Crystalline form of gamma-aminobutyric acid analog

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WO 2005/037784 PCT/US2004/033979

CRYSTALLINE FORM OF γ-AMINOBUTYRIC ACID ANALOG

1. Field

Disclosed herein is a crystalline form of an analog of γ-aminobutyric acid and 5 methods of making the crystalline form thereof. These analogs may be used as therapeutic agents in the treatment of certain diseases and disorders, including, for example, neuropathic pain and post-herpetic neuralgia.

2. Background

In general, crystalline forms of drugs are preferred over amorphous forms of drugs, in part, because of their superior stability. For example, in many situations, an amorphous drug converts to a crystalline drug form upon storage. Because amorphous and crystalline forms of a drug typically have differing physical/chemical properties, potencies and/or bioavailabilities, such interconversion is undesirable for safety reasons in pharmaceutical administration. A key characteristic of any crystalline drug substance is the polymorphic behavior of such a material.

Polymorphs are crystals of the same molecule which have different physical properties because the crystal lattice contains a different arrangement of molecules.

The different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density (important in formulation and product manufacturing) and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e.g., tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). Solubility differences between polymorphs may, in extreme situations, result in transitions to crystalline forms that lack potency or are toxic. In addition, the physical properties of the crystalline form may be important in pharmaceutical processing. For example, a particular crystalline form may form solvates more readily or may be more difficult to filter and wash free of impurities than other forms (i.e., particle shape and size distribution might be different between one crystalline form relative to other forms).

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Agencies such as the United States Food and Drug Administration closely regulate the polymorphic content of the active component of a drug in solid dosage forms. In general, the regulatory agency requires batch-by-batch monitoring for polymorphic drugs if anything other than the pure, thermodynamically preferred polymorph is marketed. Accordingly, medical and commercial reasons favor synthesizing and marketing solid drugs as the thermodynamically stable polymorph, substantially free of kinetically favored polymorphs.

- {[(oc-Isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid, (1), a prodrug of the GABA analog gabapentin (2), has high bioavailability as gabapentin when dosed either orally or directly into the colon of a mammal (Gallop et al., International Publication No. WO 02/100347). The high bio availability makes compound (1) a valuable component of oral dosage forms (including sustained-release dosage forms) useful for treating or preventing epilepsy, pain (especially, neuropathic pain and muscular and skeletal pain), depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, hot flashes, restless legs syndrome, urinary incontinence or ethanol withdrawal syndrome.

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Compound (1), prepared as described in Gallop et al., International Publication No. WO 02/100347, is isolated as a glassy solid after lyophilization from aqueous acetonitrile. The material obtained by this process is partially or wholly amorphous and certain alkali metal salt forms are hygroscopic. However, amorphous solids and particularly hygroscopic solids are difficult to handle under pharmaceutical processing conditions because of low bulk densities and unsatisfactory flow properties. Moreover, handling of hygroscopic solids requires special techniques and equipment to obtain, for example, reproducible amounts of active compound or solid formulation stability. Furthermore, drugs that are hygroscopic must be packaged in

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WO 2005/037784 PCT/US2004/033979 special containers that have water vapor barriers thus substantially increasing the cost of such products.

Accordingly, a need exists for crystalline forms of 1 -{[(ocisobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid with superior physicochemical properties that may be used advantageously in pharmaceutical processing and pharmaceutical compositions.

3. Summary

A crystalline form of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l10 cyclohexane acetic acid is provided that satisfies these and other needs. Also provided are pharmaceutical compositions of a crystalline form of l-{[(ctisobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid, methods of using the crystalline form of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-lcyclohexane acetic acid and pharmaceutical compositions thereof to treat or prevent various diseases and methods of making crystalline forms of 1-{[(ctisobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid.

In a first aspect, crystalline l-{[(a-isobutanoyloxyethoxy)carbonyl]ammomethyl}-l-cyclohexane acetic acid is provided that has characteristic absorption peaks (20) at 7.0° ± 0.3°, 8.2° ± 0.3°, 10.5° ± 0.3°, 12.8° ± 0.3°, 14.9° ± 0.3°, 16.4° ±

0.3°, 17.9° ± 0.3°, 18.1° ± 0.3°, 18.9° ± 0.3°, 20.9° ± 0.3°, 23.3° ± 0.3°, 25.3° ± 0.3° and

26.6° ± 0.3° in an X-ray powder diffractogram.

In a second aspect, pharmaceutical compositions of the crystalline form of 1{[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid are provided. The phannaceutical compositions comprise 1- {[(ct25 isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid that has characteristic absorption peaks (2Θ) at 7.0° ± 0.3°, 8.2° ± 0.3°, 10.5° ± 0.3°, 12.8° ±

0.3°, 14.9° ± 0.3°, 16.4° ± 0.3°, 17.9° ± 0.3°, 18.1° ± 0.3°, 18.9° ± 0.3°, 20.9° ± 0.3°, 23.3° ± 0.3°, 25.3° ± 0.3° and 26.6° ± 0.3° in an X-ray powder diffractogram and a pharmaceutically acceptable vehicle.

In a third aspect, methods for treating or preventing epilepsy, pain (especially, neuropathic pain and muscular and skeletal pain), depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, hot flashes,

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WO 2005/037784 PCT/US2004/033979 restless legs syndrome, urinary incontinence or ethanol withdrawal syndrome are provided. The methods generally involve administering to a patient in need of such treatment or prevention a therapeutically effective amount of 1-{[(αisobutanoyloxyethoxy)carbonyl]-aminomethyl} -1 -cyclohexane acetic acid that has 5 characteristic absorption peaks (2Θ) at 7.0° ± 0.3°, 8.2° ± 0.3°, 10.5° ± 0.3°, 12.8° ±

0.3°, 14.9° ± 0.3°, 16.4° ± 0.3°, 17.9° ± 0.3°, 18.1° ± 0.3°, 18.9° ± 0.3°, 20.9° ± 0.3°, 23.3° ± 0.3°, 25.3° ± 0.3° and 26.6° ± 0.3° in an X-ray powder diffractogram.

In a fourth aspect, pharmaceutical compositions for treating or preventing epilepsy, pain (especially, neuropathic pain and muscular and skeletal pain), depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, hot flashes, restless legs syndrome, urinary incontinence or ethanol withdrawal syndrome in a patient in need of such treatment or prevention are provided. The methods generally involve administering to a patient in need of such treatment or prevention a therapeutically effective amount of a pharmaceutical composition of 1 - {[(a-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1 -cyclohexane acetic acid that has characteristic absorption peaks (2Θ) at 7.0° ± 0.3°, 8.2° ± 0.3°,

10.5° ± 0.3°, 12.8° ± 0.3°, 14.9° ± 0.3°, 16.4° ± 0.3°, 17.9° ± 0.3°, 18.1° ± 0.3°, 18.9° ± 0.3°, 20.9° ± 0.3°, 23.3° ± 0.3°, 25.3° ± 0.3° and 26.6° ± 0.3° in an X-ray powder diffractogram.

In a fifth aspect, methods for making crystalline 1- {[(ocisobutanoyloxyethoxy)carbonyl] aminomethyl}-1-cyclohexane acetic acid that has characteristic absorption peaks (20) at 7.0° ± 0.3°, 8.2° ± 0.3°, 10.5° ± 0.3°, 12.8° ±

0.3°, 14.9° ±0.3°, 16.4° ±0.3°, 17.9° ±0.3°, 18.1° ±0.3°, 18.9° ±0.3°, 20.9° ±0.3°,

23.3° ± 0.3°, 25.3° ± 0.3° and 26.6° ± 0.3° in an X-ray powder diffractogram are provided.

4. Brief Description of the Figures

Figure 1 illustrates an X-ray powder diffractogram of crystalline 1-{[(α30 isobutanoyloxyethoxy)carbonyl]aminomethyl}-!-cyclohexane acetic acid; and

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Figure 2 illustrates a differential scanning calorimetery thermogram of crystalline 1 - {[(a-isohutanoyloxyethoxy)carbonylj aminomethyl} -1 -cyclohexane acetic acid.

5. Detailed Description

5.1 Definitions “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}10 1-cyclohexane acetic acid is administered.

“Patient” includes humans. The terms “human” and “patient” are used interchangeably herein.

“Preventing” or “prevention” refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a patient that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).

“Promoiety” refers to a form of protecting group that when used to mask a functional group within a drug molecule converts the drug into a prodrug. Typically, the promoiety will be attached to the drug via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.

“Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the patient. In yet another embodiment, “treating” or “treatment” refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.

CA 02541752 2009-11-26 “Therapeutically effective amount” means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated.

Reference will now' be made in detail to preferred embodiments. Although preferred embodiments are described, it will be understood that the invention is not limited to those preferred embodiments. To the contrary, it is intended to cover alternatives, modifications and equivalents as may be included within the spirit and scope of the invention as defined by any claim(s) issuing herefrom.

5.2 Crystalline Forms of l-{f(cx-Isobutanovloxyethoxy)carbonyl]anrinomethyl)-l-CveIohexane Acetic Acid and Preparation Thereof

Crystalline forms of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-lcyclohexane acetic acid and methods of making crystalline forms of l-{[(ctisohutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid are disclosed in detail herein.

It should be understood that referral to

- {[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl} -1 -cyclohexane acetic acid includes all substantially racemic mixtures, all possible tautomeric forms of the conventional chemical structure for tliis compound and all isotopically labeled derivatives of this compound (e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ^l70,^1SO, etc.).

The starting material (i.e., l-{[(oc-isobutanoyloxyethoxy)carbony]]aminomethyl}-l-cyclohexane acetic acid) can be made according to procedures disclosed in Example 13 of Gallop el al., International Publication No. WO 02/100347 or Example 12 of Gallop et ai.

hr one aspect, crystalline l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid is provided. In some embodiments, crystalline 1 -{[(a-isobutanoy]oxyethoxy)carbony]]-aminomethyl}-l-cyclohexane

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WO 2005/037784 PCT/US2004/033979 acetic acid has characteristic absorption peaks at 7.0° ± 0.3°, 8.2° ± 0.3°, 10.5° ± 0.3°, 12.8° ± 0.3°, 14.9° ± 0.3°, 16.4° ± 0.3°, 17.9° ± 0.3°, 18.1° ± 0.3°, 18.9° ± 0.3°, 20.9° ± 0.3°, 23.3° ± 0.3°, 25.3° ± 0.3° and 26.6° ± 0.3°. In other embodiments, crystalline l-{[(a-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-l-cyclohexane acetic acid has characteristic absorption peaks at 7.0° ± 0.2°, 8.2° ± 0.2°, 10.5° ± 0.2°, 12.8° ± 0.2°, 14.9° ± 0.2°, 16.4° ± 0.2°, 17.9° ± 0.2°, 18.1° ± 0.2°, 18.9°± 0.2°, 20.9° ± 0.2°, 23.3° ± 0.2°, 25.3° ± 0.2°, and 26.6° ± 0.2° in an X-ray powder diffractogram.

In some embodiments, crystalline

- {[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid 10 melts between about 54 °C and about 78 °C. In other embodiments, crystalline

- {[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid melts between about 58 °C and about 70 °C. In still other embodiments, crystalline 1 - {[(oc-isobutanoyloxyethoxy)carbonyl]aminomethyl} -1 -cyclohexane acetic acid melts between about 62 °C and about 68 °C. In still other embodiments, crystalline

1 - {[(cc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid melts between about 62 °C and about 66 °C. In still other embodiments, crystalline 1- {[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid melts between about 63 °C and about 66 °C. In still other embodiments, crystalline 1 - {[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid melts between about 64 °C and about 66 °C. In still other embodiments, crystalline 1 - {[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid melts between about 63 °C and about 64 °C.

In some embodiments, crystalline l-{[(cc-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid maybe prepared by first adding

1 - {[(cc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid to a solvent to form a solution or suspension. As used herein, the terms solution and suspension are used interchangeably and are meant to include circumstances where l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid is placed in a solvent or solvent mixture regardless of solubility. The solvent used in crystallization may be either a homogenous solvent, a combination of solvents, or a solvent or solvent combination in which the

1- {[(cc-isobutanoyloxyethoxy)carbonyl] aminomethyl}-1-cyclohexane acetic acid exhibits temperature dependent solubility. In general, solvents or solvent

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WO 2005/037784 PCT/US2004/033979 combinations in which l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}1-cyclohexane acetic acid is soluble within a first temperature range, and poorly soluble within a second temperature range, can be advantageously used in the methods described herein. Mixtures of a “good” solvent and an “anti-solvent” can also be used with temperature dependent solubilization, i.e., dissolving at elevated temperature and crystallizing at room temperature. Examples of suitable “good” solvents include methanol, ethanol, 1,2-propane diol, /-butanol, n-butanol, isopropanol, acetic acid, nitromethane, acetonitrile, dimethylsulfoxide, dimethylformamide, N-methyl pyrrolidone, acetone, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, methyl isobutyl ketone, 1,2-dimethoxyethane, tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, methyl /-butyl ether, chlorobenzene, 1,4-dioxane, diethylether, cumene, o-xylene, /«-xylene,//-xylene, 2ethoxyethanol, 1,2-ethandiol, ethyl formate, 2-methoxyethanol, 1-pentanol, anisole, dichloromethane, cis and trans 1,2 dichloroethylene, chloroform, dimethylacetamide, propylacetate and mixtures thereof. Examples of suitable “anti-solvents” include alkanes such as pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, cis- or /rans-decalin, cyclohexane, methylcyclohexane and mixtures thereof.

Preferably, the dissolution process is carried out at elevated temperature, up to and including the boiling point of the solvent or solvent combination. Accordingly, in some embodiments, l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}1-cyclohexane acetic acid is dissolved in a solvent or solvent mixture with heating and optionally, with shaking and stirring. The heated solution may be kept at elevated temperature to ensure complete dissolution of

1 - {[(cc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid.

The heated solution may also be filtered at elevated temperature to remove any undissolved components.

Preferably, the solution is cooled slowly to provide crystalline 1 - {[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid, which may be separated from residual solvent by filtration and/or drying under reduced pressure. In some embodiments, the solution is cooled between about 0 °C and about 25 °C. Other methods, known to those of skill in the crystallization arts, (e.g., solvent evaporation, drowning, chemical reaction, seeding with a small quantity

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WO 2005/037784 PCT/US2004/033979 of the desired crystal form, etc.) may also be employed to provide crystalline 1 - {[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid.

In some embodiments, l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}1-cyclohexane acetic acid is dissolved in heptane at a temperature between about 70 °C and about reflux temperature. Preferably, the temperature is about 70 °C and the concentration of 1 - {[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl} 1-cyclohexane acetic acid in heptane is between about 0.07 g/mL to about 0.08 g/mL. The solution is then cooled to room temperature to provide crystalline 1 - {[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid.

In other embodiments, 1 - {[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid is dissolved in a mixture of heptane/ethyl acetate (10:1 by volume) at a temperature between about 50 °C and about the reflux temperature, more preferably at a temperature of about 70 °C. The concentration of l-{[(a-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-l-cyclohexane acetic acid in the heptane/ethyl acetate mixture is between about 0.18 g/mL to about 0.22 g/mL.

The solution is then cooled to between about 0 °C and about 25 °C to provide crystalline 1 - {[(oc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid.

In yet other embodiments, l-{[(a-isobutanoyloxyethoxy)carbonyl]20 aminomethyl}-1-cyclohexane acetic acid is dissolved in a mixture of methylcyclohexane/methyl /-butyl ether (the volumetric ratio of methylcyclohexaneto methyl /-butyl ether between about 5:1 to about 20:1, preferably, around 10:1) at a temperature between about 20 and about 40 °C and the concentration of l-{[(a-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane acetic acid in the methylcyclohexane/methyl /-butyl ether mixture is between about 0.1 g/mL to about 0.25 g/mL. The solution is then cooled to between about 0 °C and about 25 °C to provide crystalline l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}1-cyclohexane acetic acid.

5.3 Therapeutic Uses

Crystalline fornis of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}1-cyclohexane acetic acid and/or pharmaceutical compositions thereof may be administered to a patient, preferably a human, suffering from epilepsy, pain

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WO 2005/037784 PCT/US2004/033979 (especially, neuropathic pain and muscular and skeletal pain), post-herpetic neuralgia, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, hot flashes, restless legs syndrome, urinary incontinence or ethanol withdrawal syndrome. Further, in certain embodiments, crystalline forms of 1 - {[(oc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof are administered to a patient, preferably a human, as a preventative measure against various diseases or disorders. Crystalline forms of l-{[(ot-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid and/or pharmaceutical compositions thereof may be administered as a preventative measure to a patient having a predisposition for epilepsy, pain (especially, neuropathic pain and muscular and skeletal pain), post-herpetic neuralgia, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, hot flashes, restless legs syndrome, urinary incontinence or ethanol withdrawal syndrome. Accordingly, crystalline forms of 1- {[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl}-1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof may be used for the prevention of one disease or disorder and concurrently treating another (e.g., prevention of psychosis while treating gastrointestinal disorders; prevention of neuropathic pain while treating ethanol withdrawal syndrome).

The suitability of crystalline forms of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid and/or pharmaceutical compositions thereof in treating epilepsy, pain (especially, neuropathic pain and muscular and skeletal pain), post-herpetic neuralgia, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, hot flashes, restless legs syndrome, urinary incontinence or ethanol withdrawal syndrome may be determined by methods known in the art (e.g., Satzinger et al., United States Patent No.

4,024,175; Satzinger et al., United States Patent No. 4,087,544; Woodruff, United

States Patent No. 5,084,169; Silverman et al., United States Patent No. 5,563,175; Singh, United States Patent No. 6,001,876; Horwell et al., United States Patent No. 6,020,370; Silverman et al., United States Patent No. 6,028,214; Horwell et al.,

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United States Patent No. 6,103,932; Silverman et al., United States Patent No. 6,117,906; Silverman, International Publication No. WO 92/09560; Silverman et al., International Publication No. WO 93/23383; Horwell et al., International Publication No. WO 97/29101, Horwell et al., International Publication No. WO 97/33858;

Horwell et al., International Publication No. WO 97/33859; Bryans et al.,

International Publication No. WO 98/17627; Guglietta et al., International Publication No. WO 99/08671; Bryans et al., International Publication No. WO 99/21824; Bryans et al., International Publication No. WO 99/31057; Magnus-Miller et al., International Publication No. WO 99/37296; Bryans et al., International Publication No. WO

99/31075; Bryans et al., International Publication No. WO 99/61424; Pande,

International Publication No. WO 00/23067; Bellioti, International Publication No.

WO 00/31020; Bryans et al., International Publication No. WO 00/50027; and Bryans et al., International Publication No. WO 02/00209). Crystalline forms of 1 - {[(oc-isobutanoyloxyethoxy)carbonyl]aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof may be used to treat or prevent epilepsy, pain (especially, neuropathic pain and muscular and skeletal pain), post-herpetic neuralgia, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, hot flashes, restless legs syndrome, urinary incontinence or ethanol withdrawal syndrome using known procedures described in the art (see references above).

The compound disclosed herein, may be more efficacious than the parent drug molecule (e.g., gabapentin or other GABA analog) in treating or preventing epilepsy, pain (especially, neuropathic pain and muscular and skeletal pain), post-herpetic neuralgia, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, hot flashes, restless legs syndrome, urinary incontinence or ethanol withdrawal syndrome because the disclosed compound may require less time to reach a therapeutic concentration in the blood, i.e., the compound disclosed herein has a shorter t_max than gabapentin when taken orally. Without wishing to bound by theory, it is believed that the compound disclosed herein is absorbed from the gastrointestinal lumen into the blood by a different mechanism than that by which gabapentin and other known GABA analogs are absorbed. For

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WO 2005/037784 PCT/US2004/033979 example, gabapentin is believed to be actively transporter across the gut wall by a carrier transporter localized in the human small intestine. The gabapentin transporter is easily saturated which means that the amount of gabapentin absorbed into the blood is not proportional to the amount of gabapentin that is administer orally, since once the transport mechanism is saturated, further absorption of gabapentin does not occur to any significant degree. In comparison to gabapentin, the compound disclosed herein, is absorbed across the gut wall along a greater portion of the gastrointestinal tract, including the colon.

Because the compound disclosed herein can be formulated in sustained release 10 formulations which provides for sustained release over a period of hours into the gastrointestinal tract and particularly, release within the colon, l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid may also be more efficacious than gabapentin in treating or preventing epilepsy, pain (especially, neuropathic pain and muscular and skeletal pain), post-herpetic neuralgia, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, hot flashes, restless legs syndrome, urinary incontinence or ethanol withdrawal syndrome. The ability of the compound disclosed herein to be used in sustained release oral dosage forms reduces the dosing frequency necessary for maintenance of a therapeutically effective drug concentration in the blood.

5.4 Modes of Administration

Crystalline forms of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}1-cyclohexane acetic acid and/or pharmaceutical compositions thereof may be advantageously used in human medicine. As previously described, crystalline forms of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid and/or pharmaceutical compositions thereof are useful for the treatment or prevention of epilepsy, pain (especially, neuropathic pain and muscular and skeletal pain), postherpetic neuralgia, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, hot flashes, restless legs syndrome, urinary incontinence or ethanol withdrawal syndrome.

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When used to treat or prevent the above disease or disorders, crystalline forms of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof may be administered or applied singly, or in combination with other agents. Crystalline forms of

1 - {[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof may also be administered or applied singly or in combination with other pharmaceutically active agents, including other GABA analogs.

Methods of treatment and prophylaxis are provided by administration to a 10 patient of a therapeutically effective amount of a crystalline form of

1- {[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof. The patient may be an animal, is more preferably, a mammal, and most preferably, a human.

Crystalline forms of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}15 1-cyclohexane acetic acid and/or pharmaceutical compositions thereof, are preferably administered orally. Crystalline forms of l-{[(cc-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid and/or pharmaceutical compositions thereof may also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.). Administration can be systemic or local. Various delivery systems are known, (e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc.) that can be used to administer crystalline forms of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}1-cyclohexane acetic acid and/or pharmaceutical compositions thereof. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, particularly to the ears, nose, eyes or skin.

In some embodiments, crystalline forms of l-{[(oc-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid and/or pharmaceutical compositions thereof can be delivered via sustained release systems, preferably, oral sustained release systems. In one embodiment, a pump may

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WO 2005/037784 PCT/US2004/033979 be used (Langer, supra·, Sefton, 1987, CRC CritRef. Biomed. Eng. 14:201; Saudek et al., 1989, N. Engl. J. Med. 321:574).

In other embodiments, polymeric materials can be used (“Medical Applications of Controlled Release,” Langer and Wise (eds.), CRC Pres., Boca Raton,

Florida (1974); “Controlled Drug Bioavailability,” Drug Product Design and

Performance, Smolen and Ball (eds.), Wiley, New York (1984); Langer et al., 1983,

J. Macromol. Sci. Rev. Macromol. Chem. 23:61; see also Levy et al., 1985, Science 228: 190; During et al., 1989, Ann. Neurol. 25/351; Howard et al., 1989, J.

Neurosurg. 71:105). In still other embodiments, polymeric materials are used for oral sustained release delivery. Polymers include, for example, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose (preferably, hydroxypropylmethylcellulose). Other cellulose ethers have been described (Alderman, Int. J. Pharm. Tech. &amp; Prod. Mfr. 1984, 5(3) 1-9). Factors affecting drug release are well known to the skilled artisan and have been described in the art (Bamba et al., Int. J. Pharm. 1979, 2, 307).

In other embodiments, enteric-coated preparations can be used for oral sustained release administration. Coating materials include, for example, polymers with a pH-dependent solubility (i.e., pH-controlled release), polymers with a slow or pH-dependent rate of swelling, dissolution or erosion (i.e., time-controlled release), polymers that are degraded by enzymes (i.e., enzyme-controlled release) and polymers that form firm layers that are destroyed by an increase in pressure (i.e., pressure-controlled release).

In still other embodiments, osmotic delivery systems are used for oral sustained release administration (Verma et al., Drug Dev. Ind. Pharm. 2000, 26:69525 708). In some embodiments, OROS™ osmotic devices are used for oral sustained release delivery devices (Theeuwes et al., United States Patent No. 3,845,770; Theeuwes et al., United States Patent No. 3,916,899).

hr yet other embodiments, a controlled-release system can be placed in proximity of the target of crystalline forms of

1 - {[(cc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof, thus requiring only a fraction of the systemic dose (e.g., Goodson, in “Medical Applications of Controlled Release,”

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WO 2005/037784 PCT/US2004/033979 supra, vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussed in Langer, 1990, Science 249; 1527-1533 may also be used.

Crystalline fonns of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}1-cyclohexane acetic acid and/or pharmaceutical compositions thereof preferably, provide gabapentin upon in vivo administration to a patient. While not wishing to bound by theory, the promoiety of crystalline forms of

- {[(oc-isobutanoyloxyethoxy)carbonyl]aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof may be cleaved either chemically and/or enzymatically. One or more enzymes present in the stomach, intestinal lumen, intestinal tissue, blood, liver, brain or any other suitable tissue of a mammal may cleave the promoiety of crystalline forms of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof. The mechanism of cleavage is not important. Preferably, gabapentin formed by cleavage of promoieties from the crystalline form of

1 - {[(oc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof does not contain substantial quantities of γ-lactam contaminant (preferably, less than 0.5 % by weight, more preferably, less than 0.2 % by weight, most preferably less than 0.1 % by weight) which is formed by intramolecular cyclization of the γ amino group with the carboxyl functionality. The extent of lactam fonnation from crystalline forms of

- {[(cc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof may be assessed using standard in vitro analytical methods.

While not wishing to bound by theory, the promoiety of crystalline forms of

1 - {[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof may be cleaved prior to absorption by the gastrointestinal tract (e.g., within the stomach or intestinal lumen) and/or after absorption by the gastrointestinal tract (e.g., in intestinal tissue, blood, liver or other suitable tissue of a mammal). If the promoiety of crystalline forms of

1 - {[(cc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof is cleaved prior to absorption by the gastrointestinal tract, gabapentin may be absorbed into the systemic circulation conventionally (e.g., via the large neutral amino acid transporter located in the small

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WO 2005/037784 PCT/US2004/033979 intestine). If the promoiety of crystalline forms of

- {[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof are cleaved after absorption by the gastrointestinal tract, this GABA analog prodrug may be absorbed into the systemic circulation either by passive diffusion, active transport or by both passive and active processes.

If the promoiety of crystalline forms of

- {[(oc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof is cleaved after absorption by the gastrointestinal tract, this GABA analog prodrug may have the opportunity to be absorbed into the systemic circulation from the large intestine. In this situation, crystalline forms of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}1-cyclohexane acetic acid and/or pharmaceutical compositions thereof are preferably administered as sustained release systems. In some embodiments, crystalline forms of

1 - {[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof are delivered by oral sustained release administration. Preferably, in these embodiments, crystalline forms of 1 - {[(oc-isobutanoyloxyethoxy)carbonyljaminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof are administered twice per day (more preferably, once per day).

5.5 Pharmaceutical Compositions

The present pharmaceutical compositions contain a therapeutically effective amount of a crystalline form of

1 - {[(oc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid together with a suitable amount of a pharmaceutically acceptable vehicle, so as to provide the form for proper administration to a patient. When administered to a patient, crystalline forms of l-{[(cc-isobutanoyloxyethoxy)carbonyl]aminomethyl}1-cyclohexane acetic acid and pharmaceutically acceptable vehicles are preferably sterile. Water is a preferred vehicle when a crystalline form of l-{[(cc-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for injectable solutions.

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Suitable phannaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, etc. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents or pH buffering agents. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used.

In some embodiments, the pharmaceutical compositions of crystalline forms of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid are free of lactam side products formed by intramolecular cyclization. In other embodiments, the pharmaceutical compositions of crystalline forms of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid are stable to extended storage (preferably, greater than one year) without substantial lactam formation (preferably, less than 0.5% lactam by weight, more preferably, less than 0.2% lactam by weight, most preferably, less than 0.1% lactam by weight).

Pharmaceutical compositions comprising crystalline forms of l-{[(oc-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries, which facilitate processing of crystalline forms of l-{[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl}-1-cyclohexane acetic acid into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.

The present pharmaceutical compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. fri some embodiments, the pharmaceutically acceptable vehicle is a capsule (e.g., Grosswald et al., United States

Patent No. 5,698,155). Other examples of suitable pharmaceutical vehicles have been described in the art (see Remington's Phannaceutical Sciences, Philadelphia College of Pharmacy and Science, 19th Edition, 1995). Compositions of crystalline forms of l-{[(oc-isobutanoyloxyethoxy)carbonyl]aminomethyl}-!-cyclohexane acetic acid are

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WO 2005/037784 PCT/US2004/033979 preferably formulated for oral delivery, particularly for oral sustained release administration.

Pharmaceutical compositions for oral delivery may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. Orally administered compositions may contain one or more optional agents, for example, sweetening agents such as fructose, aspartame or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry coloring agents and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill fonn, the pharmaceutical compositions may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. Selectively penneable membranes surrounding an osmotically active driving compound are also suitable for orally administering the compounds and compositions disclosed herein. In these later platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time delay material such as glycerol monostearate or glycerol stearate may also be used. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such vehicles are preferably of pharmaceutical grade.

For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols (e.g., polyethylene glycol) oils, alcohols, slightly acidic buffers between pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at between about 5 mM to about 50 mM), etc. Additionally, flavoring agents, preservatives, coloring agents, bile salts, acylcamitines and the like may be added.

Pharmaceutical compositions for administration via other routes may also be contemplated. For buccal administration, the compositions may take the form of tablets, lozenges, etc. formulated in conventional manner. Liquid drug formulations suitable for use with nebulizers and liquid spray devices and EHD aerosol devices will typically include a crystalline form of l-{[(a-isobutanoyloxyethoxy)carbonyl]18

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WO 2005/037784 PCT/US2004/033979 aminomethyl}-1-cyclohexane acetic acid with a pharmaceutically acceptable vehicle. Preferably, the pharmaceutically acceptable vehicle is a liquid such as alcohol, water, polyethylene glycol or perfluorocarbon. Optionally, another material may be added to alter the aerosol properties of the solution or suspension of the compounds disclosed herein. Preferably, this material is liquid such as an alcohol, glycol, polyglycol or a fatty acid. Other methods of formulating liquid drug solutions or suspension suitable for use in aerosol devices are known to those of skill in the art (see, e.g., Biesalski, United States Patent No. 5,112,598; Biesalski, United States Patent No. 5,556,611).

A crystalline form of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}10 1-cyclohexane acetic acid may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described previously, a crystalline form of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, a crystalline form of l-{[(oc-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

In some embodiments, a crystalline form of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid is formulated as a pure active agent. In other embodiments, a crystalline form of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid is formulated as a mixture with other crystalline forms of

- {[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl} -1 -cyclohexane acetic acid.

5.6 Dosages

A crystalline form of 1 - {[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl} 1-cyclohexane acetic acid and/or pharmaceutical compositions thereof, will generally be used in an amount effective to achieve the intended purpose. For use to treat or prevent diseases or disorders such as epilepsy, pain (especially, neuropathic pain and

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WO 2005/037784 PCT/US2004/033979 muscular and skeletal pain), depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, hot flashes, restless legs syndrome, urinary incontinence or ethanol withdrawal syndrome the crystalline forms of 1 - {[(oc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof are administered or applied in a therapeutically effective amount.

The amount of a crystalline form of

- {[(cc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof that will be effective in the treatment of a particular disorder or condition disclosed herein will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques known in the art as previously described. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. The amount of a crystalline forms of 1 - {[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof administered will, of course, be dependent on, among other factors, the subject being treated, the weight of the subject, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

For example, the dosage may be delivered in a pharmaceutical composition by a single administration, by multiple applications or controlled release. In some embodiments, the crystalline forms of

- {[(cc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof are delivered by oral sustained release administration. Preferably, in these embodiments, the crystalline forms of

- {[(cc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof are administered twice per day (more preferably, once per day). Dosing may be repeated intermittently, may be provided alone or in combination with other drugs and may continue as long as required for effective treatment of the disease state or disorder.

In some embodiments, the dose of the crystalline forms of {[(ct-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof may be adjusted to provide between

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WO 2005/037784 PCT/US2004/033979 about 500 mg/day and about 7000 mg/day of prodrug (equivalent to about 260 mg/day and about 3600 mg/day of gabapentin). Dosage ranges may be readily determined by methods known to the skilled artisan.

The crystalline forms of

1 - {[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof are preferably assayed in vitro and in vivo, for the desired therapeutic or prophylactic activity, prior to use in humans. Preferably, a therapeutically effective dose of a crystalline forms of 1 - {[(oc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof described herein will provide therapeutic benefit without causing substantial toxicity. Toxicity of crystalline forms of 1 - {[(cc-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof may be determined using standard pharmaceutical procedures and may be readily ascertained by the skilled artisan. The dose ratio between toxic and therapeutic effect is the therapeutic index. The dosage of crystalline forms of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}1-cyclohexane acetic acid and/or pharmaceutical compositions thereof described herein will preferably be within a range of circulating concentrations that include an effective dose with little or no toxicity.

5.7 Combination Therapy

In certain embodiments, crystalline forms of 1 - {[(oc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof can be used in combination therapy with at least one other therapeutic agent. The crystalline forms of

- {[(oc-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid and/or pharmaceutical compositions thereof and the other therapeutic agent can act additively or, more preferably, synergistically. In some embodiments, a pharmaceutical composition comprising a crystalline form of l-{[(oc-isobutanoyloxyethoxy)carbonyl]aminomethyl}~l-cyclohexane acetic acid is administered concurrently with the administration of another therapeutic agent, which can be part of the same pharmaceutical composition as the crystalline form of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid or a

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WO 2005/037784 PCT/US2004/033979 different pharmaceutical composition. In other embodiments, a pharmaceutical composition comprising a crystalline form of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid is administered prior or subsequent to administration of another therapeutic agent. For example, a crystalline fonn of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}1-cyclohexane acetic acid may be administered in combination with an amorphous form of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l -cyclohexane acetic acid, another crystalline form of

- {[(oc-isobutanoyloxyethoxy)carbonyl]aminomethyl} -1 -cyclohexane acetic acid, gabapentin or pregabalin.

6. Examples

The following examples describe in detail the preparation of 1-{[(aisobutanoyloxyethoxy)carbonyl] aminomethyl}-1-cyclohexane acetic acid and a crystalline form thereof. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, the generally accepted meaning applies

Atm

Boc Cbz DCC DMAP

DMF

DMSO Fmoc g

h

HPLC

L

LC/MS atmosphere ferz-butyloxycarbonyl carbobenzyloxy dicyclohexylcarbodiimide

4-A,A-dimethylaminopyridine

ΛζΑ-dimethylformamide dimethylsulfoxide

9-fluorenylmethyloxycarbonyl gram hour high pressure liquid chromatography liter liquid chromatography/mass spectroscopy

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<td> M</td><td> =</td><td> molar</td>

<td> min</td><td> =</td><td> minute</td>

<td> mL</td><td> =</td><td> milliliter</td>

<td> mmol</td><td></td><td> millimoles</td>

<td> NHS</td><td> =</td><td> N-hydroxysuccinimide</td>

<td> THF</td><td> =</td><td> tetrahydrofuran</td>

<td> TFA</td><td> =</td><td> trifluoroacetic acid</td>

<td> TLC</td><td> =</td><td> thin layer chromatography</td>

<td> TMS</td><td> =</td><td> trimethylsilyl</td>

<td> pL·</td><td> =</td><td> microliter</td>

<td> pM</td><td> —</td><td> micromolar</td>

<td> v/v</td><td> =</td><td> volume to volume</td>

6.1 Example 1: l-{|(a-lsobutanovloxvethoxvjcarbonvHaminomethvl}15 1-Cyclohexane Acetic Acid via Trimethylsilyl Ester Intermediate

Step A: l-{[(a-Chloroethoxv)carbonvnaminomethyl}1-Cyclohexane Acetic Acid

In a 5-liter, 3-neck, round bottom flask containing dichloromethane (1.6 L) was added gabapentin (120.4 g, 0.704 mol) followed by triethylamine (294 mL, 2.11 mol). Chlorotrimethylsilane (178 mL, 1.40 mol) was slowly added while maintaining the reaction temperature below 15 °C and the resulting suspension was stirred for 30 min. 1-Chloroethyl chloroformate (100 g, 0.704 mol) was then added slowly while maintaining the temperature below 15°C. After the addition was complete, additional triethylamine (88 mL, 0.63 mol) was added and the resulting suspension was stirred at room temperature for 30 min. The resulting silyl ester was converted via acidic work-up to the corresponding acid by washing the reaction mixture with water (2x1 L), followed by IN HCl (2 x 2 L) then brine (2 x 500 mL). After drying over anhydrous sodium sulfate and removal of the solvent in vacuo, tire crude product (190

g) was obtained as an orange oil and used in Step B without further purification.

NMR (CDCls, 400 MHz): δ 1.41 - 1.57 (m, 10H), 1.78 (d, 3H), 2.33 (s, 2H), 3.27 (d, 2H), 5.42 (br. s, 1H), 6.55 (q, 1H).

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Step B: l-{[(a-Isobutanovloxvethoxy)carbonyl1aminomethyl}5 1-Cyclohexane Acetic Acid

To a 3-liter, 3-neck, round bottom flask was added isobutyric acid (254 g, 2.9 mol) followed by triethylamine (395 ml, 2.84 mol). The reaction mixture was cooled to room temperature and a solution of crude acid from the above reaction step (190 g, 0.69 mol) in dichloromethane (80 mL) was added in a controlled fashion while maintaining the temperature below 30 °C. The resulting pale yellow solution was stirred overnight. The reaction mixture was then diluted with one volume of dichloromethane and washed with water (6 x 500 mL), aqueous potassium bicarbonate (3 x 500 mL), and brine (2 x 500 mL). After drying over anhydrous sodium sulfate, removal of the solvent in vacuo afforded the crude product as a dark red oil (87 g). A portion (35 g) of this product was loaded onto an 800 g Biotage™ normal phase silica gel flash column and eluted with 40% diethyl ether in hexane (6 L), which after removal of the solvent in vacuo afforded the product as a colorless oil (13.5 g). This was repeated with a second 35 g portion of crude product yielding a further 13.5 g of l-{[(a-isobutaiioyloxyethoxy)carbonyl]aminomethyl}-l20 cyclohexane acetic acid. A sample of the product (25 g) was recrystallized by dissolution in heptane (325 mL) at 70 °C, followed by slow cooling to room temperature. The white crystalline product (23 g) was isolated by filtration. Melting point: 63-64°C.

6.2 Example 2: l-{l(a-Isobutanoyloxyethoxy)carbonyllaminomethyl}1-Cyclohexane Acetic Acid via Allyl Ester Intermediate

Step A: Allyl Ι-Amin omethvl-1-Cyclohexane Acetate Hydrochloride

A dry 3 L, three-neck, round-bottomed flash fitted with a magnetic stirring bar and a 500 mL pressure-equalizing addition funnel was flushed with nitrogen gas. The flask was charged with gabapentin (171 g, 1.0 mol) and allyl alcohol (1 L, 852 g, 14.6 mol) and the entire mixture was cooled to 0°C in an ice-water bath. Thionyl chloride (225 mL, 360 g, 3.0 mol) was added dropwise over a period of 1 h to the stirred

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WO 2005/037784 PCT/US2004/033979 solution. The reaction mixture was allowed to stir at room temperature for 16 h, then was diluted with ethyl ether (2 L) and cooled to 0°C while stirring. After several minutes white crystals formed, which were collected by filtration. The crude product was recrystallized from a 1/3 (v/v) mixture of ethanol and ethyl ether (2 L) to give the product as a white solid (220 g 88%). m.p.: 138-142°C. Ή NMR (CD3OD, 400 MHz): δ 1.36-1.54 (m, 10H), 2.57 (s, 2H), 3.05 (s, 2H), 4.61 (d, J = 6 Hz, 2H), 5.22 (dd, Ji = 10.4 Hz, J₂ = 1.2 Hz, 1H), 5.33 (dd, Ji = 17.2 Hz, J₂= 1.4 Hz, 1H), 5.90-6.00 (m, 1H ). MS (ESI) m/z 212.0 (M-C1)⁺.

Step B: Allyl l-ll(a-Chloroethoxv)carbonvllaminomethvll-l-Cvcloliexane

Acetate

To a solution of the above hydrochloride salt (220 g, 0.89 mol) in dichloromethane (IL) was slowly added 1-chloroethyl chloroformate (101.7 mL,

132.3 g, 0.92 mol). The reaction mixture was cooled to 0°C and 4-methylmorpholine (205 mL, 188.9 g, 1.87 mol) was slowly added over a period of 1 h while maintaining a temperature of less than 10°C. The resulting turbid solution was stirred at room temperature for 1 h. Ethanol (150 mL) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then diluted with ether (2.5 L), washed with water (1 L) and brine (1 L). The organic phase was dried over sodium sulfate and concentrated to give the title compound as a light yellow viscous liquid (282 g, 100%). Ή NMR (CDC1₃,400 MHz): δ 1.35-1.58 (m, 10H), 1.78 (d, J = 5.6 Hz, 3H), 2.32 (s, 2H), 3.22 (d, J = 6.8 Hz, 2H), 4.57 (d, J = 5.6 Hz, 2H), 5.25 (dd,

Ji = 10.4 Hz, J₂ = 1 Hz, 1H), 5.32 (dd, Jj = 17.2 Hz, J₂= 1.6 Hz, 1H), 5.52 (br, 1H,

NH), 5.90-5.94 (m, 1H), 6.54 (q, J = 5.6 Hz, 1H).

Step C: Allyl l-llfa-lsobutaiiovloxvetlioxvlcarbonvllaininometlivl}1-Cyclohexane Acetate

To a mixture of isobutyric acid (432 mL, 391.5 g, 4.4 mol) and 4methylmorpholine (488 mL, 449 g, 4.4 mol) was added a solution of the chlorocarbamate from the previous step (282 g, 0.88 mol) in isobutyric acid (432 ml,, 391.5 g, 4.4 mol). The addition occurred at 0°C over a period of 30 min. The resulting turbid solution was stirred at room temperature for 16 h. The reaction mixture was diluted with ether (2.5 L) and washed with water (3x 500 mT,) followed by 10% aqueous potassium bicarbonate (6x 500 mL) then brine (500 mT,). The

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WO 2005/037784 PCT/US2004/033979 organic phase was dried over sodium sulfate and concentrated to yield the title compound as a viscous liquid (328 g, 100%). Ή NMR (CDCI3, 400 MHz): δ 1.15 (d,

J = 7.2 Hz, 6H), 1.35-1.58 (m, 10H), 2.31 (s, 2H), 2.51 (m, 1H), 3.19 (d, J = 5.6 Hz, 2H), 4.56 (d, J = 5.6 Hz, 2H), 5.24 (dd, Jj = 10 Hz, J₂ = 1 Hz, 1H), 5.32 (dd, J) = 17

Hz, J₂ = 1.2 Hz, 1H), 5.35 (br, 1H), 5.84-5.94 (m, 1H), 6.78 (q, J = 5.6 Hz, 1H). MS (ESI) m/z 392.24 (M+H)⁺.

Step D: Deprotection of Allyl l-{ |(a-Isohutanovloxvethoxv)carbonvl|aminomethyll-l-Cyclohexane Acetate

To a stirred suspension of ammonium formate (112 g, 1.7 mol) in ethanol (500 mL) was added the above allyl ester (328 g, 0.88 mol) together with 10% Pd/C (15 g) under a nitrogen atmosphere. After 6 h, the reaction mixture was worked-up by filtering off the catalyst. The catalyst was washed with ethanol (2 x 250 mL) and the filtrates were combined and evaporated. The crude product was dissolved in ether (2

L) and the organic phase was washed with 2N HC1 (2 x 2 L) to convert the ammonium salt into the acid form, followed by washing with water (1 L) and brine (1 L). The ether layer was dried over sodium sulfate and concentrated to give the crude product as a viscous liquid (240 g, 82%).

Step E: Crystallization of l-iKa-lsobutanovloxvethoxvlcarbonvH-aminometlivll·1-Cyclohexane Acetic Acid

A 3 L round-bottom flask was equipped with a heating oil bath, a nitrogen inlet adapter, an internal thennometer, an overhead mechanical stirrer, and a reflux condenser. The flask was flushed with nitrogen and charged with a 1/10 (v/v) mixture of ethyl acetate / heptane (1.2 L) and the crude product from the preceding reaction (240 g). The flask was heated until the product dissolved, then cooled according to the following schedule:

<td> Entry</td><td> Time (min.)</td><td> Temp (°C) (Internal temp)</td><td> Appearance</td><td> Remarks</td>

<td> 1</td><td> 0</td><td> 18.0</td><td> Solid in solvent</td><td> Started heating oil bath</td>

<td> 2</td><td> 10</td><td> 48</td><td> Turbid</td><td> Slow dissolution of product</td>

<td> 4</td><td> 20</td><td> 58</td><td> Clear solution</td><td> Turn off oil bath</td>

<td> 5</td><td> 25</td><td> 60</td><td> Clear solution</td><td> Maximum temp, reached</td>

<td> 6</td><td> 45</td><td> 43</td><td> Turbid</td><td> Compound crystallizing</td>

<td> 7</td><td> 60</td><td> 36</td><td> Milky solution</td><td> Seeded with pure ref. material</td>

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<td> 8</td><td> 90</td><td> 24</td><td> Solid in solution</td><td></td>

The flask was then cooled to 4°C overnight with stirring (cooling improves the yield). The product was filtered and washed with heptane (2x 100 mL), then dried under reduced pressure (25 mm of Hg (0.033 atm)) at 30°C for 18 h to yield l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid (185 g) as a white crystalline solid.

6.3 Example 3: X-Ray Powder Diffraction Analysis of Crystalline l-fKa-Isobutanoyloxyethoxylcarbonyllaminomethyll-l-CycIohexane Acetic Acid

X-ray powder diffractograms (XRPD’s) of crystalline samples of

- {[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl} -1 -cyclohexane acetic acid produced according to Examples 1 and 2 above were measured with a Bruker D8 Discover X-ray powder diffractometer using Cu Ka radiation. The instrument is equipped with parallel beam optics and a two-dimensional HI-STAR area detector.

The tube voltage and amperage were set to 40 kV and 40 mA, respectively. The collimated X-ray beam was reduced to a spot size of about 0.5 mm in diameter. The area detector was placed 15 cm from the center of the goniometer and the angular resolution is approximately 0.033°/pixel. The detector covered a range of 35° in 2theta (2Θ) within one frame. The angle between the X-ray beam and the horizontal sample plate was set to 4° and the center of the area detector was set to an angle of 18°. This geometry allowed the measurement of 2-theta from 4.5° to 39.5° within one frame. Typical averaging time was 3 minutes for each XRPD pattern collected. A corundum sample (NIST 1976) was used to calibrate the XRPD instrument. Both samples gave equivalent diffractogram patterns, as illustrated in Figure 1.

6.4 Example 4: Melting Point and Differential Scanning Calorimetry Analysis of Crystalline l-{f(a-Isobutanoyloxyethoxv)carbonynaminomethyl)1-Cyclohexane Acetic Acid

Melting points of crystalline samples of l-{[(a-isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid produced according to Examples 1 and 2 above were measured using an Electrothermal 9200 melting point apparatus and determined to be 63 - 64°C.

CA 02541752 2006-04-05

WO 2005/037784 PCT/US2004/033979

Differential scanning calorimetry (DSC) analysis of crystalline samples of 1 - {[(a-isobutanoyloxyethoxy)carbonyl] aminomethyl} -1 -cyclohexane acetic acid produced according to Examples 1 and 2 above were measured using a Perkin Elmer Series 7 instrument, scanning from 25°C to 250°C at a scan rate of 5°C/minute. A test portion of the sample was placed in an aluminum pan and the cap crimped to eliminate any visible seam between the cap and the pan. An empty pan was prepared in the same manner as a blank. The pans were placed in the Differential Scanning Calorimeter. The material was run at the appropriate temperature program (Equilibration at hiitial Temp, Isothermal, Ramp Rate, Final Temp) to produce the thermogram shown in Figure 2. DSC analysis showed an endothermic transition with an onset temperature of 58.3 °C and a ΔΗ of 72.39 J/g. At the peak endotherm of 63 64°C the sample visibly melted.

6.5 Example 5: ntl-lsobutaiiovloxvethoxv)ciirbonvl|aminomethvl)-l15 Cyclohexane Acetic Acid

To a solution of gabapentin (6.8 g, 0.04 mole) in water (40 mL) was added a solution of [(l-isobutanoyloxyethoxy)carbonyloxy] succinimide (10 g, 0.036 mol ) in acetonitrile (40 mL) over a period of 30 minutes. The reaction was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with methyl tert-butyl ether (200 mL), washed with water (2x100 mL) and brine (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a white solid (12 g, quantitative).

Crystallization: The solid compound (12 g) was suspended in methylcyclohexane: methyl tert-butyl ether 10:1 (60 mL). The suspension was slowly heated up to 50 °C over a period of 30 minutes. The clear solution was then allowed to cool to room temperature. The turbid mixture was seeded with 5 mg of the title compound in crystalline form. The mixture was further cooled to 0-4 °C for 2 hours. The solid product was filtered and washed with methylcyclohexane (2x10 mL) to yield the title compound as a white crystalline solid (10 g, 83% yield). The crystalline solid material had a melting point of about 64-66 °C as measured by open capillary melting point determination.

Finally, it should be noted that there are alternative ways of implementing the present invention. Accordingly, the present embodiments are to be considered as

CA 02541752 2009-11-26 illustrative and not restrictive, and the invention is not to be limited to the details given herein, but may be modified within the scope and equivalents of any claim(s) issuing herefrom.