetric vapor sorption (GVS). Stability to elevated temperatures and humidity can be studied by storing the solid salts at 40°C/75%RH for up to eight days, and then re-examining each by weight, appearance under the microscope, and x-ray powder diffraction (XRPD).

Although we have found that it is possible to produce salts of the invention in forms which are greater than 80% crystalline, by "substantially crystalline" we include greater than 20%, preferably greater than 30%, and more preferably greater than 40% (e.g. greater than any of 50, 60, 70, 80, or 90%) crystalline.

The degree (%) of crystallinity may be determined by the skilled person using XRPD. Other techniques, such as solid state NMR, FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC) and microcalorimetry, may also be used. The term "stability" as defined herein includes chemical stability and solid state stability.

The phrase "chemical stability", includes the potential to store salts of the invention in an isolated form, or in the form of a formulation in which it is provided in admixture with pharmaceutically acceptable carriers, diluents, or adjuvants, such as in an oral dosage form, such as a tablet, capsule, or the like, under normal storage conditions, with an insignificant degree of chemical degradation or decomposition. The phrase "solid state stability", includes the potential to store salts of the invention in an isolated solid form, or in the form of a solid formulation in which it is provided in admixture with pharmaceutically acceptable carriers, diluents, or adjuvants, such as in an oral dosage form, such as a tablet, capsule, or the like, under normal storage conditions, with an insignificant degree of solid state transformation, such as crystallization, recrystallization, solid state phase transition, hydration, dehydration, salvation, or desolvation.

Examples of "normal storage conditions" include one or more of temperatures of between -80⁰C and 50⁰C, preferably between O⁰C and 40°C and more preferably room temperatures, such as 15⁰C to 3O⁰C, pressures of between 0.1 and 2 bars, preferably at atmospheric pressure, relative humidity of between 5 and 95%, preferably 10 to 60%, and exposure to 460 lux of UV/visible light, for prolonged periods, such as greater than or equal to six months. Under such conditions, salts of the invention may be found to be less than 15%, more preferably less than 10%, and most preferably less than 5%, chemically degraded or decomposed, or solid state transformed, as appropriate. The skilled person will appreciate that the above- mentioned upper and lower limits for temperature, pressure and relative humidity represent extremes of normal storage conditions, and that certain combinations of these extremes will not be experienced during normal storage (e.g. a temperature of 50°C and a pressure of 0.1 bar).

The present invention includes a method for treating or preventing disorders and dysfunctions, such as CNS disorders and dysfunctions. The present invention includes a method for treating a wide variety of conditions, particularly pain. The present invention also relates to treatment of disorders characterized by dysfunction of nicotinic cholinergic neurotransmission including disorders involving neuromodulation of neurotransmitter release, such as dopamine release. The present invention also relates to methods for treating and preventing disorders, such as CNS disorders, which are characterized by an alteration in normal neurotransmitter release. The methods involve administering to a subject an effective amount of the salt forms, including hydrates and solvates of the salt forms, or pharmaceutical compositions including such salt forms, their hydrates and solvates.

One embodiment of the present invention includes a method for the treatment or prevention of CNS disorders and dysfunctions, comprising administering to a mammal in need of such treatment, a therapeutically effective amount of the compound of the present invention. More specifically, the disorder or dysfunction may be selected from the group consisting of age-associated memory impairment, mild cognitive impairment, pre-senile dementia, early onset Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, Lewy body dementia, vascular dementia, Alzheimer's disease, stroke, AIDS dementia complex, attention deficit disorder, attention deficit hyperactivity disorder, dyslexia, schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive deficits in schizophrenia, and cognitive dysfunction in schizophrenia. Still further, the disorder may be selected from the group consisting of mild to moderate dementia of the Alzheimer's type, attention deficit disorder, attention deficit hyperactivity disorder, mild cognitive impairment, age-associated memory impairment, cognitive deficits in schizophrenia, and cognitive dysfunction in schizophrenia.

One embodiment of the present invention includes a method for the treatment or prevention of pain, comprising administering to a mammal in need of such treatment, a therapeutically effective amount of the compound of the present invention. More specifically, the pain may be selected from the group consisting of acute pain, chronic pain, neurologic pain, neuropathic pain, female-specific pain, post-surgical pain, inflammatory pain, or cancer pain.

The present invention includes a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a salt form of (2S)-(4E)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine, or hydrate or solvate thereof, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers. The pharmaceutical compositions, incorporating a salt form of (2S)- (4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine, when employed in effective amounts, interact with relevant nicotinic receptor sites of a subject, and hence acts as a therapeutic agent to treat and prevent a wide variety of conditions and disorders, particularly pain and those disorders characterized by an alteration in normal neurotransmitter release. The pharmaceutical compositions are believed to be safe and effective with regards to prevention and treatment of a wide variety of conditions and disorders. One embodiment of the present invention includes use of a compound of the present invention in the manufacture of a medicament. One embodiment of the present invention includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and one or more pharmaceutically acceptable carriers. One embodiment of the present invention includes the use of a pharmaceutical composition of the present invention in the manufacture of a medicament for treatment of central nervous system disorders and dysfunctions. Another embodiment of the present invention includes a compound as herein described with reference to any one of the Examples. Another embodiment of the present invention includes a compound of the present invention for use as an active therapeutic substance. Another embodiment of the present invention includes a compound of the present invention for use to modulate an NNR in a subject in need thereof. Another embodiment of the present invention includes a compound of the present invention for use in the treatment or prevention of conditions or disorders mediated by NNRs. Another embodiment of the present invention includes a use of a compound of the present invention in the manufacture of a medicament for use of modulating NNRs in a subject in need thereof. Another embodiment of the present invention includes a use of a compound of the present invention in the manufacture of a medicament for use in the treatment or prevention of conditions or disorders mediated by NNRs. Another embodiment of the present invention includes a method of modulating NNRs in a subject in need thereof through the administration of a compound of the present invention. As noted, the scope of the present invention also includes combinations of embodiments.

Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of a hydrogen atom by a deuterium or tritium, or the replacement of a carbon atom by a ¹³C- or ¹⁴C-enriched carbon are within the scope of the invention.

The compounds of the present invention may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms ("polymorphs") are within the scope of the present invention. Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as XRPD patterns (diffractograms), solubility in various solvents, and melting point. The present invention includes a salt or solvate of the compounds herein described, including combinations thereof such as a solvate of a salt. The compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms, and the present invention encompasses all such forms. Typically, but not absolutely, the salts of the present invention are pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to non-toxic salts of the compounds of this invention.

As noted herein, the present invention includes specific representative compounds, which are identified herein with particularity.

The compounds of this invention may be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.

In all of the examples described below, protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991 ) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard to protecting groups). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the present invention.

The present invention also provides a method for the synthesis of compounds useful as intermediates in the preparation of compounds of the present invention along with methods for their preparation.

The compounds can be prepared according to the following methods using readily available starting materials and reagents. In these reactions, variants may be employed which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.

Methods of Treatment As used herein, an "agonist" is a substance that stimulates its binding partner, typically a receptor. Stimulation is defined in the context of the particular assay, or may be apparent in the literature from a discussion herein that makes a comparison to a factor or substance that is accepted as an "agonist" or an "antagonist" of the particular binding partner under substantially similar circumstances as appreciated by those of skill in the art. Stimulation may be defined with respect to an increase in a particular effect or function that is induced by interaction of the agonist or partial agonist with a binding partner and can include allosteric effects.

As used herein, an "antagonist" is a substance that inhibits its binding partner, typically a receptor. Inhibition is defined in the context of the particular assay, or may be apparent in the literature from a discussion herein that makes a comparison to a factor or substance that is accepted as an "agonist" or an "antagonist" of the particular binding partner under substantially similar circumstances as appreciated by those of skill in the art. Inhibition may be defined with respect to a decrease in a particular effect or function that is induced by interaction of the antagonist with a binding partner, and can include allosteric effects. As used herein, a "partial agonist" or a "partial antagonist" is a substance that provides a level of stimulation or inhibition, respectively, to its binding partner that is not fully or completely agonistic or antagonistic, respectively. It will be recognized that stimulation, and hence, inhibition is defined intrinsically for any substance or category of substances to be defined as agonists, antagonists, or partial agonists. As used herein, "intrinsic activity" or "efficacy" relates to some measure of biological effectiveness of the binding partner complex. With regard to receptor pharmacology, the context in which intrinsic activity or efficacy should be defined will depend on the context of the binding partner (e.g., receptor/ligand) complex and the consideration of an activity relevant to a particular biological outcome. For example, in some circumstances, intrinsic activity may vary depending on the particular second messenger system involved. See Hoyer, D. and Boddeke, H., Trends Pharmacol. Sci. 14(7): 270-5 (1993), herein incorporated by reference with regard to such teaching. Where such contextually specific evaluations are relevant, and how they might be relevant in the context of the present invention, will be apparent to one of ordinary skill in the art.

As used herein, modulation of a receptor includes agonism, partial agonism, antagonism, partial antagonism, or inverse agonism of a receptor.

As used herein, neurotransmitters whose release is mediated by the compounds described herein include, but are not limited to, acetylcholine, dopamine, norepinephrine, serotonin and glutamate, and the compounds described herein function as modulators at the α4β2 subtype of the CNS NNRs.

As used herein, the terms "prevention" or "prophylaxis" include any degree of reducing the progression of or delaying the onset of a disease, disorder, or condition. The term includes providing protective effects against a particular disease, disorder, or condition as well as amelioration of the recurrence of the disease, disorder, or condition. Thus, in another aspect, the invention provides a method for treating a subject having or at risk of developing or experiencing a recurrence of a NNR or nAChR mediated disorder. The compounds and pharmaceutical compositions of the invention may be used to achieve a beneficial therapeutic or prophylactic effect, for example, in a subject with a CNS dysfunction. As noted above, the compounds of the present invention are modulators of the α4β2 NNR subtype, characteristic of the CNS, and can be used for preventing or treating various conditions or disorders, including those of the CNS, in subjects which have or are susceptible to such conditions or disorders, by modulation of α4β2 NNRs. The compounds have the ability to selectively bind to the α4β2 NNRs and express nicotinic pharmacology, for example, to act as agonists, partial agonists, antagonists, as described. For example, compounds of the present invention, when administered in effective amounts to patients in need thereof, provide some degree of prevention of the progression of the CNS disorder, namely, providing protective effects, amelioration of the symptoms of the CNS disorder, or amelioration of the reoccurrence of the CNS disorder, or a combination thereof.

The compounds of the present invention can be used to treat or prevent those types of conditions and disorders for which other types of nicotinic compounds have been proposed or are shown to be useful as therapeutics. See, for example, the references previously listed hereinabove, as well as Williams et al., Drug News Perspec. 7(4): 205 (1994), Arneric et al., CNS Drug Rev. 1(1): 1-26 (1995), Arneric et al., Exp. Opin. Invest. Drugs 5(1): 79-100 (1996), Bencherif et al., J. Pharmacol. Exp. Ther. 279: 1413 (1996), Lippiello et al., J. Pharmacol. Exp. Ther. 279: 1422 (1996), Damaj et al., J. Pharmacol. Exp. Ther. 291: 390 (1999); Chiari et al., Anesthesiology 91 : 1447 (1999), Lavand'homme and Eisenbach, Anesthesiology 91 : 1455 (1999), Holladay et al., J. Med. Chem. 40(28): 4169-94 (1997), Bannon et al., Science 279: 77 (1998), PCT WO 94/08992, PCT WO 96/31475, PCT WO 96/40682, and U.S. Patent Nos. 5,583,140 to Bencherif et al., 5,597,919 to Dull et al., 5,604,231 to Smith et al. and 5,852,041 to Cosford et al., the disclosures of which are incorporated herein by reference with regard to such therapeutic teaching.

The compounds and their pharmaceutical compositions are useful in the treatment or prevention of a variety of CNS disorders, including neurodegenerative disorders, neuropsychiatric disorders, neurologic disorders, and addictions. The compounds and their pharmaceutical compositions can be used to treat or prevent cognitive deficits and dysfunctions, age-related and otherwise; attentional disorders and dementias, including those due to infectious agents or metabolic disturbances; to provide neuroprotection; to treat convulsions and multiple cerebral infarcts; to treat mood disorders, compulsions and addictive behaviors; to provide analgesia; to control inflammation, such as mediated by cytokines and nuclear factor kappa B; to treat inflammatory disorders; to provide pain relief; and to treat infections, as anti- infectious agents for treating bacterial, fungal, and viral infections. Among the disorders, diseases and conditions that the compounds and pharmaceutical compositions of the present invention can be used to treat or prevent are: age- associated memory impairment (AAMI), mild cognitive impairment (MCI), age-related cognitive decline (ARCD), pre-senile dementia, early onset Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, Alzheimer's disease, cognitive impairment no dementia (CIND), Lewy body dementia, HIV-dementia, AIDS dementia complex, vascular dementia, Down syndrome, head trauma, traumatic brain injury (TBI), dementia pugilistica, Creutzfeld-Jacob Disease and prion diseases, stroke, ischemia, attention deficit disorder, attention deficit hyperactivity disorder, dyslexia, schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive dysfunction in schizophrenia, cognitive deficits in schizophrenia, Parkinsonism including Parkinson's disease, postencephalitic parkinsonism, parkinsonism-dementia of Gaum, frontotemporal dementia Parkinson's Type (FTDP), Pick's disease, Niemann-Pick's Disease, Huntington's Disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, progressive supranuclear palsy, progressive supranuclear paresis, restless leg syndrome, Creutzfeld-Jakob disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), motor neuron diseases (MND), multiple system atrophy (MSA), corticobasal degeneration, Guillain- Barre Syndrome (GBS), and chronic inflammatory demyelinating polyneuropathy (CIDP), epilepsy, autosomal dominant nocturnal frontal lobe epilepsy, mania, anxiety, depression, premenstrual dysphoria, panic disorders, bulimia, anorexia, narcolepsy, excessive daytime sleepiness, bipolar disorders, generalized anxiety disorder, obsessive compulsive disorder, rage outbursts, oppositional defiant disorder, Tourette's syndrome, autism, drug and alcohol addiction, tobacco addiction, obesity, cachexia, psoriasis, lupus, acute cholangitis, aphthous stomatitis, ulcers, asthma, ulcerative colitis, inflammatory bowel disease, Crohn's disease, spastic dystonia, diarrhea, constipation, pouchitis, viral pneumonitis, arthritis, including, rheumatoid arthritis and osteoarthritis, endotoxaemia, sepsis, atherosclerosis, idiopathic pulmonary fibrosis, acute pain, chronic pain, neuropathies, urinary incontinence, diabetes and neoplasias.

Cognitive impairments or dysfunctions may be associated with psychiatric disorders or conditions, such as schizophrenia and other psychotic disorders, including but not limited to psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, and psychotic disorders due to a general medical conditions, dementias and other cognitive disorders, including but not limited to mild cognitive impairment, pre-senile dementia, Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, age-related memory impairment, Lewy body dementia, vascular dementia, AIDS dementia complex, dyslexia, Parkinsonism including Parkinson's disease, cognitive impairment and dementia of Parkinson's Disease, cognitive impairment of multiple sclerosis, cognitive impairment caused by traumatic brain injury, dementias due to other general medical conditions, anxiety disorders, including but not limited to panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder and generalized anxiety disorder due to a general medical condition, mood disorders, including but not limited to major depressive disorder, dysthymic disorder, bipolar depression, bipolar mania, bipolar I disorder, depression associated with manic, depressive or mixed episodes, bipolar Il disorder, cyclothymic disorder, and mood disorders due to general medical conditions, sleep disorders, including but not limited to dyssomnia disorders, primary insomnia, primary hypersomnia, narcolepsy, parasomnia disorders, nightmare disorder, sleep terror disorder and sleepwalking disorder, mental retardation, learning disorders, motor skills disorders, communication disorders, pervasive developmental disorders, attention-deficit and disruptive behavior disorders, attention deficit disorder, attention deficit hyperactivity disorder, feeding and eating disorders of infancy, childhood, or adults, tic disorders, elimination disorders, substance- related disorders, including but not limited to substance dependence, substance abuse, substance intoxication, substance withdrawal, alcohol-related disorders, amphetamine or amphetamine-like-related disorders, caffeine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen-related disorders, inhalant-related disorders, nicotine-related disorders, opioid-related disorders, phencyclidine or phencyclidine-like-related disorders, and sedative-, hypnotic- or anxiolytic-related disorders, personality disorders, including but not limited to obsessive-compulsive personality disorder and impulse-control disorders. The above conditions and disorders are discussed in further detail, for example, in the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, Washington, DC, American Psychiatric Association, 2000; incorporated herein by reference with regard to defining such conditions and disorders. The compounds of the present invention and their pharmaceutical compositions are particularly useful in treating (providing relief from) and preventing pain, including acute, persistent, and chronic pain. The pain types and painful conditions that can be treated or prevented using the compounds and their pharmaceutical compositions include nociceptive pain, neuropathic pain, inflammatory pain, fibromyalgia, post-operative pain, pain due to medical condition (such as AIDS or other disorder), arthritis pain, temporomandibular joint disorder, burn pain, injury pain, back pain, sciatica, foot pain, headache, abdominal pain, muscle and connective tissue pain, joint pain, breakthrough pain, cancer pain, somatic pain, visceral pain, chronic fatigue syndrome, psychogenic pain, and pain disorder. Neuropathic pain syndromes are the consequence of abnormal changes occurring within pain signaling systems of both the peripheral and central nervous system. Their diverse etiology and symptomatology have traditionally rendered them particularly difficult to treat with any consistency. Examples of neuropathic pain syndromes include those attributed to trigeminal or herpetic neuralgia, peripheral neuropathies (diabetic neuropathy, chemotherapy-induced neuropathy), postherpetic neuralgia, entrapment neuropathies (carpel-tunnel syndrome), radiculopathy, complex regional pain syndrome, causalgia, low back pain, spontaneous pain (pain without an external stimulus), and deafferentation syndromes such as brachial plexus avulsion and spinal cord injury. Hyperalgesia (strong pain associated with a mild stimulus), allodynia (pain due associated with an innocuous stimulus), parethesias (sensation of numbness or pricking in the absence of an external stimulus), and dythesias (exaggerated sensations in response to mild stimulus) are also typically characterized as types of neuropathic pain. The compounds of the present invention and their pharmaceutical compositions are particularly useful in treating and preventing these neuropathic pain types and associated conditions. The symptoms of neuropathic pain are incredibly heterogeneous.

Compounds of the present invention demonstrate efficacy in multiple animal models of neuropathic pain (chronic constriction injury, streptozotocin (STZ)-induced and Paclitaxel (TAXOL)-induced neuropathies), indicating promise of human efficacy for a variety of types of neuropathic pain states. In particular, the compound (2S)- (4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate has demonstrated efficacy in animal neuropathy models, including STZ-induced diabetic neuropathy, and TAXOL-induced neuropathy. Preferably, the treatment or prevention of diseases, disorders and conditions occurs without appreciable adverse side effects, including, for example, significant increases in blood pressure and heart rate, significant negative effects upon the gastro-intestinal tract, and significant effects upon skeletal muscle.

The compounds of the present invention, when employed in effective amounts, are believed to modulate the activity of the α4β2 NNRs without appreciable interaction with the nicotinic subtypes that characterize the human ganglia, as demonstrated by a lack of the ability to elicit nicotinic function in adrenal chromaffin tissue, or skeletal muscle, further demonstrated by a lack of the ability to elicit nicotinic function in cell preparations expressing muscle-type nicotinic receptors. Thus, these compounds are believed capable of treating or preventing diseases, disorders and conditions without eliciting significant side effects associated activity at ganglionic and neuromuscular sites. Thus, administration of the compounds is believed to provide a therapeutic window in which treatment of certain diseases, disorders and conditions is provided, and certain side effects are avoided. That is, an effective dose of the compound is believed sufficient to provide the desired effects upon the disease, disorder or condition, but is believed insufficient, namely is not at a high enough level, to provide undesirable side effects.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention incorporate a compound of the present invention which, when employed in effective amounts, interacts with relevant nicotinic receptor sites of a subject, and acts as a therapeutic agent to treat and prevent a wide variety of conditions and disorders. The pharmaceutical compositions provide therapeutic benefit to individuals suffering from affected disorders or exhibiting clinical manifestations of affected disorders, in that the compounds within those compositions, when employed in effective amounts, are believed to: (i) exhibit nicotinic pharmacology and affect relevant nicotinic receptors sites, for example by acting as a pharmacological agonist to activate a nicotinic receptor; or (ii) elicit neurotransmitter secretion, and hence prevent and suppress the symptoms associated with those diseases; or both. The compounds of the present invention are believed to have the potential to

(i) increase the number of nicotinic cholinergic receptors of the brain of a subject in need thereof; (ii) exhibit neuroprotective effects; and (iii) when employed in effective amounts, to not cause appreciable adverse side effects, for example, significant increases in blood pressure and heart rate, significant negative effects upon the gastro-intestinal tract, or significant effects upon skeletal muscle. The present invention further provides pharmaceutical compositions that include effective amounts of compounds of the formulae of the present invention and salts and solvates, thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of the formulae of the present invention, including salts and solvates, thereof, are as herein described. The carrier(s), diluent(s), or excipient(s) must be acceptable, in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition.

In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of the formulae of the present invention, including a salt, solvate, or prodrug thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.

The manner in which the compounds are administered can vary. The compositions are preferably administered orally, for example, in liquid form within a solvent such as an aqueous or non-aqueous liquid, or within a solid carrier. Preferred compositions for oral administration include pills, tablets, capsules, caplets, syrups, and solutions, including hard gelatin capsules and time-release capsules. Compositions may be formulated in unit dose form, or in multiple or subunit doses. Preferred compositions are in liquid or semisolid form.

Compositions including a liquid pharmaceutically inert carrier such as water or other pharmaceutically compatible liquids or semisolids may be used. The use of such liquids and semisolids is well known to those of skill in the art.

The compositions can also be administered via injection, namely, intravenously, intramuscularly, subcutaneously, intraperitoneal^, intraarterially, intrathecal^, and intracerebroventricularly. Intravenous administration is a preferred method of injection. Suitable carriers for injection are well known to those of skill in the art, and include 5% dextrose solutions, saline, and phosphate buffered saline. The compounds can also be administered as an infusion or injection, such as, as a suspension or as an emulsion in a pharmaceutically acceptable liquid or mixture of liquids.

The formulations may also be administered using other means, for example, rectal administration. Formulations useful for rectal administration, such as suppositories, are well known to those of skill in the art. The compounds can also be administered by inhalation, including, in the form of an aerosol either nasally or using delivery articles of the type set forth in U.S. Patent No. 4,922,901 to Brooks et al., the disclosure of which is incorporated herein; topically, such as, in lotion form; transdermal^, such as, using a transdermal patch, using technology that is commercially available from Novartis and Alza Corporation; by powder injection; or by buccal, sublingual, or intranasal absorption. A compositions for transdermal administration includes the active ingredient in conjunction with carriers and excipients, such as permeation enhancers, which promote transdermal absorption of the active ingredient after transdermal administration.

The amount of active ingredient absorbed depends on many factors. These factors include the active ingredient concentration, the active ingredient delivery vehicle, the skin contact time, the area of the skin dosed, the ratio of the ionized and unionized forms of the active ingredient at the pH of the absorption site, the molecular size of the active ingredient molecule, and the active ingredient's relative lipid solubility. Transdermal Devices

A transdermal device for delivering the active ingredients described herein can be of any type known in the art, including the monolithic, matrix, membrane, and other types typically useful for administering active ingredients by the transdermal route. Such devices are disclosed in U.S. Pat. Nos. 3,996,934; 3,797,494; 3,742,951 ; 3,598,122; 3,598,123; 3,731,683; 3,734,097; 4,336,243; 4,379,454; 4,460,372; 4,486,193; 4,666,441 ; 4,615,699; 4,681 ,584; and 4,558,580 among others; the disclosures of which are incorporated herein by reference.

These devices tend to be flexible, adhere well to the skin, and have a polymeric backing (covering) that is impermeable to the active ingredient to be delivered, so that the active ingredient is administered uni-directionally through the skin. The active ingredient, or pharmaceutically acceptable salt thereof, is typically present in a solution or dispersion, which can be in the form of a gel, a solution, or a semi-solid, and which aids in active ingredient delivery through the stratum corneum of the epidermis and to the dermis for absorption. Membrane Devices

Membrane devices typically have four layers: (1) an impermeable backing, (2) a reservoir layer, (3) a membrane layer (which can be a dense polymer membrane or a microporous membrane), and (4) a contact adhesive layer which either covers the entire device surface in a continuous or discontinuous coating or surrounds the membrane layer. Examples of materials that may be used to act as an impermeable layer are high, medium, and low density polyethylene, polypropylene, polyvinylchloride, polyvinylidene chloride, polycarbonate, polyethylene terepthalate, and polymers laminated or coated with aluminum foil. Others are disclosed in the standard transdermal device patents mentioned herein. In certain embodiments in which the reservoir layer is fluid or is a polymer, the outer edge of the backing layer can overlay the edge of the reservoir layer and be sealed by adhesion or fusion to the diffusion membrane layer. In such instances, the reservoir layer need not have exposed surfaces.

The reservoir layer is underneath the impermeable backing and contains a carrier liquid, typically water and/or an alcohol, or polyol or ester thereof, and may or may not contain the active ingredients. The reservoir layer can include diluents, stabilizers, vehicles, gelling agents, and the like in addition to the carrier liquid and active ingredients.

The diffusion membrane layer of the laminate device can be made of a dense or microporous polymer film that has the requisite permeability to the active ingredient and the carrier liquid. Preferably, the membrane is impermeable to ingredients other than the active ingredient and the carrier liquid, although when buffering at the skin surface is desired, the membrane should be permeable to the buffer in the composition as well. Examples of polymer film that may be used to make the membrane layer are disclosed in U.S. Pat. Nos. 3,797,454 and 4,031 ,894, each herein incorporated by reference. The preferred materials are polyurethane, ethylene vinyl alcohol polymers, and ethylene/vinyl acetate.

One embodiment of the invention relates to a transdermal composition comprising:

(1 ) an impermeable backing, (2) a reservoir layer comprising the active ingredient in a buffer solution optional further comprising a penetration enhancer.

(3) a membrane layer (which can be a dense polymer membrane or a microporous membrane), and

(4) a contact adhesive layer which either covers the entire device surface in a continuous or discontinuous coating or surrounds the membrane layer.

In another embodiment the composition above comprised in the reservoir the active ingredient in phosphate buffered saline solution.

In a further embodiment the hydroxybenzoate salt of the active ingredient is used in the composition above. In yet another embodiment the active ingredient in the reservoir of the composition above is present in a concentration of from 30 to 200 mg per gram of saline solution. In yet a further embodiment the concentration of the active ingredient in the reservoir of the composition above is 35 or 135 mg per gram of saline solution. Monolithic Matrices

The second class of transdermal systems is represented by monolithic matrices. Examples of such monolithic devices are U.S. Pat. No. 4,291 ,014, U.S. Pat. No. 4,297,995, U.S. Pat. No. 4,390,520, and U.S. Pat. No. 4,340,043, each herein incorporated by reference. Others are known to those of ordinary skill in this art.

Monolithic and matrix type barrier transdermal devices typically include: (1) Porous polymers or open-cell foam polymers, such as polyvinyl chloride

(PVC), polyurethanes, polypropylenes, and the like;

(2) Highly swollen or plasticized polymers such as cellulose, HEMA or MEMA or their copolymers, hydroxypropyl methylcellulose (HPMC), hydroxyethyl methylcellulose (HEMC), and the like, polyvinyl alcohol (PVA)/ polyvinylpyrollidone (PVP), or other hydrogels, or PVC, polyurethane, ethylene / vinyl acetate, or their copolymers;

(3) Gels of liquids, typically including water and/or hydroxyl-containing solvents such as ethanol, and often containing gelling agents such PVP, carboxymethylcellulose (CMC), hydroxypropylcellulose such as sold undere the tradename Klucel®, HPMC, alginates, kaolinate, bentonite, or montmorillonite, other clay fillers, stearates, silicon dioxide particles, and the like;

(4) Nonwoven materials made of textiles, celluloses, polyurethanes, polyester, or other fiber;

(5) Sponges, which can be formed from natural or foamed polymers; and (6) Adhesives, ideally dermatologically-acceptable pressure sensitive adhesives, for example, silicone adhesives or acrylic adhesives.

A variety of components for transdermal compositions are described hereinafter in more detail. Polymeric Barrier Materials Representative polymeric barrier materials include, but are not limited to:

Polycarbonates, such as those formed by phosgenation of a dihydroxy aromatic such as bisphenol A, including materials are sold under the trade designation Lexan® (the General Electric Company);

Polyvinylchlorides, such as Geon® 121 (B. G. Goodrich Chemical Company); Polyamides ("nylons"), such as polyhexamethylene adipamide, including

NOMEX® (E. I. DuPont de Nemours & Co.). Modacryϋc copolymers, such as DYNEL®, are formed of polyvinylchloride (60 percent) and acrylonitrile (40 percent), styrene-acrylic acid copolymers, and the like. Polysulfones, for example, those containing diphenylene sulfone groups, for example, P-1700 (Union Carbide Corporation). Halogenated polymers, for example, polyvinylidene fluoride, such as Kynar®

(Pennsalt Chemical Corporation), polyvinylfluoride, such as Tedlar® (E. I. DuPont de Nemours & Co.), and polyfluorohalocarbons, such as Aclar® (Allied Chemical Corporation).

Polychlorethers, for example, Penton® (Hercules Incorporated), and other thermoplastic polyethers.

Acetal polymers, for example, polyformaldehydes, such as Delrin® (E. I. DuPont de Nemours & Co.).

Acrylic resins, for example, polyacrylonitrile, polymethyl methacrylate (PMMA), poly n-butyl methacrylate, and the like. Other polymers such as polyurethanes, polyimides, polybenzimidazoles, polyvinyl acetate, aromatic and aliphatic, polyethers, cellulose esters, e.g., cellulose triacetate; cellulose; colledion (cellulose nitrate with 11% nitrogen); epoxy resins; olefins, e.g., polyethylene, polypropylene; polyvinylidene chloride; porous rubber; cross linked poly(ethylene oxide); cross-linked polyvinylpyrrolidone; cross-linked polyvinyl alcohol); polyelectrolyte structures formed of two ionically associated polymers of the type as set forth in U.S. Pat. Nos. 3,549,016 and 3,546,141 , herein incorporated by reference with regard to such polymer compositions; derivatives of polystyrene such as poly(sodium styrenesulfonate) and poly(vinylbenzyltrimethyl- ammonium chloride); poly(hydroxyethylmethacrylate); poly(isobutylvinyl ether), and the like, may also be used. A large number of copolymers which can be formed by reacting various proportions of monomers from the above list of polymers are also useful.

If the membrane or other barrier does not have a sufficiently high flux, the thickness of the membrane or barrier can be reduced. However, the thickness should not be reduced to the point where it is likely to tear, or to a point where the amount of active ingredient which can be administered is too low. Adhesives

The transdermal drug delivery compositions typically include a contact adhesive layer to adhere the device to the skin. The active agent may, in some embodiments, reside in the adhesive. Exemplary adhesives include polyurethanes; acrylic or methacrylic resins such as polymers of esters of acrylic or methacrylic acid with alcohols such as n- butanol, n-pentanol, isopentanol, 2-methylbutanol, 1-methylbutanol, 1- methylpentanol, 2-methylpentanol, 3-methylpentanol, 2-ethylbutanol, isooctanol, n- decanol, or n-dodecanol, alone or copolymerized with ethylenically unsaturated monomers such as acrylic acid, methacrylic acid, acrylamide, methacrylamide, N- alkoxymethyl acrylamides, N-alkoxymethyl methacrylamides, N-tertbutylacrylamide, itaconic acid, vinylacetate, N-branched alkyl maleamic acids wherein the alkyl group has 10 to 24 carbon atoms, glycol diacrylates, or mixtures of these; natural or synthetic rubbers such as styrenebutadiene, butylether, neoprene, polyisobutylene, polybutadiene, and polyisoprene; polyvinylacetate; unreaformaldehyde resins; phenolformaldehyde resins; resorcinol formaldehyde resins, cellulose derivatives such as ethylcellulose, methylcellulose, nitrocellulose, cellulose acetatebutyrate, and carboxymethyl cellulose; and natural gums such as guar, acacia, pectins, starch, dextrin, albumin, gelatin, casein, etc. The adhesives can be compounded with tackifiers and stabilizers, as is well known in the art.

Representative silicone adhesives include silicone elastomers based on monomers of silanes, halosilanes, or Ci_-I8 alkoxysilanes, especially polydimethylsiloxanes which may be used alone or formulated with a silicone tackifier or silicone plasticizer which are selected from medically acceptable silicone fluids, i.e. non-elastomeric silicones based on silanes, halosilanes or C_1-18 alkoxysilanes. Typical silicone adhesives are available from Dow Corning under the tradename SILASTIC®. Liquid Vehicles Transdermal compositions can include a variety of components, including a liquid vehicle, typically a C_2-4 alkanol such as ethanol, isopropanol, n-propanol, butanol, a polyalcohol or glycol such as propylene glycol, butylene glycol, hexylene glycol, ethylene glycol, and/or purified water. The vehicle is typically present in an amount of between about 5 and about 75% w/w, more typically, between about 15.0% and about 65.0% w/w, and, preferably, between about 20.0 and 55.0% w/w

Water augments the solubility of hydrophilic active agents in the composition, and accelerates the release of lipophilic active agents from a composition. Alcohols, such as ethanol, increase the stratum corneum liquid fluidity or function to extract lipids from the stratum corneum. As discussed herein, the glycols can also act as permeation enhancers. Permeation Enhancers Successful transdermal delivery depends among others on sufficient flux of the active ingredient across skin, and sufficient surface area of skin, to produce an efficacious plasma concentration of the active ingredient. For reasons of consumer acceptance, the practical surface area of a transdermal system is limited from approximately 4 to 100 cm². With this limitation on surface area, the therapeutic transdermal administration of many active ingredients requires an increase in the inherent skin permeability to obtain the necessary flux. Accordingly, active ingredients have been developed which enhance percutaneous absorption of the active ingredients to be administered. Permeation enhancers are described, for example, in U.S. Patent Nos.

5,785,991 ; 4,764,381 ; 4,956,171 ; 4,863,970; 5,453,279; 4,883,660; 5,719,197, and in the literature "Pharmaceutical Skin Penetration Enhancement", J. Hadgraft, Marcel Dekker, Inc. 1993; "Percutaneous Absorption", R. Bronaugh, H. Maibach, Marcel Dekker, Inc. (1989), B. W. Barry, "Penetration Enhancers in Skin Permeation", Proceedings of the 13th international Symposium on Controlled Release of Bioactive Materials, ed. by Chaudry & Thies, Controlled Release Society, Lincolnshire, III., pp. 136-137 (1986), and Cooper & Berner, "Penetration Enhancers", in The Transdermal Delivery of Ingredients, Vol. Il ed. by Kydonieus and Berner, CRC Press, Boca Raton, FIa. pp. 57-62 (1986), the contents of each of which are hereby incorporated by reference.

The permeation enhancers should both enhance the permeability of the stratum corneum, and be non-toxic, non-irritant and non-sensitizing on repeated exposure. Representative permeation enhancers include, for example, sucrose monococoate, glycerol monooleate, sucrose monolaurate, glycerol monolaureate, diethylene glycol monoalkyl ethers such as diethylene glycol monoethyl or monomethyl ether (Transcutol® P), ester components such as propylene glycol monolaurate, methyl laurate, and lauryl acetate, monoglycerides such as glycerol monolaurate, fatty alcohols such as lauryl alcohol, and 2-ethyl-1 ,3 hexanediol alone or in combination with oleic acid. In one embodiment, the transdermal compositions are provided with skin permeation enhancing benefits by combining the active ingredients with saturated fatty alcohols, or forming salts of the active ingredients with one or more fatty acids, such as those of the formula CH₃-(CH₂)_H-CH₂OH or CH₃-(CH₂)n-CH₂COOH respectively, in which n is an integer from 8 to 22, preferably 8 to 12, most preferably 10, or an unsaturated fatty alcohol or fatty acid given by the formula CH₃-(C_nH_2(H-X))- OH or CH₃-(C_nH_2(H-_Xj)-COOH respectively in which n is an integer from 8 to 22 and x is the number of double bonds; and preferably also a second component that is a monoalkyl ether of diethylene glycol, preferably diethylene glycol monoethyl ether or diethylene glycol monomethyl ether, in a vehicle or carrier composition, integrated by an C_1-4 alkanol, preferably ethanol; a polyalcohol, preferably propylene glycol and purified water.

A binary system including a combination of oleic acid or oleic alcohol and a lower alcohol, or a combination of a lower alkyl ester of a polycarboxylic acid, an aliphatic monohydroxy alcohol and an aliphatic diol, can be used.

Representative permeation enhancers include fatty alcohols and fatty acids, and monoalkyl ethers of diethylene glycol such as diethylene glycol monoethyl ether or diethylene glycol monomethyl ether. The fatty alcohols are typically present in an amount of between about 0.1 and about 20.0% w/w, preferably between about 0.2 and about 10.0% w/w, and more preferably, between about 0.4 and about 3.0% w/w. The diethylene glycol monoalkyl ethers are typically present in an amount up to 40.0% w/w, preferably between about 0.2 and 25.0% w/w, and, more preferably, between about 2.0 and about 8.0% w/w.

Although not wishing to be bound to a particular theory, it is believed that the mechanism by which certain permeation enhancers function to enhance permeability of the active agents through the stratum corneum is as follows: The fatty alcohol is mainly distributed to the stratum corneum because of its lipophilicity and interacts with the stratum corneum lipids.

The diethylene glycol monoalkyl ethers dissolve both hydrophilic and a lipophilic active agents therein, and facilitates the penetration of the active agents to the skin. Glycols, such as propylene glycol, act as a cosolvent of the active agents, and thus increase their solubility in the composition. Further, they tend to solvate the intracellular keratin of the stratum corneum, and thus enhance drug mobility and skin hydration.

Gelling Agents

Gelling agents, such as carbomer, carboxyethylene or polyacrylic acid such as Carbopol® 980 or 940 NF, 981 or 941 NF, 1382 or 1342 NF, 5984 or 934 NF, ETD 2020, 2050, 934P NF, 971 P NF, 974P NF, Noveon® AA-1 USP, etc; cellulose derivatives such as ethylcellulose, hydroxypropylmethylcellulose (HPMC), ethylhydroxyethylcellulose (EHEC), carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC) (Klucel®, different grades), hydroxyethylcellulose (HEC) (Natrosol® grades), HPMCP 55, Methocel® grades, etc; natural gums such as arabic, xanthan, guar gums, alginates, etc; polyvinylpyrrolidone derivatives such as Kollidon® grades; polyoxyethylene polyoxypropylene copolymers such as Lutrol® F grades 68, 127, etc; others like chitosan, polyvinyl alcohols, pectins, veegun grades, and the like, can also be present. Those of the skill in the art know of other gelling agents or viscosants suitable for use in the present invention.

Representative gelling agents include, but are not limited to, Carbopol® 980 NF, Lutrol® F 127, Lutrol® F 68 and Noveon® AA- 1 USP. The gelling agent is present from about 0.2 to about 30.0% w/w, depending on the type of polymer. Preservatives

The transdermal compositions can also include one or more preservatives and/or antioxidants. Representative preservatives include quaternary ammonium salts such as lauralkonium chloride, benzalkonium chloride, benzododecinium chloride, cetyl pyridium chloride, cetrimide, domiphen bromide; alcohols such as benzyl alcohol, chlorobutanol, o-cresol, phenylethyl alcohol; organic acids or salts thereof such as benzoic acid, sodium benzoate, potassium sorbate, parabens; or complex forming agents such as ethylenediaminetetraacetic acid (EDTA). Representative antioxidants include butylhydroxytoluene, butylhydroxyanisole, ethylenediaminetetraacetic acid and its sodium salts, D,L-alpha tocoferol. Other Components

Other components may include diluents such as cellulose, microcrystalline cellulose, hydroxypropyl cellulose, starch, hydroxypropylmethyl cellulose and the like. Excipients can be added to adjust the tonicity of the composition, such as sodium chloride, glucose, dextrose, mannitol, sorbitol, lactose and the like. Acidic or basic buffers can also be added to control the pH. Co-solvents or solubilizers such as glycerol, polyethylene glycols, polyethylene glycols derivatives, polyethylene glycol 660 hydroxystearate (Solutol HS15 from BASF), butylene glycol, hexylene glycol, and the like, can also be added.

Controlled Release of the Active Agent

The administration of the active agent can be controlled by using controlled release compositions, which can provide rapid or sustained release, or both, depending on the compositions.

There are numerous particulate drug delivery vehicles known to those of skill in the art which can include the active ingredients, and deliver them in a controlled manner. Examples include particulate polymeric drug delivery vehicles, for example, biodegradable polymers, and particles formed of non-polymeric components. These particulate drug delivery vehicles can be in the form of powders, microparticles, nanoparticles, microcapsules, liposomes, and the like. Typically, if the active agent is in particulate form without added components, its release rate depends on the release of the active agent itself. In contrast, if the active agent is in particulate form as a blend of the active agent and a polymer, the release of the active agent is controlled, at least in part, by the removal of the polymer, typically by dissolution or biodegradation.

In one embodiment, the compositions can provide an initial rapid release of the active ingredient followed by a sustained release of the active ingredient. U.S. Patent No. 5,629,011 provides examples of this type of composition and is incorporated herein by reference in its entirety. There are numerous transdermal compositions that use transdermal delivery to deliver nicotine in a time-release manner (such as rate-controlling membranes), including currently marketed nicotine replacement therapies. These are also suitable for administering the active compounds herein described. Semi-Solid Dosage Forms

In one embodiment, the transdermal dosage form is not a "patch," but rather, a semisolid dosage form such as a gel, cream, ointment, liquid, etc. In this embodiment, one can augment patient's compliance and cover a broader surface area than can be covered with a patch.

In this embodiment, particularly when used for pain treatment, the dosage form can include other active and inactive components typically seen in semisolid dosage forms used to treat pain. These include, but are not limited to, menthol, wintergreen, capsaicin, aspirin, NSAIDs, narcotic agents (e.g. fentanyl), alcohols, oils such as emu oil, and solvents such as DMSO.

In addition to delivery via transdermal drug delivery devices and semi-solid dosage forms, the active ingredients can also be delivered via iontophoresis. Iontophoresis is a non-invasive method of propelling high concentrations of a charged substance, such as the active ingredients described herein, transdermal^ by repulsive electromotive force. The technique involves using a small electrical charge applied to an iontophoretic chamber containing a similarly charged active agent and its vehicle. The skin's permeability is altered upon application of the charge, and this increases migration of the active ingredient into the epidermis. In use, one or two chambers are filled with a solution containing one or more of the active agents and a solvent (the "vehicle"). The positively charged chamber ("the anode") will repel a positively charged chemical into the skin. The negatively charged chamber ("the cathode"), will repel a negatively charged chemical into the skin. Because the active ingredients are cationic, they are administered iontophoretically via the anode. Iontophoresis can be used to transdermal^ deliver the active agents, using active transportation within an electric field, typically by electromigration and electroosmosis. These movements are typically measured in units of chemical flux, commonly μmol/cm²*h.

The isoelectric point of the skin is approximately 4. Under physiological conditions, where the surface of the skin is buffered at or near 7.4, the membrane has a net negative charge, and electroosmotic flow is from anode (-) to cathode (+). Electroosmosis augments the anodic delivery of the (positively charged) active agents described herein.

There are a number of factors that influence iontophoretic transport, including skin pH, the concentration and characteristics of the active agent, ionic competition, molecular size, current, voltage, time applied and skin resistance. The current density of the treatment electrode is perhaps the most important variable, relative to the degree of ion transfer. Comparable iontophoretic doses delivered at low currents over longer periods are more effective than those delivered by high currents over short periods.

Iontophoresis devices include two electrodes, which are typically attached to a patient, each connected via a wire to a microprocessor controlled electrical instrument. The active agents are placed under one or both of the electrodes, and are delivered into the body as the instrument is activated. The instrument is typically designed to regulate both current flow and application time. Examples of such instruments are described in U.S. Patent Nos. 5,254,081, and 5,431,625, the contents of which are hereby incorporated by reference. Power for these devices is usually provided by DC batteries, which when providing power for the microprocessor controlled circuitry allow application of a voltage to the electrodes to create a regulated current flow.

Wearable iontophoretic systems have been developed in which the electrical circuitry and power supplied are integrated into a single patch. These systems are advantageous in that they do not have external wires, and they are much smaller in size. Examples of such systems can be found in U.S. Patent Nos. 5,358,483; 5,458,569; 5,466,217; 5,605,536; and 5,651 ,768, the contents of which are hereby incorporated by reference. Typically, ions are delivered into the body from an aqueous drug reservoir contained in the iontophoretic device, and counter ions of opposite charge are delivered from a "counter reservoir." Solutions containing the active ingredient, and also solutions of the counter ions, can be stored remotely and introduced to an absorbent layer of the iontophoresis electrode at the time of use. Examples of such systems are described in U.S. Pat. Nos. 5,087,241 ; 5,087,242; 5,846,217; and 6,421,561, the contents of which are hereby incorporated by reference. Alternatively, as described in U.S. Patent No. 5,685,837, herein incorporated by reference, the active agents can be pre-packaged in dry form into the electrode(s). This approach requires a moisture activation step at the time of use.

Solutions of the active agents can be co-packaged with the iontophoretic device, ideally positioned apart from the electrodes and other metallic components until the time of use. This technique, and suitable devices, are described, for example, in U.S. Patent Nos. 5,158,537; 5,288,289; 5,310,404; 5,320,598; 5,385,543; 5,645,527; 5,730,716; and 6,223,075, each of which is incorporated by reference. In these devices, a co-packaged electrolyte constituent liquid is stored remotely from the electrodes, in a rupturable container and a mechanical action step at the time of use induces a fluid transfer to a receiving reservoir adjacent to the electrodes. These systems enable precise fluid volumes to be incorporated at the time of manufacture to avoid overfilling.

In addition to solutions, the active agents can be present in a pre-formed gel, as described in U.S. Patent No. 4,383,529, incorporated by reference. Thus, a preformed gel containing the active agent can be transferred into an electrode receptacle at the time of use. This system can be advantageous in that it provides a precise pre-determined volume of the gel, thus preventing over-filling. Further, since the active agent is present in a gel composition, it is less likely to leak during storage or transfer.

Although it is possible to administer the compounds in the form of a bulk active chemical, it is preferred to present each compound in the form of a pharmaceutical composition or formulation for efficient and effective administration.

Exemplary methods for administering such compounds will be apparent to the skilled artisan. The usefulness of these formulations may depend on the particular composition used and the particular subject receiving the treatment. For example, the compositions can be administered in the form of a tablet, a hard gelatin capsule or as a time release capsule. These formulations may contain a liquid carrier that may be oily, aqueous, emulsified or contain certain solvents suitable to the mode of administration.

The administration of the pharmaceutical compositions described herein can be intermittent, or at a gradual, continuous, constant or controlled rate to a warmblooded animal, for example, a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey; but advantageously is administered to a human being. In addition, the time of day and the number of times per day that the pharmaceutical composition is administered can vary.

The appropriate dose of the compound is that amount effective to prevent occurrence of the symptoms of the disorder or to treat some symptoms of the disorder from which the patient suffers. By "effective amount", "therapeutic amount," or "effective dose" is meant that amount sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in effective prevention or treatment of the disorder. Thus, when treating a CNS disorder, an effective amount of compound is an amount sufficient to pass across the blood-brain barrier of the subject, to bind to relevant receptor sites in the brain of the subject, and to modulate the activity of relevant nicotinic receptor subtypes, namely modulate neurotransmitter secretion, thus resulting in effective prevention or treatment of the disorder. As noted herein, prevention of the disorder may be manifested by delaying the onset of the symptoms of the disorder and treatment of the disorder may be manifested by a decrease in the symptoms associated with the disorder or an amelioration of the reoccurrence of the symptoms of the disorder.

The effective dose can vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered. For human patients, the effective dose of typical compounds generally requires administering the compound in an amount sufficient to modulate disease-relevant receptors to affect neurotransmitter (e.g., dopamine) release but the amount should be insufficient to induce effects on skeletal muscles and ganglia to any significant degree. The effective dose of compounds will of course differ from patient to patient but in general includes amounts starting where CNS effects or other desired therapeutic effects occur, but below the amount where muscular and ganglionic effects are observed.

Typically, to be administered in an effective dose, compounds require administering in an amount of less than 5 mg/kg of patient weight. Often, the compounds may be administered in an amount from less than about 1 mg/kg patient weight to less than about 100 μg/kg of patient weight, and occasionally between about 10 μg/kg to less than 100 μg/kg of patient weight. The foregoing effective doses typically represent that amount administered as a single dose, or as one or more doses administered over a 24 hours period. For human patients, the effective dose of the compounds may require administering the compound in an amount of at least about 1 , but not more than about 1000, and often not more than about 500 mg/ 24 hr/ patient.

The present invention also encompasses combination therapy for treating or preventing a disorder mediated by a NNR or nAChR in a subject. The combination therapy comprises administering to the subject a therapeutically or prophylactically effective amount of a compound of the present invention and one or more other therapy including chemotherapy, radiation therapy, gene therapy, or immunotherapy.

In an embodiment of the present invention and as will be appreciated by those skilled in the art, the compounds of the present invention may be administered in combination with other therapeutic compounds. For example, a compound of this invention can be used in combination with other NNR ligands (such as varenicline), antioxidants (such as free radical scavenging agents), antibacterial agents (such as penicillin antibiotics), antiviral agents (such as nucleoside analogs, like zidovudine and acyclovir), anticoagulants (such as warfarin), anti-inflammatory agents (such as NSAIDs), anti-pyretics, analgesics, anesthetics (such as used in surgery), acetylcholinesterase inhibitors (such as donepezil and galantamine), antipsychotics (such as haloperidol, clozapine, olanzapine, and quetiapine), immuno-suppressants (such as cyclosporin and methotrexate), neuroprotective agents, steroids (such as steroid hormones), corticosteroids (such as dexamethasone, predisone, and hydrocortisone), vitamins, minerals, nutraceuticals, anti-depressants (such as imipramine, fluoxetine, paroxetine, escitalopram, sertraline, venlafaxine, and duloxetine), anxiolytics (such as alprazolam and buspirone), anticonvulsants (such as phenytoin and gabapentin), vasodilators (such as prazosin and sildenafil), mood stabilizers (such as valproate and aripiprazole), anti-cancer drugs (such as antiproliferatives), antihypertensive agents (such as atenolol, clonidine, amlopidine, verapamil, and olmesartan), laxatives, stool softeners, diuretics (such as furosemide), anti-spasmotics (such as dicyclomine), anti-dyskinetic agents, and antiulcer medications (such as esomeprazole).

In the treatment of pain in particular, the compounds of the present invention may be administered in combination with other compounds known to provide relief from pain. Such compounds include opioids (such as morphine), NSAIDs (such as aspirin or ibuprofen), and anticonvulsants (such as gabapentin and pregabalin). The compounds of the present invention may be employed alone or in combination with other therapeutic agents, including other compounds of the present invention. Such a combination of pharmaceutically active agents may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order. The amounts of the compounds or agents and the relative timings of administration will be selected in order to achieve the desired therapeutic effect. The administration in combination of a compound of the formulae of the present invention including salts or solvates thereof with other treatment agents may be in combination by administration concomitantly in: (1) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time. The compounds of the present invention may be used in the treatment of a variety of disorders and conditions and, as such, the compounds of the present invention may be used in combination with a variety of other suitable therapeutic agents useful in the treatment or prophylaxis of those disorders or conditions.

The following examples are provided to illustrate the present invention, and should not be construed as limiting thereof. In these examples, all parts and percentages are by weight, unless otherwise noted.

List of Abbreviations

The following definitions for abbreviations used herein are meant to clarify, but not limit, the terms defined. If a particular abbreviation used herein is not specifically defined, the abbreviation term should not be considered indefinite. Rather, abbreviations are used within their accepted meanings in the art.

THF (tetrahydrofuran) DMF (dimethylformamide)

NMR (nuclear magnetic resonance)

DMSO (dimethylsulfoxide)

MTBE (methyl tert-butyl ether)

TFA (trifluoroacetic acid) HPLC (high performance liquid chromatography) V. Examples

Example 1: Scalable Synthesis of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine and formation of the hemi-galactarate salt

(2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine hemi- galactarate can be produced according to the following techniques. (2S)-N-Methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine

The synthesis of (2S)-N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine is described in US Patent Application 11/270,018 (Publication No. 2006/0122237), herein incorporated by reference. 3-Bromo-5-methoxypyridine

Sodium methoxide (124 g, 2.30 mol), 3,5-dibromopyridine (300 g, 1.26 mol) and a mixture of DMF and methanol (1200 ml_, 4:1) were added to a 2-L 3-neck flask fitted with a reflux condenser and under a nitrogen atmosphere. The resulting suspension was heated (8O⁰C external temperature) for 1.5 h. The dark solution was cooled to ambient temperature, and the resulting suspension was poured into water (600 ml_) and extracted with di-isopropyl ether (4 x 600 ml_). The combined organic phases were washed with saturated aqueous sodium chloride (500 ml_), dried (anhydrous sodium sulfate), filtered, and concentrated by rotary evaporation to give 3-bromo-5-methoxoxypyridine (187 g, 79.4% yield) of suitable purity for use in the synthesis of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine hemi-galactarate.

(2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine hemi- galactarate

A 20-L glass reaction flask was equipped with a mechanical stirrer, temperature probe and condenser, and the flask was placed under as inert atmosphere. 3-Bromo-5-methoxypyridine (1.50 kg, 8.00 mol) and (3.45 kg) of toluene were added to the flask. To the stirring mixture, palladium(ll) acetate (19.2 g, 0.0855 mol), triphenylphosphine (44.7 g, 0.170 mol), potassium carbonate (1.40, 10.1 mol), and (2S)-N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.68 kg, factored for purity, 8.43 mol) was added. The temperature of the reaction was gradually increased (in 10°C increments) to 110⁰C ± 5⁰C. The reaction was stirred for 16 h, maintaining the temperature at 115⁰C ± 5°C, at which time the reaction appeared to be complete by thin layer chromatographic analysis.

After cooling the reaction to 40 ± 4⁰C, activated carbon (165 g) was added and the mixture was stirred for about 1 h, maintaining the temperature at 40 ± 5°C. The contents of the reaction flask were then filtered through a cake of diatomaceous earth (250 g) in a Bϋchner funnel, into a 20-L Bϋchner flask. The reaction vessel and the filter cake were rinsed with ethyl acetate (1.80 kg), and the filter cake was washed with an additional portion (1.80 kg) of ethyl acetate. The contents of the Bϋchner flask were transferred to a clean, dry 20-L glass reaction flask equipped with a mechanical stirrer, temperature probe, condenser, and under an inert atmosphere. The temperature of the mixture was increased to 40°C ± 5°C and maintained at that temperature as thiol-functionalized silica gel (540 g) was added. The resulting mixture was stirred for 6 h and filtered through a cake of diatomaceous earth (250 g) in a Bϋchner funnel into a 20-L Bϋchner flask. The reaction vessel and the filter cake were rinsed with ethyl acetate (1.0 L), and the filter cake was washed with an additional portion (1.0 kg) of ethyl acetate. The contents of the Bϋchner flask were transferred to a dry rotary evaporator flask and concentrated to constant volume, using a bath temperature of 40⁰C ± 5°C. The residue was dissolved in toluene (2.00 kg) in the rotary evaporator flask, and the mixture was concentrated to constant volume, again using a bath temperature of 40⁰C ± 5°C.

The contents of the rotary evaporator flask were dissolved in methanol (790 g), by rotation of the flask for about 0.5 h, and transferred to a 20-L glass reaction flask equipped with a mechanical stirrer, temperature probe, condenser and inert atmosphere. As this solution was stirred and cooled in an ice bath, it was treated with a solution made by combining concentrated aqueous hydrochloric acid (2.0 kg) and water (2.0 L). This addition took about 2 h. The ice bath was then removed, and the contents of the reaction flask were stirred for 5 h at 24°C ± 4⁰C, at which time thin layer chromatographic analysis indicated that the reaction was complete. The contents of the reaction flask were transferred to a clean, dry 20-L rotary evaporator flask and concentrated at 35⁰C ± 5°C. The remaining aqueous solution was transferred to a 20-L glass reaction flask, equipped with a mechanical stirrer, temperature probe, condenser and inert atmosphere. The solution was washed twice with portions of dichloromethane (1.0 L each) by adding the dichloromethane, stirring for about 10 min, separating the layers, and discarding the dichloromethane layer. Dichloromethane (5.0 L) was again added to the aqueous layer, and the stirred mixture was cooled (initially to <10°C and maintained at <15°C) as aqueous sodium hydroxide solution (made by dissolving 2.0 kg of sodium hydroxide in 15.0 L of water), sufficient to adjust the pH to 13 ± 0.5, was added. The reaction mixture was stirred for an additional 10 min, and the organic layer was separated and placed in a clean, dry 20-L reaction flask. The aqueous layer was extracted with an additional portion of dichloromethane (5.0 L), and the two organic layers were combined and washed with saturated aqueous sodium chloride solution (2.0 L) by stirring the mixture for about 10 min. The organic layer was then transferred to a clean, dry 20-L rotary evaporator flask and concentrated the under vacuum at 4O⁰C ± 15°C to obtain (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine as an oil (1.40 kg; 0.92 kg when adjusted for purity, 56% yield).

A clean 20-L glass reaction flask was equipped with a mechanical stirrer and condenser and charged with (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten- 2-amine from the previous step (0.92 kg, 4.5 mol), using 2-propanol (-100 mL) to aid in the transfer. An additional 9.22 L of 2-propanol was then added to the flask, followed by mucic (galactaric) acid (521 g, 2.48 mol) and water (1.17 L). The temperature was gradually increased (in 10⁰C increments) to 8O⁰C ± 1O⁰C with stirring. The reaction mixture was heated at 8O⁰C ± 10⁰C for about 30 min and filtered under vacuum into a 20-L Bϋchner flask. The hot contents of the Bϋchner flask were transferred into a clean, dry 20-L glass reaction flask and were stirred as the flask was allowed to cool to ambient temperature (25°C ± 2⁰C). Further cooling of the slurry to 5⁰C ± 2⁰C for 5 h, followed vacuum filtration of the slurry through a Bϋchner funnel into a 20-L Bϋchner flask, provided the crude salt. Cold 2-propanol (2.0 L) was used to rinse the flask with and wash the filter cake. After being maintaining under vacuum on the Bϋchner funnel for 0.5 h, the filter cake was again rinsed with 2-propanol (2.0 L). After another 0.5 h under vacuum on the Bϋchner funnel, the filter cake was placed under high vacuum at 4O⁰C ± 1O⁰C for 16 h, leaving 1.16 kg of salt (83% yield).

The salt was recrystallized in a 20-L glass reaction flask, equipped with a mechanical stirrer and inert atmosphere, using 2-propanol (6.58 L) and water (484 mL). The mixture was stirred and heated to about 80⁰C, and this temperature was maintained for about 30 minutes, to obtain a clear solution. The hot solution was filtered under vacuum into a 20-L Bϋchner flask, and the still hot filtrate was transferred into a clean, dry 20-L flask. The contents of the flask were stirred as the flask was cooled to ambient temperature (25⁰C ± 2⁰C). The slurry was further cooled at 5⁰C ± 2°C for 5 h and vacuum filtered through a Bϋchner funnel into a 20-L Bϋchner flask. The flask and filter cake were rinsed with cold 2-propanol (2.0 L). After maintaining the vacuum on the filter cake in the Bϋchner funnel for 0.5 h, the filter cake was rinsed with an additional portion of 2-propanol (2.0 L). After another 0.5 h under vacuum on the Bϋchner funnel, the filter cake was placed under high vacuum at 4O⁰C ± 10⁰C for 16 h, leaving 835 g of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine hemi-galactarate (72% recovery; 97.3% purity by HPLC analysis).

Various batches of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2- amine hemi-galactarate have been produced using the above and similar procedures. In every case, the stoichiometry of the salt was confirmed by NMR. MP 137-140°C. ¹H NMR (D₂O, 300 MHz): 5 8.14 (s, 1H), 8.11 (d, 1H), 7.43 (t, 1H), 6.61 (d, 1H), 6.36 (m, 1H), 4.28 (s, 1H, galactaric acid), 3.96 (s, 1H, galactaric acid), 3.90 (s, 3H), 3.44 (m, 1H), 2.76 (s, 3H), 2.65 (m, 2H), 1.38 (d, 3H). ¹H NMR (d₆-DMSO, 400 MHz): δ 8.20 (d, 1H), 8.14 (d, 1H), 7.46 (t, 1H), 6.52 (d, 1 H), 6.44 (m, 1H), 3.88 (s, 1H, galactaric acid), 3.84 (s, 3H), 3.60 (s, 1H, galactaric acid), 3.05 (m, 1H), 2.56 (m, 1H), 2.49 (d, 3H), 2.36 (m, 1H), 1.17 (d, 3H) (Note: the exchangeable hydrogen nuclei appear as a broad resonance, δ 2.5-5.0). MS (m/z): 207 (M+1).

The XRPD diffractogram of the hemi-galactarate salt is shown in Figure 1.

Example 2: Instrumentation and experimental protocols for characterization of salt forms of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine

X-Rav Powder Diffraction (XRPD)

X-Ray Powder Diffraction patterns were collected either or both of two instruments. Some were collected on a Siemens D5000 diffractometer using CuKa radiation (4OkV, 40mA), θ-θ goniometer, V20 divergence and receiving slits, a graphite secondary monochromator and a scintillation counter. The instrument was performance checked using a certified Corundum standard (NIST 1976). Samples run under ambient conditions were prepared as flat plate specimens using powder as received. Approximately 35 mg of the sample was gently packed into a cavity cut into polished, zero-background (510) silicon wafer. The sample was rotated in its own plane during analysis, scanning from 2° to 42° in steps of 0.05° at 4 seconds per step, using CuKcrt (λ = 1.5406A).

Some X-Ray Powder Diffraction patterns were collected on a Bruker AXS C2 GADDS diffractometer using CuKa radiation (4OkV, 4OmA), automated XYZ stage, laser video microscope for auto-sample positioning and a HiStar 2-dimensional area detector. X-ray optics consists of a single Gδbel multilayer mirror coupled with a pinhole collimator of 0.3mm. The beam divergence (i.e. the effective size of the X- ray beam on the sample) was approximately 4 mm. A θ-θ continuous scan mode was employed with a sample - detector distance of 20 cm which gives an effective 2Θ range of 3.2° - 30.0°. Typically the sample would be exposed to the X-ray beam for 120 seconds. Samples run under ambient conditions were prepared as flat plate specimens using powder as received without grinding. Approximately 1-2 mg of the sample was lightly pressed on a silicon wafer to obtain a flat surface. Samples run under non-ambient conditions were mounted on a silicon wafer with heat-conducting compound. The sample was then heated to the appropriate temperature at ca. 10°C/min and subsequently held isothermally for about 5 min before data collection was initiated.

Nuclear Magnetic Resonance (NMR) Spectrometry

NMR spectra were collected on one or more of three instruments: a Varian Unity 300 MHz, a Bruker 400 MHz equipped with an auto-sampler, and a Varian INOVA 500 MHz. Differential Scanning Calorimetrv (DSC)

DSC data were collected on a TA Instruments Q1000 equipped with a 50 position auto-sampler. The instrument was calibrated for energy and temperature calibration using certified indium. Typically 0.5-1.5 mg of each sample, in a pin- holed aluminum pan, was heated at 10°C/min from 25⁰C to 175-200⁰C. A nitrogen purge at 30 ml_/min was maintained over the sample. Thermo-Gravimetric Analysis (TGA)

TGA data were collected on a TA Instruments Q500 TGA, equipped with a 16 position auto-sampler. The instrument was temperature calibrated using certified Alumel. Typically 5-10 mg of each sample was loaded onto a pre-tared platinum crucible and aluminum DSC pan, and was heated at 10°C/min from ambient temperature to 35O⁰C. A nitrogen purge at 60 mL/min was maintained over the sample. Polarized Light Microscopy (PLM)

Samples were studied on a Leica LM/DM polarized light microscope with a digital video camera for image capture. A small amount of each sample was placed on a glass slide, mounted in immersion oil and covered with a glass slip, the individual particles being separated as well as possible. The sample was viewed with appropriate magnification and partially polarized light, coupled to a λ false-color filter. Hot Stage Microscopy (HSM)

Hot Stage Microscopy was carried out using a Leica LM/DM polarized light microscope combined with a Mettler-Toledo MTFP82HT hot-stage and a digital video camera for image capture. A small amount of each sample was placed onto a glass slide with individual particles separated as well as possible. The sample was viewed with appropriate magnification and partially polarized light, coupled to a λ false-color filter, whilst being heated from ambient temperature typically at 10°C/min. Melting Point

A Fisher-Johns hot stage melting point apparatus was used, at a setting corresponding to a heating rate of about 5°C per min. Gravimetric Vapor Sorption (GVS)

Sorption isotherms were determined on either or both of two instruments. Some were experiments were run using a VTI Corporation SGA-100 moisture sorption analyzer, controlled by VTI FlowSystem 4 software. The sample temperature was maintained at 25°C with the aid of a Polyscience constant temperature bath. The humidity was controlled by mixing streams of dry and wet nitrogen. The weight change as a function of %RH was monitored using a Cahn Digital Recording Balance D-200 with an accuracy of +/-0.0001 g.

Typically a 10-20 mg sample was placed on the tared balance pan under ambient conditions. The sample was dried at 50⁰C for 1 h. The standard adsorption isotherm was performed at 25°C at 5% RH intervals over a 5-95% RH range, and the desorption isotherm was similarly done at 25°C at 5% RH intervals over a 95-5% RH range. Sample equilibration criteria included 0.0100 wt% in 5 min or a maximum equilibration time of 180 min for each %RH data point. Some sorption isotherms were obtained using a Hiden IGASorp moisture sorption analyser, controlled by CFRSorp software. The sample temperature was maintained at 25°C by a Huber re-circulating water bath. The humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 250 mL/min. The relative humidity was measured by a calibrated Vaisala RH probe (dynamic range of 0-95% RH), located near the sample. The weight change, (mass relaxation) of the sample as a function of % RH was constantly monitored by the microbalance (accuracy ±0.001 mg). Typically 10-20 mg of sample was placed in a tared mesh stainless steel basket under ambient conditions. The sample was loaded and unloaded at 40% RH and 25⁰C (typical ambient conditions). A moisture sorption isotherm was performed as outlined below (2 scans giving 1 complete cycle). The standard isotherm was performed at 25⁰C at 10% RH intervals over a 0- 90% RH range.

GVS Generic method parameters

The software uses a least squares minimization procedure together with a model of the mass relaxation, to predict an asymptotic value. The measured mass relaxation value must be within 5% of that predicted by the software, before the next % RH value is selected. The minimum equilibration time was set to 1 h and the maximum to 4 h. Typically, samples were recovered after completion of the isotherm and re-analyzed by XRPD. Water Determination by Karl Fischer (KF)

The water content of each sample was measured on a Mettler Toledo DL39 Coulometer using Hydranal Coulomat AG reagent and an argon purge. Weighed solid samples were introduced into the vessel on a platinum TGA pan which was connected to a subaseal to avoid water ingress. Approx 10 mg of sample was used per titration and duplicate determination were made. Thermodynamic Aqueous Solubility bv HPLC

Aqueous solubility was determined by suspending sufficient compound in 0.25 ml_ of water to give a maximum final concentration of ≥10 mg/mLof the parent free-form of the compound. The suspension was equilibrated at 25°C for 24 h, and then the pH was measured. The suspension was then filtered through a glass fiber C filter into a 96 well plate. The filtrate was then diluted by a factor of 101. Quantitation was by HPLC with reference to a standard solution of approximately 0.1 mg/mL in DMSO. Different volumes of the standard, diluted and undiluted sample solutions were injected. The solubility was calculated using the peak areas determined by integration of the peak found at the same retention time as the principal peak in the standard injection. If there was sufficient solid in the filter plate, the XRPD was collected.

Generic method details for thermodynamic aqueous solubility method

Chemical Puritv bv HPLC

Purity analysis was performed on an Agilent HP1100 series system equipped with a diode array detector and using ChemStation software v9. One of the two methods detailed below was used. Method 1

Method 2

Ion Chromatography

Data were collected on a Metrohm 861 Advanced Compact IC using IC Net software v2.3. Samples were prepared as 1000 ppm stocks in water. Where sample solubility was low, a suitable co-solvent such as DMSO was used. Samples were diluted to 50 ppm or 100 ppm with an appropriate solvent prior to testing. Quantification was achieved by comparison with standard solutions of known concentration of the ion being analyzed.

Ion Chromatography method for anions

Liquid Chromatography / Mass Spectrometry (LCMS)

The liquid chromatography separation was performed using a Waters 2695 Separations Module System with a Waters 2996 Photodiode Array Detector. The positive ion electrospray mass spectrum was obtained using a Waters Micromass ZQ spectrometer fitted with an electrospray source.

Generic method details for LCMS analysis

Example 3: Screen for 1:1 acid addition salts of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2 -amine

To a stirred mixture of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4- penten-2-amine hemi-galactarate (2.00 g, 6.43 mmol), water (6 mL) and dichloromethane (8 mL) was added 6 M aqueous sodium hydroxide (8.0 mL, 48 mmol). This mixture was vigorously stirred for 1 h at ambient temperature. The organic phase was washed with water and dried over anhydrous magnesium sulphate. Filtration and evaporation (rotary followed by high vacuum) of the solvent left 1.28 g (97% yield) (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2- amine free base as a colorless oil, 98.4% pure by HPLC analysis. This process was repeated with a second 2 g sample of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]- 4-penten-2-amine hemi-galactarate to yield 1.18 g (89% yield) of (2S)-(4E)-N-methyl- 5-[3-(5-methoxypyridin)yl]-4-penten-2-amine free base. These free base samples were used without further purification in the subsequent salt screens.

Samples of the free base oil were dissolved in each of three solvents (methanol, isopropyl acetate, and dichloromethane) at a concentration of 25 mg/mL. Vials were cooled to 1O⁰C and portions of free base solution equivalent to 30 mg (0.15 mmol) were dispensed into the vials. Various carboxylic acids (1.1 equivalents, 0.165 mmol) were added as either solids or stock solutions. The stock solutions used were either 1.0 M or 0.50 M in THF or THF/water, with the exception of pamoic acid, which was 0.30 M in DMSO. The vials were then capped and the contents stirred at 800 rpm for 2 h. During this time, the reactions in methanol and isopropyl acetate were maintained at 50⁰C, and the samples in dichloromethane were maintained at ambient temperature. After the 2 h period, the reactions in methanol and isopropyl acetate were cooled from 50⁰C to 25°C at a rate of 0.4°C/h.

Observations were made, and all samples were cooled to 4⁰C over the next 4 h and stirred at 4°C for a further 2 h.

The initial results were recorded, and samples were split into three groups: 1 ) clear solutions were stored in the freezer overnight then allowed to evaporate at ambient temperature; 2) oils and gums were maturated in a heat/cool cycle at 50°C/ambient with shaking; 3) solids were filtered, dried in a vacuum oven, and characterized.

Any samples that did not yield solids were then vacuum concentrated at 25⁰C to obtain a solvent-free residue. These residues were then dissolved in a new solvent at temperature (50⁰C) and cooled to ambient temperature overnight and then maintained at 4°C for several hours. Again, the samples were split into three groups and treated as above. This process was carried out with the following solvents: acetone, isopropanol, acetonitrile, a 60/40 toluene/methanol mixture, water, methyl ethyl ketone and methanol with methyl tert-butyl ether (MTBE) added as an anti- solvent.

The following acids were screened, using the above procedures for forming 1 :1 salts: hydrochloric acid, sulfuric acid, L-aspartic acid, maleic acid, phosphoric acid, L-glutamic acid, pamoic acid, xinafoic acid (1-hydroxy-2-naphthoic acid), α- ketoglutaric acid, galactaric (mucic) acid, L-tartaric acid, fumaric acid, citric acid, D- glucuronic acid, L-malic acid, hippuric acid, D-gluconic acid, L-lactic acid, oleic acid (9Z-octadecenoic acid), L-ascorbic acid, benzoic acid, p-hydroxybenzoic acid, succinic acid, adipic acid, acetic acid, propionic acid, stearic acid (octadecanoic acid), malonic acid, lactobionic acid, D-glucoheptonic acid, (+)-camphoric acid, caprylic acid (octanoic acid) and orotic acid (uracil-6-carboxylic acid). In this experiment, the following salts were found to be solids: hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, pamoic acid, xinafoic acid (1- hydroxy-2-naphthoic acid), galactaric (mucic) acid, L-tartaric acid, hippuric acid, fumaric acid, citric acid, D-glucuronic acid, L-malic acid, D-gluconic acid, L-ascorbic acid, p-hydroxybenzoic acid, stearic acid (octadecanoic acid), lactobionic acid and orotic acid (uracil-6-carboxylic acid). These salts were analyzed using instrumentation and techniques described in example 2. In this experiment, the following salts were found to be crystalline solids: hydrochloric acid, maleic acid, phosphoric acid, pamoic acid, xinafoic acid, fumaric acid, galactaric (mucic) acid, p-hydroxybenzoic acid, stearic acid and orotic acid. Further characterization of these salts is reported in the examples which follow (see examples 5-14).

Example 4: Screen for "hemi" acid addition salts of (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine

A stock solution of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2- amine free base was prepared in acetone at a concentration of 25 mg/mL. Vials were cooled to 10⁰C and portions of free base solution equivalent to 40 mg (0.19 mmol) were dispensed into the vials. Various carboxylic acids (0.6 equivalents, 0.11 mmol) were added as either solids or stock solutions. The vials were then capped and the contents stirred at 800 rpm for 2 h at 50⁰C. After the 2 h period, the reactions were cooled from 5O⁰C to 25⁰C at a rate of 0.4°C/h. Observations were made, and all samples were cooled to 4°C over the next 4 h and stirred at 4°C for a further 2 h.

Any samples that did not yield solids were then vacuum concentrated at 25⁰C to obtain a solvent-free residue. These residues were then dissolved in ethyl acetate at temperature (5O⁰C) and cooled to ambient temperature overnight and then maintained at 4°C for several hours.

The following acids were screened, using the above procedures for forming "hemi" salts: sulfuric acid, L-aspartic acid, maleic acid, phosphoric acid, L-glutamic acid, pamoic acid, xinafoic acid (1-hydroxy-2-naphthoic acid), α-ketoglutaric acid, L- tartaric acid, fumaric acid, citric acid, L-malic acid, L-ascorbic acid, succinic acid, adipic acid, malonic acid, lactobionic acid, D-glucoheptonic acid, (+)-camphoric acid, caprylic acid (octanoic acid) and orotic acid (uracil-6-carboxylic acid).

In this experiment, the following salts were found to be solids: sulfuric acid, phosphoric acid, L-tartaric acid, fumaric acid and citric acid. In this experiment, all of these salts appeared to be amorphous, and none was investigated further. Example 5: (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate

Solid phosphate salts were obtained according to the 1 :1 salt screening procedure, from acetone, isopropanol, acetonitrile or methyl ethyl ketone by evaporation. Ion chromatography established the 1 :1 stoichiometry of these salts. The XRPD diffractograms of these salts are shown in Figure 2.

The following procedure is representative larger scale preparation of the salt. (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine (5.13 g, 24.9 mmol) was dissolved in ethyl acetate (80 mL) in a 250-mL round bottom. The solution was warmed to 45-5O⁰C, and to the stirred, warm solution was added phosphoric acid (1.69 mL of 85%, 24.9 mmol), drop-wise, over a 10 min period. Almost immediately a mixture of granular solids and glassy masses formed. The mixture was heated to near boiling, and absolute ethanol (30 mL) was added over a 10 min period (the addition of ethanol hastened granular solid formation). The mixture was stirred and heated for an additional 15 min and then cooled to ambient temperature and stirred overnight. The solids were collected by suction filtration, and the filter cake was washed with ethyl acetate (20 mL) and air dried for 30 min. Further drying, in a vacuum oven at 7O⁰C for 2 h, afforded 7.50 g (99%) of fine white powder with a melting point of 150-152⁰C. Elemental analyses established the 1:1 stoichiometry of the (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate salt. Elemental analysis: Calc'd for C₁₂H₁₈N₂O H₃PO₄ (C, 47.37%; H, 6.96%; N, 9.21%); Found (C, 47.38%, 47.29%; H, 7.05%, 6.96%; N, 9.16%, 9.26%). ¹H NMR (D₂O, 300 MHz): δ 8.00 (s, 1H), 7.96 (d, 1H), 7.33 (t, 1H), 6.46 (d, 1H), 6.22 (m, 1H), 3.74 (s, 3H), 3.28 (m, 1H), 2.58 (s, 3H), 2.49 (m, 2H), 1.20 (d, 3H). ¹H NMR (d₆-DMSO, 500 MHz): δ 8.18 (d, 1H, J=1.5 Hz), 8.12 (d, 1H, J=2.8 Hz), 7.47 (m, 1H), 6.51 (d, 1H, J=16 Hz), 6.47 (dt, 1 H, J=16, 6.5 Hz), 3.84 (s, 3H), 3.05 (m, 1H), 2.62 (m, 1H), 2.46 (s, 3H), 2.39 (m, 1H), 1.20 (d, 3H, J=6.5 Hz) (Note: the exchangeable hydrogen nuclei appear as a very broad resonance, δ 7.5-9.0). ¹³C NMR (d₆-DMSO, 500 MHz, proton decoupled): δ 155.5, 140.1, 136.5, 133.3, 129.1 , 128.5, 116.2, 55.5, 53.3, 36.3, 30.0, 15.9. MS (m/z): 207 (M+1), 176, 150. The XRPD diffractogram of this salt is shown in Figure 3. This crystalline form was designated Form 1.

Example 6: (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine maleate Solid maleate salts were obtained according to the 1:1 salt screening procedure, by precipitation from isopropyl acetate, and from acetone or methyl ethyl ketone by evaporation. The XRPD diffractogram of the salt, as precipitated from isopropyl acetate, is shown in Figure 4.

The following procedure was used to make a larger quantity of the salt. A solution of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine (166 mg, 0.804 mmol) in isopropyl acetate (7 ml_) was warmed to 5O⁰C, and maleic acid (8.8 ml of 1 M solution in THF, 0.880 mmol) was added. The mixture was stirred at 50⁰C for 4 h, cooled to ambient overnight, cooled in the refrigerator for 6 h, and then cooled in a freezer overnight. The sample then consisted of a white precipitate and a yellow gum. The sample was warmed to 5O⁰C and additional isopropyl acetate (4 ml_) was added in an attempt to dissolve the gum. The gum would not dissolve, so it was broken up and stirred. The sample was allowed to cool back to ambient temperature was stored in the refrigerator and then in the freezer. The sample was then equilibrated at room temperature, and the precipitate was collected by suction filtration. The sample was dried in a vacuum oven at 25⁰C to give an off-white powder. NMR analysis established the 1:1 stoichiometry of the salt. ¹H NMR (d₆- DMSO, 400 MHz): δ 8.22 (d, 1H), 8.17 (d, 1H)₁ 7.45 (t, 1H), 6.56 (d, 1H), 6.41 (m, 1H), 6.01 (s, 2H, maleic acid), 3.85 (s, 3H), 3.29 (m, 1 H), 2.61 (m, 1H), 2.50 (d, 3H), 2.43 (m, 1H), 1.23 (d, 3H) (Note: the exchangeable hydrogen nuclei appear as a broad resonance, δ 8.0-8.5).

Example 7: (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine xinafoate (1 -hydroxy-2-naphthoate)

A solid xinafoate salt was obtained according to the 1:1 salt screening procedure, from water by evaporation. The XRPD diffractogram of this salt is shown in Figure 5.

The following procedure is representative larger scale preparation of the salt. A solution of xinafoic acid (266 mg, 1.42 mmol) in ethanol (10 ml_) was added to (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine (250 mg, 1.42 mmol). The reaction mixture was stirred at ambient temperature for 3 h and diluted with ether (7 ml.) before cooling at O⁰C for overnight. No solid separated out. The solvent was evaporated, and the resulting residue was crystallized from 20 mL of methanol-ether (3:7). The solution was cooled at O⁰C for overnight, and the resulting solid was filtered and washed with ether to obtain the salt (0.66 g, 69%) as off-white solid, mp 109-110⁰C. NMR analysis established the 1:1 stoichiometry of the salt. ¹H NMR (CDCI₃, 300 MHz): δ 8.37 (d, 1H, xinafoic acid), 8.06 (s, 1H), 8.05 (s, 1H), 7.87 (d, 1H, xinafoic acid), 8.75 (d, 1H, xinafoic acid), 8.56 (t, 1H, xinafoic acid), 8.47 (t, 1H₁ xinafoic acid), 7.25 (d, 1 H, xinafoic acid), 7.08 (s, 1H), 6.42 (d, 1H), 6.22 (m,

1H), 3.67 (s, 3H), 3.28 (m, 1H), 2.77 (m, 1H), 2.71 (s, 3H), 2.61 (m, 1H), 1.44 (d,

3H). Elemental analysis: Calculated for C₁₂H₁₈N₂O C₁₁H₈O₃ (C, 70.03%; H, 6.64%;

N₁ 7.10%); Found (C, 69.87%, 69.76%; H, 6.74%, 6.63%; N, 7.09%, 7.14%).

Example 8: (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine hydrochloride

The hydrochloride salt was obtained according to the 1 :1 salt screening procedure, by precipitation from acetone or isopropanol. Filtration and vacuum drying gave a hygroscopic solid. ¹H NMR (d₆-DMSO, 400 MHz): δ 8.20 (d, 1H), 8.15

(d, 1H), 7.52 (dd, 1H), 6.56 (d, 1H), 6.47 (m, 1 H), 3.85 (s, 3H), 3.25 (m, 1H), 2.65

(m, 1H), 2.49 (d, 3H), 2.46 (m, 1H), 1.25 (d, 3H) (Note: the exchangeable hydrogen nuclei appear as a broad resonance centered at δ 9.05). The XRPD diffractograms of these salts are shown in Figure 6.

Example 9: (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine orotate (uracil-6-carboxylate)

A solid orotate salt was obtained according to the 1:1 salt screening procedure, by precipitation from isopropyl acetate. NMR analysis established the 2:1 (acid/base) stoichiometry of the salt. The XRPD diffractogram of this salt is shown in

Figure 7.

The following procedure was used to make a larger quantity of the salt.

Orotic acid (415 mg, 2.66 mmol) was added to a solution of (2S)-(4E)-N-methyl-5-[3-

(5-methoxypyridin)yl]-4-penten-2-amine (550 mg, 2.67 mmol) in ethanol (4 mL). An additional 6 mL of ethanol was added as the mixture was heated, at which point all of the orotic acid dissolved. Cooling to ambient temperature, followed by suction filtration and air drying, produced 438 mg (63% yield) of fine white powder, mp 245-

248°C. NMR analysis established that this is a di-orotate salt. ¹H NMR (d₆-DMSO,

400 MHz): δ 8.21 (d, 1H), 8.16 (d, 1H), 7.46 (t, 1H), 6.56 (d, 1H), 6.41 (m, 1H), 5.83 (s, 2H, orotic acid), 3.84 (s, 3H), 3.28 (m, 1 H), 2.65 (m, 1 H), 2.54 (d, 3H), 2.43 (m,

1 H), 1.23 (d, 3H) (Note: the exchangeable hydrogen nuclei appear as broad resonances centered at δ 11.1 , 10.2 and 8.8).

The filtrate was concentrated to give an oily residue, which was re-dissolved in warm mixture of ethyl acetate (3 mL) and ethanol (2 mL). Cooling to ambient temperature, suction filtration and air drying gave 206 mg (21% yield) of beige crystals, mp 133-135°C. NMR analysis established that this is a mono-orotate salt. ¹H NMR (d₆-DMSO, 400 MHz): δ 8.16 (d, 1H)₁ 8.12 (d, 1 H), 7.42 (t, 1H), 6.52 (d, 1H), 6.40 (m, 1H), 5.73 (s, 1 H, orotic acid), 3.80 (s, 3H), 3.27 (m, 1H), 2.60 (m, 1H), 2.55 (d, 3H), 2.42 (m, 1 H), 1.22 (d, 3H) (Note: the exchangeable hydrogen nuclei appear as broad resonances centered at δ 10.9, 9.7, 8.9 and 3.6).

Example 10: (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine pamoate

Solid pamoate salts were obtained according to the 1:1 salt screening procedure, by precipitation from acetone, toluene/methanol or acetonitrile. Filtration and vacuum drying gave a solid. The XRPD diffractogram of these salts are shown in Figure 8. NMR analysis established the 1 :1 stoichiometry of the salt, as precipitated from acetone. ¹H NMR (d₆-DMSO, 400 MHz): δ 8.32 (s, 2H, pamoic acid), 8.23 (d, 1H), 8.19 (d, 1H), 8.16 (d, 2H, pamoic aicd), 7.76 (d, 2H, pamoic acid), 7.45 (t, 1H), 7.24 (m, 2H, pamoic acid), 7.10 (m, 2H, pamoic acid), 6.57 (d, 1 H), 6.41 (m, 1 H), 4.74 (s, 2H, pamoic acid), 3.83 (s, 3H), 3.31 (m, 1 H), 2.67 (m, 1H), 2.62 (s, 3H), 2.45 (m, 1 H), 1.25 (d, 3H) (Note: the exchangeable hydrogen nuclei appear as a broad resonances centered at δ 8.65 and 3.25).

Example 11 : (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine galactarate

A solid galactarate (mucate) salt was obtained according to the 1:1 salt screening procedure, by precipitation from isopropyl acetate. Filtration and vacuum drying gave a solid which had physical and spectral properties characteristic of a mixture of the hemi-galactarate salt, reported in Example 1 , and free galactaric acid. The mixture was not further characterized.

Example 12: (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine fumarate

Solid fumarate salts were obtained according to the 1 :1 salt screening procedure, from either isopropyl acetate, dichloromethane, methanol/MTBE or methyl ethyl ketone, by evaporation. The XRPD diffractogram of the salt, from methanol/MTBE, is shown in Figure 9. Chemical analysis indicated that the sample contained impurities resulting from the Michael addition of the secondary amine of the base to the fumaric acid. Example 13: (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2 -amine stearate

Solid stearate salts were obtained according to the 1:1 salt screening procedure, from acetone or isopropyl acetate, by evaporation. The XRPD diffractogram of the salt, from isopropyl acetate, is shown in Figure 10.

Example 14: (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine p- hydroxybenzoate

Solid p-hydroxybenzoate salts were obtained according to the 1:1 salt screening procedure, from isopropyl acetate, by evaporation and from maturation in acetone. The XRPD diffractogram of the salt, form acetone, is shown in Figure 11.

Example 15: (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine R- mandelate R-(-)-Mandelic acid (14.59 g, 96.0 mmol) was added to a stirring solution of

(2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine (19.82 g, 96.0 mmol) in acetone (90 ml_), producing a mild exotherm (32°C). MTBE (180 mL) was added drop-wise, via addition funnel, to the yellow solution. After -60% of the MTBE was added, the solution was seeded producing an immediate precipitate. Following addition of the remaining MTBE, the mixture was cooled at 5°C for -18 h. The off- white to light beige solids were filtered under a nitrogen atmosphere, washed with MTBE (2 x 25 mL) and vacuum dried at 3O⁰C for -18 h. The yield was 30.39 g of a white to off-white powder. The crude salt was recrystallized by dissolution in acetone (85 mL), assisted by heating to near reflux and the subsequent drop-wise addition of MTBE (170 mL) via addition funnel. After cooling to room temperature and further cooling at 5°C for -18 h, the resulting solids were filtered under a nitrogen atmosphere, washed with MTBE (2 x 25 mL) and vacuum dried at 4O⁰C for -18 h. The yield was 28.87 g (83.8%) of a white powder, mp 85.5-87⁰C. NMR and elemental analyses established the 1:1 stoichiometry of the (2S)-(4E)-N-methyl-5-[3- (5-methoxypyridin)yl]-4-penten-2-amine R-mandelate salt. ¹H NMR (D₂O, 300 MHz): δ 8.03 (s, 1 H), 7.99 (d, 1H), 7.34 (m, 6H, includes 5H from mandelic acid), 6.50 (d, 1H), 6.24 (m, 1H), 4.86 (s, 1H, mandelic acid), 3.77 (s, 3H), 3.31 (m, 1H), 2.61 (s, 3H), 2.50 (m, 2H), 1.24 (d, 3H). MS (m/z): 207 (M+1), 176. Elemental analysis: Calculated for C₁₂H₁₈N₂O C₈H₈O₃ (C, 67.02%; H, 7.31%, N, 7.82%); Found (C, 67.10%, 66.95%; H, 7.36%, 7.33%; N, 7.76%, 7.78%). The XRPD diffractogram of the salt is shown in Figure 12. Example 16: (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2 -amine S- mandelate

S-(+)-Mandelic acid (1.987 g, 5.23 mmol) was added to a stirring solution of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine (0.796 g, 5.23 mmol) in ethyl acetate (12 ml_), producing a light-yellow solution. The solvent was evaporated via rotary evaporation, and the resulting off-white to yellow solid was dried on a vacuum pump at 72°C. This crude salt was dissolved in acetone (4.5 mL), assisted by heating to reflux. The resulting solution was cooled slightly, seeded and MTBE (9 mL) was added drop-wise, via addition funnel, causing precipitation of a white to off-white solid. After cooling to room temperature, the resulting solids were filtered, washed with MTBE (2 x 10 mL), re-slurried in MTBE (20 mL) to remove absorbed moisture, filtered, washed with MTBE (10 mL) and vacuum dried at 4O⁰C for -18 h. The yield was 1.56 g (83.0%) of an off-white to light-beige powder, mp 84.5-85.5⁰C. ¹H NMR (D₂O, 300 MHz): δ 7.96 (s, 1 H), 7.92 (s, 1 H), 7.27 (m, 6H, includes 5H from mandelic acid), 6.44 (d, 1 H), 6.18 (m, 1 H), 4.85 (s, 1 H, mandelic acid), 3.73 (s, 3H), 3.27 (m, 1 H), 2.58 (s, 3H), 2.48 (m, 2H), 1.22 (d, 3H). MS (m/z): 207 (M+1 ), 176. Elemental analysis: Calculated for C₁₂H₁₈N₂O C₈H₈O₃ (C, 67.02%; H, 7.31%, N, 7.82%); Found (C, 66.99%, 66.92%; H, 7.32%, 7.25%; N, 7.84%, 7.83%).

Example 17: (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2 -amine di-oxalate

A warm solution of oxalic acid (0.446 g, 4.96 mmol) in methanol (10 mL) was added to a stirring solution of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4- penten-2-amine (1.024 g, 4.96 mmol) in acetone (10 mL) in an attempt to form the mono-oxalate. Following cooling at 5⁰C, the solution was concentrated by rotary evaporation. The resulting residue was slurried in 2-propanol, concentrated, treated with a second equivalent of oxalic acid (0.446 g, 4.96 mmol) in methanol (3.2 mL). After refluxing this solution and cooling to room temperature, addition of acetone (10 mL) deposited a yellow gum. Following solvent removal, the yellow residue was treated with a 1 :1 mixture of ethanol-THF (10 mL). As crystallization did not occur, this solution was allowed to slowly evaporate producing light-yellow solids. The solids were stirred and slurried in ethyl acetate (10 mL) for ~18 h. The product was filtered, washed with ethyl acetate (2 x 5 mL) and vacuum dried at 40⁰C for 4 h to give 1.40 g (73.3%) of di-oxalate salt (stoichiometry established by elemental analysis) as a fine, off-white powder, mp 118-119.5⁰C. ¹H NMR (D₂O, 300 MHz): δ 8.27 (s, 1 H), 8.21 (d, 1H), 8.00 (s, 1 H), 6.60 (d, 1 H), 6.46 (m, 1 H), 3.89 (s, 3H), 3.35 (m, 1 H), 2.65 (m, 1 H), 2.61 (s, 3H), 2.50 (m, 1 H), 1.22 (d, 3H). Elemental analysis: Calculated for C₁₂H₁₈N₂O 2C₄H₄O₄ (C, 49.74%; H, 5.74%; N, 7.25%); Found (C, 49.87%, 49.77%; H, 5.88%, 5.80%; N, 7.18%, 7.24%).

Example 18: (2S)-(4E)-N-Methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2 -amine di-hydrochloride and di-hydrobromide

The di-hydrochloride salt was obtained by mixing an ethanol solution of the (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine with >2 equivalents of concentrated hydrochloric acid and evaporating to dryness (rotary evaporation, followed by high vacuum treatment). The residue was recrystallized from an ethanol/ether mixture to give a white solid, mp 158-16O⁰C. A di-hydrobromide salt (pale yellow solid, mp 87-89⁰C) was isolated in a similar fashion, using hydrobromic acid.

Example 19: Polymorph screen for (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine phosphate

Maturations of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2- amine phosphate (the crystalline sample reported in Example 5) were carried out as follows. Twenty-four lots (10 mg) of the crystalline material were each treated with a different solvent (200 μL), in an HPLC vial, and the vials were capped and placed in a maturation chamber that cycled from ambient to 5O⁰C, with four hours spent under each condition on each cycle. After three days the samples were filtered and analyzed by XRPD. In order to provide enough material for further characterization, the experiments that showed a new solid form were repeated at a larger scale (100 mg of salt and 2 ml of solvent).

The maturation experiments were repeated, in exactly the same manner, using both an amorphous gummy material and an amorphous solid that had been isolated from various preparations of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]- 4-penten-2-amine phosphate. As before, the experiments that showed new XRPD patterns were scaled up to approximately 100 mg of salt in 2 ml of solvent.

Additional maturation experiments were performed in aqueous solvents. The solvents chosen were at least partially miscible with water, and the water contents were 2-5% by volume, depending on the miscibility. Both the crystalline material and the amorphous gum were used, and samples were maturated under the standard conditions (as described above) for four days.

Three crystalline forms were identified from these experiments. Form 1 was most common. Forms 2 and 3 were seen only in a few 10 mg scale experiments, and in every case the corresponding scaled up experiments gave only Form 1. The XRPD d iff ractog rams for Forms 1 , 2 and 3, as obtained from this experiment, are shown in Figures 13, 14 and 15 respectively.

Form 1 is stable at 4O⁰C and 75% RH for one week (see Figure 16), and is soluble in water at >100 mg/mL It exhibits gain of water at RH values greater than 75%, but this gain of water reversed by lowering the RH.

Example 20 - Allodynia in Streptozotocin-lnduced Model of Diabetic Neuropathy

One complication of diabetes is peripheral neuropathy, which is indicated by spontaneous pain and the perception of pain from a normally non-noxious stimulation. Streptozotocin (STZ) -induced diabetes in rats is a well-documented model in which a chemotherapeutic drug is administered peripherally, causing irreversible damage to the pancreatic β and α cells and inhibiting islet synthesis of proinsulin. The model mimics clinical diabetes and onset of hyperglycemia can be seen in rats within 24 hours. Initial onset of peripheral neuropathy is typically demonstrated in control animals 3-4 weeks following STZ administration. (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate was administered acutely and chronically, just before the test at Week 6. (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate was evaluated for effects on mechanical allodynia, an assessment of pain response to a normally non-noxious stimulus, in the STZ animal model of peripheral neuropathy.

Along with Gabapentin (positive control), acute and chronic administration of (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate was effective in increasing the allodynia threshold in diabetic rats, thereby reducing the pain associated with diabetic neuropathy. (2S)-(4E)-N-methyl-5-(5-methoxy-3- pyridinyl)-4-pentene-2-amine hemigalactarate, a powder, was formulated in deionized water to its highest concentration (1 mg/kg) and then serial dilutions were performed for remaining dose concentrations. (2S)-(4E)-N-methyl-5-(5-methoxy-3- pyridinyl)-4-pentene-2-amine hemigalactarate had a Formula Weight of 311.356 with a salt/base ratio of 1.509. The calculations for total amount of compound needed for the formulary took into account the multiplier of salt/base ratio. Doses are expressed as the free-base equivalents. The materials, once formulated, were considered stable for the entire 6-week period of the study when stored at 4° C.

The dose of 100 mg/kg Gabapentin is commonly used as a positive control in neuropathic pain models (Gilron and Flatters, 2006) and has previously been demonstrated to be an effective dose for reversing allodynia in pain models.

Animals

Adult male Sprague-Dawley rats were received from Harlan Sprague Dawley, Inc. (Indianapolis, Indiana, USA) for this study. The rats were specific pathogen free and approximately 8 weeks old upon arrival. Upon receipt the rats were unpacked and placed in cages. A visual health inspection was performed on each animal to include evaluation of the coat, extremities and orifices. Each animal was also examined for any abnormal signs in posture or movement. The rats were acclimated for approximately one week prior to the commencement of the experimental procedures. No rats were found to be abnormal during the quarantine period. During the course of the study, animals had ad libitum access to oval pellet Certified Picolab Rodent Diet 20 (PMI Feeds Inc., Richmond, Indiana, USA).

Allocation to Treatment Groups

As described in Table A, rats were allocated to treatment groups, twelve (12) rats per group with the exception of satellite groups with six (6) rats in each group, based on baseline allodynia scores collected prior to the start of dosing. The mean allodynia scores for each group were reviewed to ensure that the mean values and standard deviation satisfy the assumption of homogeneity.

Table A — Treatment Groups

- Streptozotocin (75 mg/kg)

Disease Induction

On Day 1 , the animals were dosed with an Lp. injection of 75mg/kg Streptozotocin.

Blood Glucose Monitoring

Diabetes was confirmed by assessing blood glucose levels. All groups had their glucose levels checked once between 3 and 5 days post STZ dosing. Approximately 50 μl_ of blood was collected via the tail vein for glucose level assessments. The animals were restrained and a needle was introduced into the tail vein to extract sufficient blood for the glucose strip. The glucose strip was inserted into the blood glucose meter and within 15 sec, the reading displayed on the meter was recorded on a Blood Glucose Test Record Form. The glucose levels had to be > 400 mg/dL for the animal to be considered diabetic. If the meter read "HI", it was considered to indicate that the glucose levels were above approximately 503 mg/dl, and therefore within the diabetic range.

Dosing

Starting at Day 0, all animals were dosed daily throughout the study by oral gavage with either test or control article at a dose volume of 5 mL/kg. The acute groups were given an oral gavage of vehicle daily, except at 6 week, on the day of allodynia testing when they were dosed with the test article.

Behavior

Acclimation

The animals were acclimated to the allodynia procedure approximately 2 to 3 days prior to testing. The rats were habituated to procedures in the testing devices in order to allow the animals to be calm enough to be properly tested.

Mechanical Allodynia (Von Frey)

At baseline (several days prior to the start of dosing), and at 6 weeks post STZ injections, the animals underwent Von Frey testing for mechanical allodynia. At 6 weeks the animals were tested prior to (2S)-(4E)-N-methyl-5-(5-methoxy-3- pyridinyl)-4-pentene-2-amine hemigalactarate dosing (time point = 0) and then dosed with (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate, reference compound, or vehicle. Allodynia testing followed at 0.5, 2, 4, and 24-hour post test compound dose. Tactile sensitivity (i.e. mechanical allodynia) was measured using calibrated filaments touched to the plantar surface of the affected limb. Any rat that showed allodynia (score of 5 or less) at baseline testing was not included in the study.

Procedurally, the rats were placed in a plexiglas cage with a wire mesh bottom and allowed to acclimate for at least 10 minutes. Once the animals were settled, the plantar surface of the right hind paw was touched with a 2.0g von Frey filament. In the absence of a paw withdrawal response to the initially selected filament, a stronger stimulus was presented; in the event of paw withdrawal, the next weaker stimulus was chosen. In this fashion, the resulting pattern of positive and negative responses was used to determine the paw withdrawal threshold, according to the method of Chaplan, et al., 1994. Clinical Health

Body weights were measured prior to the start of the study and then weekly during the course of the study. Due to the dehydration and excessive urination associated with this model, all animals were given 5 mL of subcutaneous fluid up to twice daily starting at Day 14.

Animals were monitored for health and well-being throughout this study by clinical observations taken daily during dosing. The declining health of animals was noted on clinical observation forms. If the animal appeared moribund, it was documented and the animal was humanely euthanized. Terminal Blood Collection

At 6 weeks, following the allodynia testing, blood was collected under isofluorane anesthetic via cardiac puncture from all animals for plasma. Animals were then euthanized by carbon dioxide asphyxiation. Statistics

An initial one-way ANOVA was performed on baseline behavioral data to determine any differences in treatment group responses prior to STZ induction or treatment. Two-way ANOVAs were performed on the behavioral end points and evaluated for treatment and time to determine the effect of treatment on pain response. When there were overall significant differences by ANOVA, Holm-Sidak post-hoc analyses for multiple comparisons versus a control group were used to evaluate individual treatment group differences from the vehicle-treated / time- matched controls.

Results

Non-diabetic animals excluded

Table B summarizes the percentage of animals that were excluded from the data analysis due to a clear or suspected non-diabetic state based on two sets of blood glucose readings. The first was taken at 4 days post-STZ injection and the second was from blood or plasma that was sampled at approximately 6 wk post-STZ injection. An animal was only accepted as diabetic if it had high (>400 mg/dl) readings for both samples. In the occasional cases where the 6 wk sample was missing, the animal was excluded.

The results in this table indicate that a large percentage of rats were eliminated from the group chronically dosed (2S)-(4E)-N-methyl-5-(5-methoxy-3- pyridinyl)-4-pentene-2-amine hemigalactarate at 0.3 and 1 mg/kg. It is likely to be sheer coincidence that this particular group contained a large number of non-diabetic animals, rather than anything related to the test compound. This conclusion cannot be firmly determined for the chronically dosed (2S)-(4E)-N-methyl-5-(5-methoxy-3- pyridinyl)-4-pentene-2-amine hemigalactarate groups, as animals had received (2S)- (4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate prior to the glucose assessments at day 4, but the number of non-diabetic animals was similar to that of other test groups in the study. Thus, it remains unclear whether repeat administration of (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2- amine hemigalactarate at 0.3 and 1 mg/kg interfered with the diabetic state of these rats.

Table B - Summary of non-diabetic rats removed from the study

Mechanical allodynia

Mechanical allodynia was tested with Von Frey filaments to determine pain thresholds at baseline (prior to STZ administration) and at 6 weeks post-STZ. The baseline data did not differ among any of the treatment groups [F(8,69)= 0.286; P=0.97)]. In contrast, an Overall Two-Way ANOVA on behavioral data collected at week 6 demonstrated significant effects of treatment group [F(8,349)=8.17; P<0.001] and time [F(4,349)=8.50; P<0.001].

Gabapentin At the 6 week timepoint, the mechanical allodynia results for Gabapentin (100 mg/kg; i.p.) demonstrate a significant increase in allodynia thresholds at 0.5 and 2 hr post-dosing as compared to vehicle controls (p<0.05; See figure below).

As shown in Figure 17, Gabapentin and vehicle-treated groups tested for allodynia at 6 weeks post-STZ treatment. Gabapentin significantly reversed the allodynia (p<0.05).

As illustrated in Figure 18, (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4- pentene-2-amine hemigalactarate also demonstrated significant improvement at the 2 hr timepoint post-dosing when the animals were treated either acutely with 1 mg/kg or chronically with 0.03 mg/kg (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4- pentene-2-amine hemigalactarate(p<0.05; See Figure 18). There were no significant effects for other time points or for higher doses of chronically administered (2S)-(4E)- N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate tested.

(2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate and vehicle-treated groups tested for allodynia at 6 weeks post-STZ treatment. (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate demonstrated a significantly increased allodynia threshold at 2 hr post-dosing (p<0.05).

General animal health

The health of the diabetic rats in this study was generally poor. As is consistent with this model of progressive diabetes, the animals lost a lot of weight and appeared lethargic, unkempt, and weak. Several animals had to be euthanized during the study due to extreme weight loss (>40% vs vehicle-treated controls) and a small number of animals died for unidentified reasons. Just prior to the allodynia testing at 6 weeks, the technician stimulated the rats¹ paws using their fingers from below. Any animal that did not respond by moving away from this "poking" was eliminated from the study because it was reasoned that such a rat would not be able to demonstrate a proper withdrawal response during allodynia testing. The following symptoms were noted at the time of allodynia testing 6 wks post-STZ: inactivity, poorly groomed, constant rearing, excessive urination and defecation, hobbling, cupping the right foot to avoid placing weight, dragging feet, "dead foot" (which refers to an animal that doesn't respond when it's foot is squeezed hard), wheezing, sleepy, and extreme difficulty walking and moving.

This study of STZ-induced diabetic neuropathy produced more variable results than the study regarding the incidence of diabetes and the reduced severity of the allodynia at 6 weeks post-STZ. It is not clear why this occurred but it resulted in fewer animals that could be tested for allodynia. Despite the smaller group size in several of the groups, it was still possible to determine significant effects for the test compound and positive control groups as compared to the vehicle-treated groups. (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate significantly reversed allodynia at 2 hr post-dosing at 1 mg/kg after acute dosing and also for the low dose (0.03 mg/kg) in the chronic dosing regimen. The reduced group size that resulted from eliminating non-diabetic rats most affected the higher doses of the chronically administered (2S)-(4E)-N-methyl-5-(5- methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate groups so it is possible that the chronic dosing actually contributed to the reduced incidence of diabetes in these two treatment groups. It is also the case that these higher doses may have been more likely to demonstrate a significant effect on allodynia had there been a larger sample size in those groups.

Reference is made to the following, each incorporated by reference for this pharmacological example: Calcutt N, Jorge M, Yaksh T, and Chaplan, S. Tactile allodynia and formalin hyperalgesia in streptozotocin-diabetic rats: effects of insulin, aldose reductase inhibition and lidocaine. Pain. (1996) 68: 293 — 299; Agarwal M. Streptozotocin: Mechanisms of Action. FEBS Letters Volume 120, Number 1. October 1980; Rittenhouse PA, Marchand JE, Chen J., Kream RM, Leeman SE. Streptozotocin-induced diabetes is associated with altered expression of peptide- encoding mRNAs in rat sensory neurons. Peptides. (1996) 17:1017-22; Jarvis MF, Wessale JL, Zhu CZ, Lynch JJ, Dayton BD, Calzadilla, SV, Padley RJ, Opgenorth TJ, Kowaluk EA. ABT-627, an endothelin ET(A) receptor-selective antagonist attenuates tactile allodynia in a diabetic rat model of neuropathic pain. Eur J Pharmacology. (2000) 388:29-35; and Chaplan, SR, Bach, FW, Pogrel, JW, Chung, JM, Yaksh, TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. (1994) 53: 55-63. Example 21 - Pain in an Animal Model of TAXOL-induced Sensory Neuropathy

Peripheral neuropathies are chronic conditions that arise when nerves are damaged by trauma, disease, metabolic insufficiency, or by certain drugs and toxins. The sensory disturbances associated with chemotherapeutic agents, such as Paclitaxel (herein referred to as TAXOL), range from mild tingling to spontaneous burning, typically in the hands and feet. Symptoms become more intense with continued therapy and can lead to weakness, ataxia, numbness, and pain.

In this study, an animal model of TAXOL-induced sensory neuropathy was employed to evaluate the effects of test compounds for response to tactile sensitivity using the Von Frey test for mechanical allodynia. Animals were administered TAXOL and then dosed with vehicle, acute Gabapentin, or one of three doses of the test compound daily, throughout the course of the study. Testing for mechanical allodynia was performed at three weeks and four weeks post-TAXOL. After the final behavioral test, the sciatic nerve and hind paw were harvested and retained for possible histological analysis. Results demonstrated significant effects of both test compounds in reversing the allodynia levels associated with TAXOL-induced neuropathy.

Disease Induction Agent Preparation A stock TAXOL solution of 6.0 mg/mL was prepared by the following methods. A quantity of 299.9 mg of TAXOL was weighed on analytical balance and transferred to a container with a stir bar; then 25 mL of Cremaphor (Cremaphor EL, Sigma Aldrich) was added using a syringe and stirred until dissolved; then 25mL of Ethyl alcohol was added and stirred for approximately 5 min. The dosing solution was prepared by diluting the stock solution with deionized water for a concentration of 1 mg/mL. 208.33 mL of saline was added to 41.67 mL of stock TAXOL solution. The Dosing solution was aliquoted into four conical tubes and placed in 2-8 ⁰C storage until used for dose administration. Animals Animals were obtained, selected, and maintained as indicated in Example 20.

Allocation to Treatment Groups Rats were randomly allocated to treatment group based on their baseline Von Frey scores. The group means were reviewed to ensure the mean values and standard deviations satisfied the assumption of homogeneity.

As described in Table C, rats were allocated to treatment groups, ten (10) rats per group, based on baseline allodynia scores collected prior to the start of dosing. The mean allodynia scores for each group were reviewed to ensure that the mean values and standard deviation satisfied the assumption of homogeneity.

Table C — Treatment Groups

*Group 2 — Gabapentin, reference article, was administered 90 minutes prior to the scheduled three and four week von Frey testing time points. On all other days these animals were orally gavaged with water.

Dosing

Animals in Groups 1-8 were given TAXOL (2mg/kg) i.p. on Days 1, 3, 5 & 7. Animals received daily oral gavage of test compound or vehicle (5 mL/kg), starting the day of the first TAXOL injection and continuing once daily for the entire 4 weeks of the study. On the four days that TAXOL was administered, the test compound was dosed approximately 60 min after TAXOL. The reference compound was given by IP injection at a volume of 2 mL/kg, 90 minutes prior to the allodynia testing only on the day of testing at weeks 3 and 4.

Behavioral Testing Acclimation

The animals were acclimated to the allodynia procedure. The acclimation to the apparatus occurred approximately 2 to 3 days prior to initial testing, as this habituated the rats to the testing devices and allowed the animals to be calm enough to be properly tested.

Mechanical Allodynia (Von Frey)

At baseline and at week three and week four post-TAXOL injection, the animals underwent Von Frey testing for mechanical allodynia. At the three and four week time points, testing began 30 minutes after dosing with the test compound except for Group 2 which was tested at 90 minutes post-dosing. Tactile sensitivity (i.e. mechanical allodynia) was measured using calibrated filaments touched to the plantar surface of the affected limb. Procedurally, the rats were placed in a plexiglas cage with a wire mesh bottom and allowed to acclimate for at least 10 minutes. Once the animals settled, the plantar surface of the right hind paw was touched with a 2.Og von Frey filament. In the absence of a paw withdrawal response to the initially selected filament, a stronger stimulus was presented; in the event of paw withdrawal, the next weaker stimulus was chosen. In this fashion, the resulting pattern of positive and negative responses was used to determine the paw withdrawal threshold, according to the method of Chaplan, et al The optimal threshold calculation by this method requires six responses in the immediate vicinity of the 50% threshold. The resulting pattern of positive and negative responses is tabulated using the convention, X=withdrawal; 0=no withdrawal, and the 50% response threshold is interpolated using the formula: 50% gram threshold = (10 [Xf + kδ])/10,000 where:

Xf = value (in log units) of the final von Frey hair used K = value for the pattern of positive/negative responses δ = mean difference (in log units) between stimuli.

Statistics The data were analyzed using two-way ANOVAs to determine the effects of test compound on mechanical allodynia at two time points (3 and 4 weeks post- TAXOL treatment initiation). Appropriate post-hoc tests were used when the data were significant. Statistical significance was accepted when p<0.05.

Results The allodynia data, tested at 3 weeks and 4 weeks post-TAXOL dosing, were significantly reduced from baseline levels in the vehicle treated group, indicating onset of neuropathic pain by these timepoints.

Positive control / Validation of Assay A two-way ANOVA for all the data indicated a treatment effect, an effect of time, and an interaction (all p<0.0001). Gabapentin at 100 mg/kg, was effective at reversing the allodynia observed in the vehicle-treated groups when delivered acutely 90 min prior to testing (p<0.001 ; Bonferroni post-hoc test) at both Weeks 3 and 4, see Figure 19, Gabapentin and vehicle-treated groups tested for allodynia at baseline, 3 and 4 weeks post-TAXOL administration. Gabapentin significantly reversed the allodynia (p<0.001 ).

As illustrated in the Figure 20, there was a significant difference between the high dose of (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate and the vehicle-treated group at both 3 and 4 weeks post-TAXOL dosing. A two-way ANOVA examining the effects of chronically administered (2S)- (4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate determined that there was a significant effect of treatment (p<0.05) and time (p<0.0001 ). A Bonferroni post-hoc test revealed a significant effect for the 1 mg/kg dose of (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate at 3 and 4 weeks (p<0.05).

(2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate and vehicle-treated groups tested for allodynia at baseline, 3 and 4 weeks post-TAXOL administration. Only the high dose of (2S)-(4E)-N-methyl-5-(5- methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate significantly reversed the allodynia (p<0.05) at both weeks 3 and 4. In the Figure, the white bar = vehicle; very lightly shaded bar = 0.03 mg/kg (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4- pentene-2-amine hemigalactarate; medium shaded bar = 0.3 mg/kg (2S)-(4E)-N- methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate; and darkly shaded bar = 1 mg/kg (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2- amine hemigalactarate

This study of TAXOL-induced neuropathy demonstrated an analgesic effect of chronically administered (2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-pentene- 2-amine hemigalactarate as well as acutely administered Gabapentin. Notably, at the 4 week allodynia assessment, the vehicle allodynia response had dropped compared to the 3 week assessment indicating a greater degree of allodynia from which alleviation could be demonstrated. Thus, at three weeks following TAXOL, significant reversal of allodynia demonstrated by the vehicle group was achieved at a 50% threshold of about 10 g force whereas only about 7.5 g was required by week 4.

At testing time points both three and four weeks post-TAXOL, (2S)-(4E)-N- methyl-5-(5-methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate was effective at 1 mg/kg in reducing allodynia. These data indicate that (2S)-(4E)-N-methyl-5-(5- methoxy-3-pyridinyl)-4-pentene-2-amine hemigalactarate is a potential candidate for pain control for TAXOL-induced neuropathy

Reference is made to the following, each incorporated by reference for this pharmacological example: Flatters, SJL and Bennett, GJ. Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. Pain, 109: 150-161, 2004; Palomano, RC, Mannes, AJ, Clark, US, and Bennett, GJ. A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel. Pain, 94: 293-304, 2001; Chaplan , SR, Bach, FW, Pogrel, JW, Chung, JM, and Yaksh, TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Meth, 53:55- 63, 1994; and Gilron, I and Flatters, SJL. Gabapentin and pregabalin for the treatment of neuropathic pain: A review of laboratory and clinical evidence. Pain Res Manage, 11 , Suppl A: 16A-29A, Summer 2006.

The specific responses observed may vary according to and depending on the particular compound selected. Expected variations or differences in the results are contemplated in accordance with practice of the present invention.

Although specific embodiments of the present invention are herein illustrated and described in detail, the invention is not limited thereto. The above detailed descriptions are provided as exemplary of the present invention and should not be construed as constituting any limitation of the invention. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included with the scope of the appended claims.

Claims

Claims:

1. A solid acid addition salt of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4- penten-2-amine, or a hydrate or solvate thereof.

2. The salt of claim 1 , wherein the acid is selected from hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, pamoic acid, xinafoic acid, galactaric acid, L-tartaric acid, hippuric acid, fumaric acid, citric acid, D- glucuronic acid, L-malic acid, D-gluconic acid, L-ascorbic acid, p- hydroxybenzoic acid, stearic acid, lactobionic acid, orotic acid, R-mandelic acid, S-mandelic acid, oxalic acid, or hydrobromic acid, or a hydrate or solvate thereof.

3. The salt of claims 1 or 2, having a stoichiometry of acid to (2S)-(4E)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine of 1 :2, 1:1, or 2:1.

4. The salt of claims 1 or 2, having a stoichiometry of acid to (2S)-(4E)-N- methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine of 1 :1.

5. A hydrochloric acid, maleic acid, phosphoric acid, pamoic acid, xinafoic acid, fumaric acid, galactaric acid, p-hydroxybenzoic acid, stearic acid, orotic acid, R-mandelic acid, S-mandelic acid, oxalic acid, or hydrobromic acid salt of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine, or a hydrate or solvate thereof, in substantially crystalline form.

6. (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine hemi- galactarate or a hydrate or solvate thereof.

7. (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate or a hydrate or solvate thereof.

8. A polymorphic form of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4- penten-2-amine phosphate characterized by a powder x-ray diffraction pattern comprising at least one of the following peaks:

2-Theta (deg)

10.4 + 0.5

13.1 + 0.5

15.0 + 0.5

16.2 + 0.5

17.1 + 0.5

18.1 + 0.5

18.6 + 0.5

21.2 + 0.5

9. A polymorphic form of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4- penten-2-amine phosphate whose XRPD pattern substantially corresponds to that shown in one or more of Figures 13, 14, or 15.

10. A polymorphic form of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4- penten-2-amine phosphate whose XRPD pattern substantially corresponds to that shown in Figure 15.

11. Form 3 of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate

12. A pharmaceutical composition comprising a compound of any one of claims 1 to 11 , and one or more pharmaceutically acceptable diluent, excipient, or carrier.

13. The pharmaceutical composition of claim 12 formulated for transdermal administration.

14. A compound or pharmaceutical composition according to any one of claims 1 to 13, for use in therapy.

15. Use of a compound according to any one of claims 1 to 11 , in the manufacture of a medicament for the treatment or prevention of a central nervous system disorder.

16. A method of treating or preventing a central nervous system disorder, comprising administering a compound or pharmaceutical composition of any one of claims 1 to 11.

17. The compound, use, or method of claims 14, 15, or 16, wherein the therapy or disorder is selected from age-associated memory impairment, mild cognitive impairment, pre-senile dementia, early onset Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, Lewy body dementia, vascular dementia, Alzheimer's disease, stroke, AIDS dementia complex, attention deficit disorder, attention deficit hyperactivity disorder, dyslexia, schizophrenia, schizophreniform disorder, or schizoaffective disorder.

18. Use of a compound according to any one of claims 1 to 11 , in the manufacture of a medicament for the treatment or prevention of pain.

19. A method of treating or preventing pain comprising administering a compound or pharmaceutical composition of any one of claims 1 to 11.

20. The compound, use, or method of claims 14, 18, or 19, wherein the therapy or pain is acute pain, persistent pain, chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, fibromyalgia, post-operative pain, pain due to medical condition, arthritis pain, temporomandibular joint disorder, burn pain, injury pain, back pain, sciatica, foot pain, headache, abdominal pain, muscle and connective tissue pain, joint pain, breakthrough pain, cancer pain, somatic pain, visceral pain, chronic fatigue syndrome, psychogenic pain, or pain disorder.

21. The method of claim 20, wherein the neuropathic pain is trigeminal or herpetic neuralgia, diabetic neuropathy, chemotherapy-induced neuropathy, post-herpetic neuralgia, carpel-tunnel syndrome, radiculopathy, complex regional pain syndrome, causalgia, low back pain, spontaneous pain, brachial plexus avulsion, pain resulting from spinal cord injury, hyperalgesia, allodynia, parathesia, or dysthesia.

22. A method of making (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten- 2-amine of high chemical purity, comprising: reacting (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine with galactaric acid to make (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4- penten-2-amine hemi-galactarate.

23. A method of making (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten- 2-amine phosphate, comprising: a) palladium catalyzed coupling of 3-bromo-5-methoxypyridine and a protected (2S)-N-methyl-4-penten-2-amine; b) removing the protecting group; c) treatment with galactaric acid to precipitate (2S)-(4E)-N-methyl-5-[3- (5-methoxypyridin)yl]-4-penten-2-amine hemi-galactarate; d) converting (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2- amine hemi-galactarate into (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine by treatment with a base and a suitable solvent; e) treating the (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2- amine, in a suitable solvent, with phosphoric acid to produce (2S)- (4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine phosphate.

24. The method of claim 23 wherein said protected (2S)-N-methyl-4-penten-2- amine is (2S)-N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine and said protecting group is tert-butoxycarbonyl.