Solid forms of (r)-n-(3-(7-methyl-1h-indazol-5-YL)-1-(4-(1-methylpiperidin-4-YL)piperazin-1-YL)-1-oxopropan-2-YL)-4-(2-OXO-1,2-dihydroquinolin-3-YL)piperidine-1-carboxamide

Abstract

Disclosed herein is a crystalline form of zavegepant, wherein the crystalline form is a crystalline monohydrochloride acetone solvate. Also disclosed herein is an amorphous form of the hydrochloride salt of zavegepant. Methods of making these solid forms as well as pharmaceutical compositions comprising the same are also disclosed.

Description

[0001] SOLID FORMS OF (R)-N-(3-(7-METHYL-1 H-INDAZOL-5-YL)-1 -(4-(1 - METHYLPIPERIDIN-4-YL)PIPERAZIN-1 -YL)-1 -OXOPROPAN-2-YL)-4-(2-OXO-1 ,2- DIHYDROQUINOLIN-3-YL)PIPERIDINE-1 -CARBOXAMIDE

[0002] FIELD OF THE DISCLOSURE

[0003] The present disclosure relates to solid forms (e.g., crystalline and amorphous forms) of (F?)-A / -(3-(7-methyl-1 / - / -indazol-5-yl)-1 -(4-(1 -methylpiperidin-4-yl)piperazin-1 - yl)-1 -oxopropan-2-yl)-4-(2-oxo-1 ,2-dihydroqu inolin-3-yl)pi peridine- 1 -carboxamide also known as zavegepant and referred to herein as Compound I. The disclosure also relates to pharmaceutical compositions and methods for using the compound in the treatment of CGRP related disorders including migraine headaches, neurogenic vasodilation, neurogenic inflammation, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cancer.

[0004] BACKGROUND OF THE DISCLOSURE

[0005] Calcitonin gene-related peptide (CGRP) is a naturally occurring 37-amino-acid peptide first identified in 1982 (Amara, S. G. et al, Science 1982, 298, 240-244). Two forms of the peptide are expressed (aCGRP and CGRP), which differ by one and three amino acids in rats and humans, respectively. The peptide is widely distributed in both the peripheral (PNS) and central nervous system (CNS), principally localized in sensory afferent and central neurons, and displays a number of biological effects, including vasodilation.

[0006] When released from the cell, CGRP binds to specific cell surface G protein- coupled receptors and exerts its biological action predominantly by activation of intracellular adenylate cyclase (Poyner, D. R. et al, Br J Pharmacol 1992, 105, 441 -7; Van Valen, F. et al, Neurosci Lett 1990, 119, 195-8.). Two classes of CGRP receptors, CGRP1 and CGRP2, have been proposed based on the antagonist properties of the peptide fragment CGRP (8-37) and the ability of linear analogues of CGRP to activate CGRP2 receptors (Juaneda, C. et al. TiPS 2000, 21 , 432-438). However, there is lack of molecular evidence for the CGRP2 receptor (Brain, S. D. et al, TiPS 2002, 23, 51 - 53). The CGRP1 receptor has three components: (i) a 7 transmembrane calcitonin receptor-like receptor (CRLR); (ii) the single transmembrane receptor activity modifying protein type one (RAMP1 ); and (iii) the intracellular receptor component protein (RCP) (Evans B. N. et aL, J Biol Chem. 2000, 275, 31438-43). RAMP 1 is required for transport of CRLR to the plasma membrane and for ligand binding to the CGRP- receptor (McLatchie, L. M. et al, Nature 1998, 393, 333-339). RCP is required for signal transduction (Evans B. N. et aL, J Biol Chem. 2000, 275, 31438-43). There are known species-specific differences in binding of small molecule antagonists to the CGRP- receptor with typically greater affinity seen for antagonism of the human receptor than for other species (Brain, S. D. et al, TiPS 2002, 23, 51 -53). The amino acid sequence of RAMP1 determines the species selectivity, in particular, the amino acid residue Trp74 is responsible for the phenotype of the human receptor (Mallee et al. J Biol Chem 2002, 277, 14294-8).

[0007] Inhibitors at the receptor level to CGRP are postulated to be useful in pathophysiologic conditions where excessive CGRP receptor activation has occurred. Some of these include neurogenic vasodilation, neurogenic inflammation, migraine, cluster headache and other headaches, thermal injury, circulatory shock, menopausal flushing, and asthma. CGRP receptor activation has been implicated in the pathogenesis of migraine headache (Edvinsson L. CNS Drugs 2001 ; 15(10):745-53; Williamson, D. J. Microsc. Res. Tech. 2001 , 53, 167-178.; Grant, A. D. Brit. J. Pharmacol. 2002, 135, 356-362.). Serum levels of CGRP are elevated during migraine (Goadsby P J, et al. Ann Neurol 1990; 28:183-7) and treatment with anti-migraine drugs returns CGRP levels to normal coincident with alleviation of headache (Gallai V. et al. Cephalalgia 1995; 15: 384-90). Migraineurs exhibit elevated basal CGRP levels compared to controls (Ashina M, et aL, Pain 2000, 86(1 -2):133-8.2000). Intravenous CGRP infusion produces lasting headache in migraineurs (Lassen L H, et aL Cephalalgia 2002 February; 22(1 ):54-61 ). Preclinical studies in dog and rat report that systemic CGRP blockade with the peptide antagonist CGRP (8-37) does not alter resting systemic hemodynamics nor regional blood flow (Shen, Y-T. et al, J Pharmacol Exp Ther 2001 , 298, 551 -8). Thus, CGRP-receptor antagonists may present a novel treatment for migraine that avoids the cardiovascular liabilities of active vasoconstriction associated with non-selective 5-HT1 B / 1 D agonists, ‘triptans’ (e.g., sumatriptan).

[0008] CGRP antagonists have shown efficacy in human clinical trials. See Davis C D, Xu C. Curr Top Med Chem. 2008 8(16):1468-79; Benemei S, Nicoletti P, Capone J G, Geppetti P. Curr Opin Pharmacol. 2009 9(1 ):9-14. Epub 2009 Jan. 20; Ho T W, Ferrari M D, Dodick D W, Galet V, Kost J, Fan X, Leibensperger H, Froman S, Assaid C, Lines C, Koppen H, Winner P K. Lancet. 2008 372:2115. Epub 2008 Nov. 25; Ho T W, Mannix L K, Fan X, Assaid C, Furtek C, Jones C J, Lines C R, Rapoport A M; Neurology 2008 70:1304. Epub 2007 Oct. 3. In recent years, zavegepant has been reported in patent application WO2011 / 123232 to be effective as a CGRP antagonist.

[0009] Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice-like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a noncrystalline form. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and, in some cases, different bioavailability patterns compared to the crystalline form. For some therapeutic indications, one bioavailability pattern may be favored over another. An amorphous form of Rosuvastatin Calcium, Rabeprazole sodium are some of the examples of one amorphous drug exhibiting much higher bioavailability than the crystalline forms, which led to the selection of the amorphous form as the final drug substance for pharmaceutical dosage from development.

[0010] Therefore, it is desirable to develop various solid forms of a drug including crystalline and amorphous forms, to be able to take advantage of the best bioavailability pattern for the therapeutic indication being developed.

[0011] SUMMARY OF THE DISCLOSURE

[0012] The present disclosure is directed to a crystalline form of zavegepant, wherein the crystalline form is a crystalline monohydrochloride acetone solvate.

[0013] The present disclosure is also directed to a method of producing the crystalline form of any of the preceding claims, comprising forming a mixture comprising zavegepant and a solution comprising acetone; adding a zavegepant seed to the mixture; forming a slurry from the mixture; and separating the crystalline form from the slurry.

[0014] The present disclosure is also directed to a method of producing a monohydrochloride anhydrous form of Compound I, comprising desolvating the crystalline form to form the monohydrochloride anhydrous form.

[0015] The present disclosure is also directed to an amorphous form of the hydrochloride salt of zavegepant, or a pharmaceutically acceptable salt thereof. The present disclosure is also directed to a method of producing the amorphous form, comprising mixing zavegepant in an acetone solution to form a mixture; forming a slurry from the mixture; separating the zavegepant from the slurry; and desolvating the zavegepant to form the amorphous form of the zavegepant.

[0016] The present disclosure is also directed to a pharmaceutical composition comprising a therapeutically effective amount of at least one of the crystalline forms or the amorphous form of the zavegepant; and a pharmaceutically acceptable carrier.

[0017] The present disclosure is also directed to a method of treating a CGRP related disorder comprising administering the pharmaceutical composition to a patient.

[0018] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure, as claimed.

[0019] BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The figures provided are provided to illustrate the present disclosure and are not intended to be limiting.

[0021] FIG. 1 is a graphical illustration of the characteristic powder x-ray diffraction (PXRD) pattern showing the crystalline, anhydrous Form 2 of Example 2 (Vertical Axis: Intensity (Counts); Horizontal Axis: Two theta (degrees)).

[0022] FIG. 2 is a graphical illustration of the characteristic PXRD pattern obtained from the single crystalline, anhydrous Form 2 of Example 2 (Vertical Axis: Intensity (Counts); Horizontal Axis: Two theta (degrees)).

[0023] FIG. 3 is a graphical illustration of the PXRD Pattern of Compound I, monohydrochloride amorphous Form 3 of Example 3.

[0024] DETAILED DESCRIPTION OF THE DISCLOSURE

[0025] The present disclosure may be understood more readily by reference to the following detailed description of exemplary embodiments of the disclosure and the examples included herein. Specifically, the present disclosure relates to various forms of (F?)- / V-(3-(7-methyl-1 / - / -i ndazol-5-yl)- 1 -(4- ( 1 -methylpiperidin-4-yl)piperazin-1 -yl)-1 - oxopropan-2-yl)-4-(2-oxo-1 ,2-dihydroqu i noli n-3-yl) pi peridi ne- 1 -carboxamide, which is illustrated below.

[0026] As used herein Form 1 refers to the monohydrochloride anhydrous form of Compound I, Form 2 refers to the monohydrochloride acetone solvate form of Compound I, and Form 3 refers to the amorphous form of the hydrochloride salt of Compound I.

[0027] In an aspect, the zavegepant can include a crystalline form that includes Form 2, a crystalline monohydrochloride acetone solvate.

[0028] In an aspect, the crystalline form, Form 2, can have a powder x-ray diffraction pattern comprising 2-theta values of (CuKa radiation, wavelength of 1 .54056 A) 9.4 ± 0.2 and 12.1 ± 0.2.

[0029] In an aspect, the crystalline form, Form 2, can have a powder x-ray diffraction pattern comprising 2-theta values of (CuKa radiation, wavelength of 1 .54056 A) of two or more or three or more peaks of 9.4 ± 0.2, 12.1 ± 0.2, 13.1 ± 0.2, 13.5 ± 0.2, 16.7 ± 0.2, 17.0 ± 0.2, 18.4 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 20.9 ± 0.2, 21 .4 ± 0.2, 22.9 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.0 ± 0.2, 27.1 ± 0.2, and 27.6 ± 0.2.

[0030] In an aspect, the zavegepant can be present in the crystalline form, Form 2, of the monohydrochloride acetone solvate in an amount of greater than or equal to 85 wt% based on the total weight of the zavegepant.

[0031] In an aspect, a method of producing the crystalline form, Form 2, can comprise forming a mixture comprising zavegepant and a solution comprising acetone; adding a zavegepant seed to the mixture; forming a slurry from the mixture; and separating the crystalline form from the slurry. In an aspect, a method of producing a monohydrochloride anhydrous form of Compound I, can comprise desolvating the crystalline form to form the monohydrochloride anhydrous form.

[0032] In an aspect, the zavegepant can include an amorphous form of the hydrochloride salt of zavegepant.

[0033] In an aspect, the zavegepant can be present in the amorphous form in an amount of greater than or equal to 85 wt% based on the total weight of the zavegepant.

[0034] In an aspect, a method of producing the amorphous form, can comprise mixing zavegepant in an acetone solution to form a mixture; forming a slurry from the mixture; separating the zavegepant from the slurry; and desolvating the zavegepant to form the amorphous form of the zavegepant.

[0035] In an aspect, a pharmaceutical composition can comprise a therapeutically effective amount of at least one of the crystalline form or the amorphous form of the zavegepant; and a pharmaceutically acceptable carrier.

[0036] In an aspect, a method of treating a CGRP related disorder can comprise administering the pharmaceutical composition to a patient.

[0037] In an aspect, the CGRP related disorder can include migraine.

[0038] It is to be understood that this disclosure is not limited to specific synthetic methods of making that may of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings:

[0039] As used herein in the specification, "a" or "an" may mean one or more. As used herein in the claim(s), when used in conjunction with the word "comprising", the words "a" or "an" may mean one or more than one. As used herein "another" may mean at least a second or more.

[0040] The term “about” refers to a relative term denoting an approximation of plus or minus 10% of the nominal value it refers, in one embodiment, to plus or minus 5%, in another embodiment, to plus or minus 2%. For the field of this disclosure, this level of approximation is appropriate unless the value is specifically stated to require a tighter range.

[0041] “Compounds” when used herein includes any pharmaceutically acceptable derivative or variation, including conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salt forms, and prodrugs.

[0042] “Patient” refers to warm blooded animals such as, for example, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, cattle, goats, sheep, horses, monkeys, chimpanzees, and humans.

[0043] The term “pharmaceutically acceptable” means the substance (e.g., Compound I) and any salt thereof, or composition containing the substance or salt of the disclosure is suitable for administration to a patient.

[0044] Salts encompassed within the term “pharmaceutically acceptable salts” refer to the compounds of this disclosure which are generally prepared by reacting the free base or free acid with a suitable organic or inorganic acid, or a suitable organic or inorganic base, respectively, to provide a salt of the compound of the disclosure that is suitable for administration to a patient.

[0045] Any solid form of the present disclosure can be substantially pure. As used herein, the term "substantially pure" with reference to a particular solid form (e.g., a crystalline form or amorphous form) means that the particular solid form includes less than 15%, less than 10%, less than 5%, less than 3%, or less than 1% by weight of any other physical form of Compound I. The term "substantially the same" when used to describe powder X-ray diffraction patterns is meant to include patterns in which peaks are within a standard deviation of ± 0.2° 20.

[0046] “Therapeutically effective amount” means an amount of Compound I that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

[0047] The term "treating", "treat" or "treatment" as used herein embraces both preventative, i.e., prophylactic, and palliative treatment, i.e., relieve, alleviate, or slow the progression of the patient’s disease (or condition) or any tissue damage associated with the disease.

[0048] The solid forms of Compound I may be isolated and used per se, or when possible, in the form of its pharmaceutically acceptable salt. The term “salts” refers to inorganic and organic salts of Compound I. These salts can be prepared in situ during the final isolation and purification of a compound, or by separately treating the compound with a suitable organic or inorganic acid or base and isolating the salt thus formed. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this disclosure are those which form nontoxic acid addition salts.

[0049] Compound I may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. Moreover, the compounds may exist for a time in admixture with various solid-state forms (e.g., amorphous form in admixture with crystalline form). The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order ('melting point').

[0050] Compound I may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules which possess an ionic (such as -COO Na+, -COO K+, or -SO Na+) or non-ionic (such as -N N+(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N H. Hartshorne and A. Stuart, 4thEdition (Edward Arnold, 1970).

[0051] Compound I can be present as a crystalline form. The crystalline form can comprise a crystalline monohydrochloride acetone solvate (Form 2). The crystalline form can be characterized by a powder x-ray diffraction pattern comprising 2-theta values (CuKa radiation, wavelength of 1 .54056 A) of 9.4 ± 0.2 and 12.1 ± 0.2. The crystalline form can be characterized by a powder x-ray diffraction pattern comprising 2- theta values (CuKa radiation, wavelength of 1.54056 A) of 9.4 ± 0.2 and 12.1 ± 0.2 and at least one of 13.1 ± 0.2, 13.5 ± 0.2, 16.7 ± 0.2, 17.0 ± 0.2, 18.4 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 20.9 ± 0.2, 21 .4 ± 0.2, 22.9 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.0 ± 0.2, 27.1 ± 0.2, and 27.6 ± 0.2. Form 2 can include 0.25 to 2 moles, or 0.5 to 1 .5 moles, or 0.3 to 1 .1 moles of acetone for every one mole of Compound I. Compound I can be present in Form 2 in an amount of 0.01 to 100 weight percent (wt%), or greater than or equal to 85 wt%, or 90 to 100 wt%, or 99 to 100 wt% based on the total weight of Compound I. Compound I can be present in Form 2 in an amount of less than or equal to 15 wt%, or 0.01 to 10 wt%, or 0.01 to 1 wt% based on the total weight of Compound I.

[0052] A method of producing the crystalline monohydrochloride acetone solvate (Form 2) of Compound I can comprise forming a mixture comprising Compound I (for example, as a free base or in the monohydrochloride anhydrous form) and a solution comprising acetone. The solution can comprise an alkyl alcohol (for example, methanol or ethanol) and the acetone. The solution can have a volume ratio of the alkyl alcohol to acetone of 2:1 to 1 :2. An amount of a seed compound can be added to the mixture. The seed compound can comprise Compound I and can be formed by adding Compound I monohydrochloride anhydrous to acetone and slurrying at 20 to 30 degrees Celsius (°C) for 2 to 4 days. The amount of the seed compound added to the mixture can be 1 wt% based on the total weight of the Compound I in the mixture. The mixture can be slurried at 40 to 50°C. The mixture can be slurried for 2 to 4 days. The crystalline form can then be separated from the slurry. The crystalline monohydrochloride acetone solvate can be desolvated to form the monohydrochloride anhydrous form. The separation can occur by filtration via centrifugation through a 0.3 to 0.6 micron filter. Prior to the separation, the slurry can be cooled to room temperature, for example, 20 to 23°C. Compound I can be present in an amorphous form (Form 3) or a pharmaceutically acceptable salt thereof. The amorphous form can include the hydrochloride salt amorphous form, for example, a monohydrochloride salt amorphous form. Compound I can be present in the amorphous form in an amount of 0.01 to 100 wt%, or greater than or equal to 85 wt%, or 90 to 100 wt%, or 99 to 100 wt% based on the total weight of Compound I. Compound I can be present in Form 3 in an amount of less than or equal to 15 wt%, or 0.01 to 10 wt%, or 0.01 to 1 wt% based on the total weight of Compound I.

[0053] A method of producing the amorphous form (Form 3) of Compound I can comprise mixing Compound I in an acetone solution to form a mixture. The acetone solution can comprise an alkyl alcohol (for example, methanol or ethanol) and acetone. The alkyl alcohol and the acetone can be present in the acetone solution in a volume ratio of 8:1 to 15:1 . The mixture can be slurried. The slurrying can occur at a temperature of 40 to 50°C. The slurrying can occur for 0.2 to 2 days. Compound I can be separated from the slurry and desolvated, for example, by evaporation, to form the amorphous form.

[0054] The disclosure also relates to pharmaceutical compositions comprising Compound I and methods for using the compound in the treatment of CGRP related disorders including migraine headaches, neurogenic vasodilation, neurogenic inflammation, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cancer. Accordingly, a pharmaceutical composition can comprise a therapeutically effective amount of at least one of Form 2 or Form 3 of Compound I and a pharmaceutically acceptable carrier.

[0055] Inhibitors at the receptor level to CGRP are postulated to be useful in pathophysiologic conditions where excessive CGRP receptor activation has occurred. Some of these include neurogenic vasodilation, neurogenic inflammation, migraine, cluster headache and other headaches, thermal injury, circulatory shock, menopausal flushing, and asthma. CGRP receptor activation has been implicated in the pathogenesis of migraine headache (Edvinsson L. CNS Drugs 2001 , 15(10), 745-53; Williamson, D. J. Microsc. Res. Tech. 2001 , 53, 167-178.; Grant, A. D. Brit. J. Pharmacol. 2002, 135, 356-362.). Serum levels of CGRP are elevated during migraine (Goadsby P. J. et al. Ann. Neurol. 1990, 28, 183-7) and treatment with anti-migraine drugs returns CGRP levels to normal coincident with alleviation of headache (Gallai V. et al. Cephalalgia 1995, 15, 384-90). Migraineurs exhibit elevated basal CGRP levels compared to controls (Ashina M. et al., Pain 2000, 86(1 -2), 133-8). Intravenous CGRP infusion produces lasting headache in migraineurs (Lassen L. H. et al. Cephalalgia. 2002, 22(1 ), 54-61 ). Preclinical studies in dog and rat report that systemic CGRP blockade with the peptide antagonist CGRP (8-37) does not alter resting systemic hemodynamics nor regional blood flow (Shen, Y-T. et al. J. Pharmacol. Exp. Ther.

[0056] 2001 , 298, 551 -8). Thus, CGRP-receptor antagonists may present a novel treatment for migraine that avoids the cardiovascular liabilities of active vasoconstriction associated with non-selective 5-HT1 B / 1 D agonists, "triptans" (e.g., sumatriptan).

[0057] Another aspect of the disclosure is a method of inhibiting the CGRP receptor comprising contacting the CGRP receptor with Compound I.

[0058] Another aspect of the disclosure is a method for treating conditions associated with aberrant levels of CGRP or CGRP receptor signaling comprising the administration of a therapeutically effective amount of Compound I to a patient.

[0059] Another aspect of the disclosure is the use of Compound I in the manufacture of a medicament for the treatment of conditions related to aberrant levels of CGRP or CGRP receptor signaling.

[0060] Another aspect of the disclosure is a method of treating migraine or headache.

[0061] Another aspect of the disclosure is a method of treating neuropathic pain.

[0062] Another aspect of the disclosure relates to a method of treating inflammation (particularly neurogenic inflammation), pain, thermal injury, circulatory shock, diabetes, Reynaud's syndrome, peripheral arterial insufficiency, subarachnoid / cranial hemorrhage, tumor growth, flushing associated with menopause and other conditions the treatment of which can be affected by the antagonism of the CGRP receptor by the administration of pharmaceutical compositions comprising Compound I as defined herein.

[0063] Another aspect of the disclosure relates to methods selected from the group consisting of (a) immune regulation in gut mucosa (b) protective effect against cardiac anaphylactic injury (c) stimulating or preventing interleukin-1 b(IL-1 b)-stimulation of bone resorption (d) modulating expression of NK1 receptors in spinal neurons and (e) airway inflammatory diseases and chronic obstructive pulmonary disease including asthma. See (a) Calcitonin Receptor-Like Receptor Is Expressed on Gastrointestinal Immune Cells. Hagner, Stefanie; Knauer, Jens; Haberberger, Rainer; Goeke, Burkhard; Voigt, Karlheinz; McGregor, Gerard Patrick. Institute of Physiology, Philipps University, Marburg, Germany. Digestion (2002), 66(4), 197-203; (b) Protective effects of calcitonin gene-related peptide-mediated evodiamine on guinea-pig cardiac anaphylaxis. Rang, Wei-Qing; Du, Yan-Hua; Hu, Chang-Ping; Ye, Feng; Tan, Gui-Shan; Deng, Han-Wu; Li, Yuan-Jian. School of Pharmaceutical Sciences, Department of Pharmacology, Central South University, Xiang-Ya Road 88, Changsha, Hunan, Naunyn-Schmiedeberg's Archives of Pharmacology (2003), 367(3), 306-311 ; (c) The experimental study on the effect calcitonin gene-related peptide on bone resorption mediated by interleukin-1 . Lian, Kai; Du, Jingyuan; Rao, Zhenyu; Luo, Huaican. Department of Orthopedics, Xiehe Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Peop. Rep. China. Journal of Tongji Medical University (2001 ), 21 (4), 304-307, (d) Calcitonin gene-related Peptide regulates expression of neurokinin) receptors by rat spinal neurons. Seybold V S, McCarson K E, Mermelstein P G, Groth R D, Abrahams L G. J. Neurosci. 2003 23 (5): 1816-1824. Department of Neuroscience, University of Minnesota, Minneapolis, Minn. 55455, and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kans. 66160 (e) Attenuation of antigen-induced airway hyperresponsiveness in CGRP-deficient mice. Aoki-Nagase, Tomoko; Nagase, Takahide; Oh-Hashi, Yoshio; Shindo, Takayuki; Kurihara, Yukiko; Yamaguchi, Yasuhiro; Yamamoto, Hiroshi; Tomita, Tetsuji; Ohga, Eijiro; Nagai, Ryozo; Kurihara, Hiroki; Ouchi, Yasuyoshi. Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. American Journal of Physiology (2002), 283(5, Pt. 1 ), L963-L970; (f) Calcitonin gene-related peptide as inflammatory mediator. Springer, Jochen; Geppetti, Pierangelo; Fischer, Axel; Groneberg, David A. Charite Campus- Virchow, Department of Pediatric Pneumology and Immunology, Division of Allergy Research, Humboldt-University Berlin, Berlin, Germany. Pulmonary Pharmacology and Therapeutics (2003), 16(3), 121 -130; and (g) Pharmacological targets for the inhibition of neurogenic inflammation. Helyes, Zsuzsanna; Pinter, Erika; Nemeth, Jozsef; Szolcsanyi, Janos. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pecs, Pecs, Hung. Current Medicinal Chemistry: Anti-Inflammatory and Anti-Allergy Agents (2003), 2(2), 191 -218.

[0064] Another aspect of this disclosure relates to a method of treatment for cancer and proliferative diseases and conditions. CGRP antagonists have also been proposed to show utility in the treatment of malignant disease, particularly against gliomas and breast cancer that metastasizes to the brain. CGRP antagonists may be especially useful against hypoxic tumors and in the prevention of metastatic implantation. See PCT application publication WO2010006168.

[0065] "Migraine," "headache," and related terms are as understood by medical practitioners. Migraine encompasses all classes of migraine including common, classic, cluster, fulgurating, hemiplegic, opthalmoplegic, and opthomalmic.

[0066] Compound I can be administered alone or in combination with one or more additional therapeutic agents. By "administered in combination" or "combination therapy" it is meant that Compound I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Thus, the methods of prevention and treatment described herein include use of combination agents. Examples of combination agents include COX-2 inhibitors, NSAIDS, aspirin, acetaminophen, triptans, ergotamine, and caffeine, for example, for the treatment of migraine.

[0067] The combination agents are administered to a mammal in a therapeutically effective amount. By "therapeutically effective amount" it is meant an amount of Compound I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat the desired disease / condition, e.g., migraine, pain, or cancer.

[0068] The dosage of the additional pharmaceutical agent is generally dependent upon a number of factors including the health of the subject being treated, the extent of treatment desired, the nature and kind of concurrent therapy, if any, and the frequency of treatment and the nature of the effect desired. In general, the dosage range of the additional pharmaceutical agent is in the range of from about 0.001 mg to about 100 mg per kilogram body weight of the individual per day, preferably from about 0.1 mg to about 10 mg per kilogram body weight of the individual per day. However, some variability in the general dosage range may also be required depending upon the age and weight of the subject being treated, the intended route of administration, the particular agent being administered and the like. The determination of dosage ranges and optimal dosages for a particular patient is also well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure.

[0069] According to the methods of treatment of the disclosure, Compound I or a combination of Compound I and at least one additional pharmaceutical agent (referred to herein as a "combination") is administered to a subject in need of such treatment, preferably in the form of a pharmaceutical composition. In the combination aspect of the disclosure, Compound I and at least one other pharmaceutical agent (e.g., another migraine reducing agent,) may be administered either separately or in a pharmaceutical composition comprising both. It is generally preferred that such administration be oral and / or nasal.

[0070] When a combination of Compound I and at least one other pharmaceutical agent is administered together, such administration may be sequential in time or simultaneous. Simultaneous administration of drug combinations is generally preferred. For sequential administration, Compound I and the additional pharmaceutical agent may be administered in any order. It is generally preferred that such administration be oral and / or the administration of Compound I is intranasal. It is especially preferred that the administration of Compound I is intranasal, and the administration of the other pharmaceutical agent is oral. When Compound I and the additional pharmaceutical agent are administered sequentially, the administration of each may be by the same or by different methods.

[0071] According to the methods of the disclosure, Compound I or a combination can be administered in the form of a pharmaceutical composition. Accordingly, Compound I or a combination can be administered to a patient separately or together in any conventional oral, rectal, transdermal, parenteral (e.g., intravenous, intramuscular, or subcutaneous), intracisternal, intravaginal, intraperitoneal, topical (e.g., powder, ointment, cream, spray, or lotion), buccal, or nasal dosage form (a.k.a. intranasally, e.g., spray, drops, or inhalant).

[0072] The Compound I or a combination can be administered alone but will generally be administered in an admixture with one or more suitable pharmaceutical excipients, adjuvants, diluents or carriers known in the art and selected with regard to the intended route of administration and standard pharmaceutical practice. Compound I or a combination may be formulated to provide immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release dosage forms depending on the desired route of administration and the specificity of release profile, commensurate with therapeutic needs.

[0073] The pharmaceutical composition comprises Compound I or a combination in an amount generally in the range of about 1% to about 75%, 80%, 85%, 90% or even 95% (by weight) of the composition, usually in the range of about 1%, 2% or 3% to about 50%, 60% or 70%, more frequently in the range of about 1%, 2% or 3% to less than 50% such as about 25%, 30% or 35%, based on the total weight of the composition. The pharmaceutical composition can comprise Compound I in Form 2 or Form 3, each independently, in an amount of less than or equal to 15 wt%, or 0.01 to 10 wt%, or 0.01 to 1 wt% based on the total weight of Compound I.

[0074] Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known to those skilled in this art. For example, see Remington: The Practice of Pharmacy, Lippincott Williams and Wilkins, Baltimore Md. 20thed. 2000.

[0075] Compositions suitable for parenteral injection generally include pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers or diluents (including solvents and vehicles) include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, triglycerides including vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. A preferred carrier is MIGLYOL™. brand caprylic / capric acid ester with glycerin or propylene glycol (e.g., MIGLYOL™ 812, MIGLYOL™ 829, MIGLYOL™ 840) available from Condea Vista Co., Cranford, N.J. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0076] These compositions for parenteral injection may also contain excipients such as preserving, wetting, emulsifying, and dispersing agents. Prevention of microorganism contamination of the compositions can be accomplished with various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents capable of delaying absorption, for example, aluminum monostearate and gelatin.

[0077] Solid dosage forms for oral administration include capsules, tablets, chews, lozenges, pills, powders, and multi-particulate preparations (granules). In such solid dosage forms, Compound I or a combination is admixed with at least one inert excipient, diluent, or carrier. Suitable excipients, diluents or carriers include materials such as sodium citrate or dicalcium phosphate and / or (a) one or more fillers or extenders (e.g., microcrystalline cellulose (available as AVICEL™ from FMC Corp.) starches, lactose, sucrose, mannitol, silicic acid, xylitol, sorbitol, dextrose, calcium hydrogen phosphate, dextrin, alpha-cyclodextrin, beta-cyclodextrin, polyethylene glycol, medium chain fatty acids, titanium oxide, magnesium oxide, aluminum oxide, and the like); (b) one or more binders (e.g., carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia, and the like); (c) one or more humectants (e.g., glycerol and the like); (d) one or more disintegrating agents (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, sodium lauryl sulphate, sodium starch glycolate (available as EXPLOTAB™ from Edward Mendell Co.), cross-linked polyvinyl pyrrolidone, croscarmellose sodium A-type (available as AC-DI-SOL™), polyacrilin potassium (an ion exchange resin), and the like); (e) one or more solution retarders (e.g., paraffin and the like); (f) one or more absorption accelerators (e.g., quaternary ammonium compounds and the like); (g) one or more wetting agents (e.g., cetyl alcohol, glycerol monostearate, and the like); (h) one or more adsorbents (e.g., kaolin, bentonite, and the like); and / or (i) one or more lubricants (e.g., talc, calcium stearate, magnesium stearate, stearic acid, polyoxyl stearate, cetanol, talc, hydrogenated castor oil, sucrose esters of fatty acid, dimethylpolysiloxane, microcrystalline wax, yellow beeswax, white beeswax, solid polyethylene glycols, sodium lauryl sulfate, and the like). In the case of capsules and tablets, the dosage forms may also comprise buffering agents.

[0078] Solid compositions of a similar type may also be used as fillers in soft or hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like. Solid dosage forms such as tablets, dragees, capsules, and granules may be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may also contain opacifying agents, and can also be of such composition that they release the compound of the present disclosure and / or the additional pharmaceutical agent in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The drug may also be in micro- encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0079] For tablets, the active agent will typically comprise less than 50% (by weight) of the formulation, for example less than about 10% such as 5% or 2.5% by weight, based on the total weight of the tablet. The predominant portion of the formulation comprises fillers, diluents, disintegrants, lubricants and optionally, flavors. The composition of these excipients is well known in the art. Frequently, the fillers / diluents will comprise mixtures of two or more of the following components: microcrystalline cellulose, mannitol, lactose (all types), starch, and di-calcium phosphate. The filler / diluent mixtures typically will be present in an amount of less than 98% of the formulation and preferably less than 95%, for example, 93.5%. Preferred disintegrants include AC-DI- SOLTM, EXPLOTAB™, starch, and sodium lauryl sulphate. When present, a disintegrant will usually be present in an amount of less than 10% (by weight) of the formulation or less than 5%, for example, about 3%. A preferred lubricant is magnesium stearate. When present, a lubricant will usually be present in an amount of less than 5% (by weight) of the formulation or less than 3%, for example, about 1 %.

[0080] Tablets may be manufactured by standard tableting processes, for example, direct compression or a wet, dry or melt granulation, melt congealing process and extrusion. The tablet cores may be mono or multi-layer(s) and can be coated with appropriate overcoats known in the art.

[0081] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the compound of the present disclosure or the combination, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame seed oil, and the like), MIGLYOLE™ (available from CONDEA Vista Co., Cranford, N.J.), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like.

[0082] Besides such inert diluents, the composition may also include excipients, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0083] Oral liquid forms of the compounds of the disclosure or combinations include solutions, wherein the active compound is fully dissolved. Examples of solvents include all pharmaceutically precedented solvents suitable for oral administration, particularly those in which the compounds of the disclosure show good solubility, e.g., polyethylene glycol, polypropylene glycol, edible oils, and glyceryl- and glyceride-based systems. Glyceryl- and glyceride-based systems may include, for example, the following branded products (and corresponding generic products): CAPTEX™ 355 EP (glyceryl tricaprylate / caprate, from Abitec, Columbus Ohio), CRODAMOL™ GTC / C (medium chain triglyceride, from Croda, Cowick Hall, UK), or LABRAFAC™ CC (medium chain triglycerides, from Gattefosse), CAPTEX™ 500P (glyceryl triacetate i.e. triacetin, from Abitec), CAPMUL™ MCM (medium chain mono- and diglycerides, from Abitec), MIGYOL™ 812 (caprylic / capric triglyceride, from Condea, Cranford N.J.), MIGYOL™ 829 (caprylic / capric / succinic triglyceride, from Condea), MIGYOL™ 840 (propylene glycol dicaprylate / dicaprate, from Condea), LABRAFIL™ M1944CS (oleoyl macrogol-6 glycerides, from Gattefosse), PECEOL™ (glyceryl monooleate, from Gattefosse), and MAISINE™ 35-1 (glyceryl monooleate, from Gattefosse). Of particular interest are the medium chain (about Cs to C10) triglyceride oils. These solvents frequently make up the predominant portion of the composition, i.e., greater than about 50% (by weight), usually greater than about 80%, for example, about 95% or 99%. Adjuvants and additives may also be included with the solvents principally as taste-mask agents, palatability and flavoring agents, antioxidants, stabilizers, texture and viscosity modifiers, and solubilizers.

[0084] Suspensions, in addition to the compound of the present disclosure or the combination, may further comprise carriers such as suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like. Compositions for rectal or vaginal administration preferably comprise suppositories, which can be prepared by mixing Compound I or a combination with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity thereby releasing the active component(s).

[0085] Dosage forms for topical administration of the compounds of the present disclosure or combinations include ointments, creams, lotions, powders and sprays. The drugs are admixed with a pharmaceutically acceptable excipient, diluent or carrier, and any preservatives, buffers, or propellants that may be required.

[0086] Many of the present compounds are poorly soluble in water, e.g., less than about 1 microgram per milliliter (pg / mL). Therefore, liquid compositions in solubilizing, nonaqueous solvents such as the medium chain triglyceride oils discussed above are a preferred dosage form for these compounds.

[0087] The dosage form of Compound I can also include a solid amorphous dispersion, including dispersions formed by a spray-drying process. By "solid amorphous dispersion" is meant a solid material in which at least a portion of the poorly soluble compound is in the amorphous form and dispersed in a water-soluble polymer. By "amorphous" is meant that the poorly soluble compound is not crystalline. By "crystalline" is meant that the compound exhibits long-range order in three dimensions of at least 100 repeat units in each dimension. Thus, the term amorphous is intended to include not only material that has essentially no order, but also material that may have some small degree of order, but the order is in less than three dimensions and / or is only over short distances. Amorphous material may be characterized by techniques known in the art such as powder x-ray diffraction (PXRD) crystallography, solid state NMR, or thermal techniques such as differential scanning calorimetry (DSC).

[0088] At least a major portion (i.e., at least about 60 wt%) of the poorly soluble compound in the solid amorphous dispersion can be amorphous. The compound can exist within the solid amorphous dispersion in relatively pure amorphous domains or regions, as a solid solution of the compound homogeneously distributed throughout the polymer or any combination of these states or those states that lie intermediate between them. The solid amorphous dispersion can be substantially homogeneous so that the amorphous compound is dispersed as homogeneously as possible throughout the polymer. As used herein, "substantially homogeneous" means that the fraction of the compound that is present in relatively pure amorphous domains or regions within the solid amorphous dispersion is relatively small, on the order of less than 20 wt%, and preferably less than 10 wt% of the total amount of drug.

[0089] Water-soluble polymers suitable for use in the solid amorphous dispersions should be inert, in the sense that they do not chemically react with the poorly soluble compound in an adverse manner, are pharmaceutically acceptable, and have at least some solubility in aqueous solution at physiologically relevant pHs (e.g., 1 to 8). The polymer can be neutral or ionizable, and should have an aqueous-solubility of at least 0.1 milligrams per milliliter (mg / mL) over at least a portion of the pH range of 1 to 8.

[0090] Water-soluble polymers suitable for use with the present disclosure may be cellulosic or non-cellulosic. The polymers may be neutral or ionizable in aqueous solution. Of these, ionizable and cellulosic polymers are preferred, with ionizable cellulosic polymers being more preferred.

[0091] Exemplary water-soluble polymers include hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose phthalate (HPMCP), carboxy methyl ethyl cellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVPVA), hydroxypropyl cellulose (HPC), methyl cellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO / PPO, also known as poloxamers), copolymers of methacrylic acid and methyl methacrylate (MAA / MMA, also known as eudragits), and mixtures thereof. Especially preferred polymers include HPMCAS, HPMC, HPMCP, CMEC, CAP, CAT, PVP, PVPVA, poloxamers, eudragits, and mixtures thereof. Most preferred is HPMCAS. See European Patent Application Publication No. 0 901 786 A2, the disclosure of which is incorporated in its entirety herein by reference.

[0092] The solid amorphous dispersions may be prepared according to any process for forming solid amorphous dispersions that results in at least a major portion (at least 60 wt%) of the poorly soluble compound being in the amorphous state. Such processes include mechanical, thermal and solvent processes. Exemplary mechanical processes include milling and extrusion; melt processes including high temperature fusion, solvent-modified fusion and melt-congeal processes; and solvent processes including non-solvent precipitation, spray coating and spray drying. See, for example, the following U.S. Patents, the pertinent disclosures of which are incorporated herein by reference: Nos. 5,456,923 and 5,939,099, which describe forming dispersions by extrusion processes; Nos. 5,340,591 and 4,673,564, which describe forming dispersions by milling processes; and Nos. 5,707,646 and 4,894,235, which describe forming dispersions by melt congeal processes. In a preferred process, the solid amorphous dispersion is formed by spray drying, as disclosed in European Patent Application Publication No. 0 901 786 A2. In this process, the compound and polymer are dissolved in a solvent, such as acetone or methanol, and the solvent is then rapidly removed from the solution by spray drying to form the solid amorphous dispersion. The solid amorphous dispersions may be prepared to contain up to about 99 wt% of the compound, e.g., 1 wt%, 5 wt%, 10 wt%, 25 wt%, 50 wt%, 75 wt%, 95 wt%, or 98 wt% as desired.

[0093] The solid dispersion may be used as the dosage form itself or it may serve as a manufacturing-use-product (MUP) in the preparation of other dosage forms such as capsules, tablets, solutions or suspensions. An example of an aqueous suspension is an aqueous suspension of a 1 :1 (w / w) compound / HPMCAS-HF spray-dried dispersion containing 2.5 mg / mL of compound in 2% polysorbate-80. Solid dispersions for use in a tablet or capsule will generally be mixed with other excipients or adjuvants typically found in such dosage forms. For example, an exemplary filler for capsules contains a 2:1 (w / w) compound / HPMCAS-MF spray-dried dispersion (60%), lactose (fast flow) (15%), microcrystalline cellulose (e.g., Avicel.sup.(R0-102) (15.8%), sodium starch (7%), sodium lauryl sulfate (2%) and magnesium stearate (1%).

[0094] The HPMCAS polymers are available in low, medium, and high grades as Aqoa.sup.(R)-LF, Aqoat.sup.(R)-MF and Aqoat.sup.(R)-HF respectively from Shin-Etsu Chemical Co., LTD, Tokyo, Japan. The higher MF and HF grades are generally preferred.

[0095] The pharmaceutical composition can be in the form of a soft gel dosage formulation. The soft gel dosage formulation can comprise Compound I in an amount 0.01 to 20 wt% of the total weight of the formulation; a lipophilic phase comprising triglycerides of fatty acids in an amount of 50 to 80 wt% of the total weight of the formulation; and at least one lipophilic surfactant comprising partial esters of polyol and fatty acids in an amount of 10 to 50 wt% of the total weight of the formulation. The formulation can further comprise at least one hydrophilic surfactant with a hydrophilic lipophilic balance (“HLB”) above 10 in an amount of 1 to 30 wt% of the total weight of the formulation. The at least one hydrophilic surfactant can comprise at least one of polyoxyethylene (20) monooleate, PEG 8 caprylic / capric glycerides, PEG 6 caprylic / capric glycerides, or poly(oxyethylene)(4)Lauryl ether.

[0096] The pharmaceutical composition can be a formulation for intranasal administration. The formulation can comprise 1 to 200 mg / mL of Compound I in 50 mM succinate solution and comprising 1 to 2% (w / w) dextrose at a pH of 5.5 to 6.5 (preservative free). The formulation can comprise Compound I, a pharmaceutically acceptable solubilizing agent (for example, water or an alcohol) in an amount effective to solubilize Compound I, a receptivity agent capable of mitigating an undesirable response to the pharmaceutical composition at or in proximity to the locus of administration in or on the subject (for example, at least one of a natural sweetener, a synthetic sweetener, a flavorant, an aromatic compound, or a taste-masking compound), succinic acid, and an optional acid or base.

[0097] The following paragraphs describe exemplary formulations, dosages, etc. useful for non-human animals. The administration of the compounds of the present disclosure and combinations of the compounds of the present disclosure with other agents can be affected orally or non-orally.

[0098] An amount of Compound I or combination of Compound I with another agent is administered such that an effective dose is received. Generally, a daily dose that is administered orally to an animal is about 0.01 to about 1 ,000 milligrams per kilogram (mg / kg) of body weight, e.g., about 0.01 to about 300 mg / kg or about 0.01 to about 100 mg / kg or about 0.01 to about 50 mg / kg of body weight, or about 0.01 to about 25 mg / kg, or about 0.01 to about 10 mg / kg, or about 0.01 to about 5 mg / kg.

[0099] Conveniently, Compound I (or a combination) can be carried in the drinking water so that a therapeutic dosage of the compound is ingested with the daily water supply. The compound can be directly metered into drinking water, preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water- soluble salt).

[0100] Conveniently, Compound I (or a combination) can also be added directly to the feed, as such, or in the form of an animal feed supplement, also referred to as a premix or concentrate. A premix or concentrate of the compound in an excipient, diluent or carrier is more commonly employed for the inclusion of the agent in the feed. Suitable excipients, diluents or carriers are liquid or solid, as desired, such as water, various meals such as alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, corncob meal and corn meal, molasses, urea, bone meal, and mineral mixes such as are commonly employed in poultry feeds. A particularly effective excipient, diluent, or carrier is the respective animal feed itself; that is, a small portion of such feed. The carrier facilitates uniform distribution of the compound in the finished feed with which the premix is blended. Preferably, the compound is thoroughly blended into the premix and, subsequently, the feed. In this respect, the compound may be dispersed or dissolved in a suitable oily vehicle such as soybean oil, corn oil, cottonseed oil, and the like, or in a volatile organic solvent and then blended with the carrier. It will be appreciated that the proportions of compound in the concentrate are capable of wide variation since the amount of the compound in the finished feed may be adjusted by blending the appropriate proportion of premix with the feed to obtain a desired level of compound.

[0101] High potency concentrates may be blended by the feed manufacturer with proteinaceous carrier such as soybean oil meal and other meals, as described above, to produce concentrated supplements, which are suitable for direct feeding to animals. In such instances, the animals are permitted to consume the usual diet. Alternatively, such concentrated supplements may be added directly to the feed to produce a nutritionally balanced, finished feed containing a therapeutically effective level of Compound I. The mixtures are thoroughly blended by standard procedures, such as in a twin shell blender, to ensure homogeneity.

[0102] If the supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the compound across the top of the dressed feed.

[0103] Drinking water and feed effective for increasing lean meat deposition and for improving lean meat to fat ratio are generally prepared by mixing Compound I with a sufficient amount of animal feed to provide from about 10. sub. -3 to about 500 ppm of the compound in the feed or water.

[0104] The preferred medicated swine, cattle, sheep and goat feed generally contain from about 1 to about 400 grams of Compound I (or a combination) per ton of feed, the optimum amount for these animals usually being about 50 to about 300 grams per ton of feed. The preferred poultry and domestic pet feeds usually contain about 1 to about 400 grams and preferably about 10 to about 400 grams of Compound I (or a combination) per ton of feed.

[0105] For parenteral administration in animals, the compounds of the present disclosure (or combination) may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal in which increase in lean meat deposition and improvement in lean meat to fat ratio is sought.

[0106] Paste Formulations may be prepared by dispersing the drug in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.

[0107] Pellets containing an effective amount of Compound I, pharmaceutical composition, or combination may be prepared by admixing Compound I or combination with a diluent such as carbowax, carnauba wax, and the like, and a lubricant, such as magnesium or calcium stearate, may be added to improve the pelleting process.

[0108] It is, of course, recognized that more than one pellet may be administered to an animal to achieve the desired dose level which will provide the increase in lean meat deposition and improvement in lean meat to fat ratio desired. Moreover, implants may also be made periodically during the animal treatment period in order to maintain the proper drug level in the animal's body.

[0109] The present disclosure has several advantageous veterinary features. For the pet owner or veterinarian who wishes to increase leanness and / or trim unwanted fat from pet animals, the instant disclosure provides the means by which this may be accomplished. For poultry, beef and swine breeders, utilization of the method of the present disclosure yields leaner animals that command higher sale prices from the meat industry.

[0110] Compound I may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wl) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1 -19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der orqanischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)). Many of the compounds used herein, are related to, or are derived from compounds in which there is a large scientific interest and commercial need, and accordingly many such compounds are commercially available or are reported in the literature or are easily prepared from other commonly available substances by methods which are reported in the literature.

[0111] The following examples are provided to help illustrate the present disclosure and are not intended to be limiting.

[0112] EXAMPLES

[0113] Abbreviations generally follow conventions used in the art. Some chemical abbreviations used in the specification and Examples are defined as follows: "DMF" for N,N-dimethylformamide; "MeOH" for methanol; "Ar" for aryl; "TFA" for trifluoroacetic acid; "DMSO" for dimethylsulfoxide; and "THF" for tetrahydrofuran. The following abbreviations are defined: "MS" or "Mass Spec" for mass spectrometry, "HPLC" for high pressure liquid chromatography, "NMR" for nuclear magnetic resonance spectroscopy, "1H" for proton, "13C" for carbon, "5" for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" for broad, "Hz" for hertz, and "a", " beta ", "R", "S", "E", and "Z" are stereochemical designations familiar to one skilled in the art.

[0114] Example 1 : Preparation of zavegeoant. Compound I

[0115] Preparation of Compound I was described in WO201 1 / 123232 and is reproduced below.

[0116] Compound I can be prepared according to Scheme 1 . This synthesis is 14 chemical steps and highly convergent, coupling the three major fragments in the last three steps. As such, the synthesis begins with the preparation of major fragments A (Scheme 2) and B (Scheme 3). Scheme 1

[0117] The synthesis of fragment A begins with Horner-Emmons reaction of N-Boc-4- piperidone with the ylide generated from trimethylphosphonoacetate to afford tert-butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1 -carboxylate in excellent yield (Scheme 2). Catalytic hydrogenation mediated by palladium on carbon reduces the unsaturated double bond. Treatment of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1 -carboxylate with LDA generates the enolate which upon trapping with 2-nitrobenzaldehyde provides the nitro alcohol. Reduction of the nitro group with iron in acetic acid followed by treatment with hydrogen chloride in dioxane completes the synthesis of fragment A. Scheme 2

[0118] The synthesis of indazole amino acid B begins with the iodination of 2,6- dimethylaniline by the action of iodine monochloride (Scheme 3). This intermediate was temporarily set aside. N-CBZ-L-serine methyl ester undergoes a one-pot methanesulfonylation / elimination reaction to afford N-CBZ-dehydroalanine methyl ester. With the iodide and dehydroalanine in hand, they are efficiently coupled using palladium (II) acetate in a Heck coupling to afford the product in 65 percent yield. At this point, the chiral center is installed using a catalytic asymmetric hydrogenation utilizing (-)-1 ,2- bis((2R,5R)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(l) tetrafluoroborate and hydrogen (60 pounds per square inch (psi) (414 kilopascal)) to give the chiral amino acid in "96 percent enantiomeric excess (ee). The indazole ring is then formed by the action of iso-amyl nitrite. The resulting indazole is highly crystalline. One recrystallization from acetone / hexanes affords the indazole amino acid in excellent purity and with an improved 99.8 percent ee. Removal of the CBZ protecting group under hydrogenation conditions completes the preparation of fragment B. Indazole amino acid B can also be prepared using enzymatic resolution of the racemic amino acid or keto acid (Hanson, Ronald L.; Davis, Brian L.; Goldberg, Steven L.; Johnston, Robert M.; Parker, William L.; Tully, Thomas P.; Montana, Michael A.; Patel, Ramesh N. Process Research and Development, Bristol-Myers Squibb, New Brunswick, N.J., USA. Organic Process Research and Development (2008), 12(6), 1119-1129.). Scheme 3

[0119] Fragments A and B are efficiently coupled using / V, / V-disuccinimidyl carbonate to install the urea moiety in 78 percent yield (Scheme 4). Saponification of the methyl ester with lithium hydroxide gives a nearly quantitative yield of the carboxylic acid. TBTU™ mediated coupling of acid with 1 -(1 -methylpiperidin-4-yl)piperazine completes the synthesis of Compound I. Flash chromatography affords the product as an amorphous powder which can be crystallized from acetone to afford Compound I as a fine white crystalline powder.

[0120] Scheme 4 tert-butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1 -carboxylate. Sodium hydride in mineral oil (60 percent, 7.92 grams (g), 198.02 millimoles (mmoles)) was washed with hexanes then suspended in dimethylformamide (220 milliliters (mL)). The mixture was cooled to 0 degrees centigrade Trimethyl phosphonoacetate (29.0 mL, 189.82 mmoles) was added dropwise to the stirred reaction mixture. After 20 minutes at 0 degrees centigrade (°C), a solution of N-tert-butoxycarbonyl-4-piperidone (30.41 g, 152.62 mmoles) in dimethylformamide (80 mL) was added to the mixture dropwise. The reaction was stirred at room temperature for 3 hours and then diluted with diethyl ether (650 mL). The mixture was washed once with water and the aqueous layer was extracted once with diethyl ether. The combined organic layers were washed 4 times with water and the aqueous phase was discarded. The organic phase was washed with brine and dried over magnesium sulfate, filtered, and concentrated to dryness. The title compound was obtained as a white solid in 92 percent yield.1H-NMR (300 megahertz (MHz), CDCI3): 6=5.68 (s, 1 H), 3.66 (s, 3H), 3.40-3.51 (m, 4H), 2.90 (t, J=5.49, 2H), 2.25 (t, J=5.49, 2H), 1 .44 (s, 9H). tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1 -carboxylate. A solution of tertbutyl 4-(2-methoxy-2-oxoethylidene)piperidine-1 -carboxylate (35.71 g, 140 mmoles) in a mixture of 1 :1 ethyl acetate / methanol (220 mL) was carefully treated with 50 percent wet 10 percent palladium on carbon (3.3 g). The reaction vessel was charged with 55 psi (379 kPa) of hydrogen gas and the mixture was shaken on a Parr apparatus at room temperature for 16 hours. The reaction mixture was then filtered to remove the catalyst and the filtrate concentrated in vacuo. The title compound was obtained as a clear colorless oil in 97 percent yield.1H-NMR (300 MHz, CDCI3): 6 =4.04 (d, J=10.25, 2H), 3.64 (s, 3H), 2.68 (t, =12.44, 2H), 2.21 (d, J=6.95, 2H), 1 .98-1 .77 (m, 1 H), 1 .64 (d, J=13.54, 2H), 1.41 (s, 9H), 1.25-0.99 (m, 2H).

[0121] 4-[2-Hydroxy- 1 -methoxycarbonyl-2-(2-nitro-phenyl)-ethyl]-piperidine- 1 -carboxylic acid tert-butyl ester. N,N-diisopropylamine (4.40 mL, 31 .3 mmoles) was dissolved in tetrahydrofuran (50 mL). The mixture was cooled to -78°C Butyllithium (2.5 molar (M) in hexanes, 12.4 mL, 31 mmoles) was added dropwise to the stirred solution. After stirring at -78°C for 30 minutes (min), a solution of tert-butyl 4-(2-methoxy-2- oxoethyl)piperidine-1 -carboxylate (6.65 g, 25.8 mmoles) in tetrahydrofuran (15 mL) was added dropwise to the mixture. Stirring was continued at -78°C for 1 hour (h). A solution of 2-nitrobenzaldehyde (3.90 g, 25.8 mmoles) in tetrahydrofuran (20 mL) was then added to the mixture dropwise, and then stirring was continued at -78°C for a further 2.5 h. The reaction was quenched with cold aqueous ammonium chloride and then diluted with water. The mixture was extracted twice with ethyl acetate and the aqueous phase was discarded. The material was dried (magnesium sulfate) filtered, and concentrated to dryness. Silica gel chromatography afforded the desired product in 94 percent yield as light-yellow foam. MS m / e (M-C4H8+H)+=353.1 .

[0122] 4-(4-Hydroxy-2-oxo- 1 ,2,3, 4-tetrahydro-quinolin-3-yl)-piperidine-1 -carboxylic acid tert-butyl ester. In a 3-neck flask fitted with a nitrogen inlet, thermometer, and a mechanical stirrer, 4-[2-hydroxy-1 -methoxycarbonyl-2-(2-nitro-phenyl)-ethyl]-piperidine- 1 -carboxylic acid tert-butyl ester (9.93 g, 24.3 mmoles) was dissolved in acetic acid (1.75 moles, 100 mL). Iron powder (8.90 g, 159 mmoles) was added to the vessel with stirring. The stirred mixture was slowly heated to 80 degrees centigrade for 30 min and then cooled to room temperature. It was then diluted with ethyl acetate and filtered through a pad of celite. Solids were washed with 20 percent methanol / ethyl acetate, and then with methanol. The filtrate was concentrated, and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate. The layers were separated. The resulting aqueous phase was extracted twice with ethyl acetate. The organic layers were combined. The mixture was washed twice with water and the aqueous phase was discarded. The material was dried (magnesium sulfate) filtered, and concentrated to dryness. Silica gel chromatography afforded the title compound as light-yellow foam in 77 percent yield. MS m / e (M-H) =345.1 .

[0123] 3-(Piperidin-4-yl)quinolin-2(1 H) hydrochloride. A stirred solution of 4-(4-hydroxy- 2-oxo-1 , 2, 3, 4-tetrahydro-quinolin-3-yl)-piperidine-1 -carboxylic acid tert-butyl ester (5.60 g, 16.2 mmoles) in ethyl acetate (70 mL) was treated with HCI in dioxane (4N, 40 mmoles, 10 mL). The mixture was stirred at room temperature for 45 min. More HCI in dioxane (4N, 120 mmoles, 30 mL) was then added and stirring was continued at room temperature for 16 h. The resulting solid was collected by filtration and washed with ethyl acetate. It was then suspended in 5 percent water-isopropanol (100 mL) and the mixture was warmed to reflux and stirred for 20 min. The mixture was cooled to room temperature and stirred at room temperature for 16 h. The solid was collected by filtration, washed with isopropanol, and dried under high vacuum. The title compound was obtained as white solid in 75 percent yield.1H-NMR (DMSO-de) 6 11 .85 (s, 1 H), 9.02 (bs, 1 H), 8.88 (bs, 1 H), 7.70 (t, J=3.81 Hz, 2H), 7.53-7.30 (d, J=8.24 Hz, 1 H), 7.17 (t, J=7.48 Hz, 2H), 3.36 (d, J=12.51 Hz, 2H), 3.10-2.94 (m, 3H), 2.01 (d, J=13.43 Hz, 2H), 1 .87-1 .73 (m, 2H); MS m / e (M+H)+=229.0.

[0124] 4-lodo-2,6-dimethylbenzenamine hydrochloride. To a suspension of sodium bicarbonate (126 g, 1.5 moles) and 2,6-dimethylaniline (61.5 mL, 500 mmoles) in methanol (700 mL) was added iodine monochloride (1 .0 M in dichloromethane, 550 mL, 550 mmoles) at room temperature over 1 h. After addition was complete, stirring was continued for 3 h. The reaction was filtered to remove excess sodium bicarbonate and the solvent removed in vacuo. The residue was re-dissolved in diethyl ether (1 .5 L) and treated with hydrochloric acid (2M in ether, 375 mL, 750 mmoles). The resulting suspension was stored in the freezer (-15°C) overnight. The solid was filtered and washed with diethyl ether until it became colorless, to give 126.5 g (89 percent) as a grey-green powder.1H-NMR (DMSO-d6) 5 2.33 (s, 6H), 7.48 (s, 2H), 9.05 (bs, 3H);13C- NMR (DMSO-de) 6 17.4, 91.5, 133.1 , 131.2, 136.9.

[0125] Methyl 2-(benzyloxycarbonyl)acrylate. To a flame dried three-neck round bottom flask, fitted with a mechanical stirrer, was added (S)-methyl 2-(benzyloxycarbonyl)-3- hydroxypropanoate (129 g, 509 mmoles), anhydrous dichloromethane (2 L), and methanesulfonyl chloride (49.3 mL, 636 mmoles). The mixture was cooled to -15°C, and treated with triethylamine (213 mL, 1527 mmoles), dropwise, to ensure the temperature of the reaction mixture did not exceed 0°C. The addition of the first equivalent of triethylamine was exothermic. After addition of triethylamine, the mixture was stirred at 0°C for 30 min. The cooling bath was removed, and the mixture stirred at room temperature for 1 .5 h. The reaction was quenched by addition of methanol (21 mL). The mixture was washed with 0.5 percent aqueous potassium bisulfate until the washings were pH 5, then saturated sodium bicarbonate, and brine, dried over sodium sulfate, and concentrated. Flash chromatography (silica gel, 1 :9 ethyl acetate / hexanes) gave 1 1 1 g (92 percent) as a viscous colorless oil, which crystallized upon standing.1H- NMR (DMSO-de) 5 3.71 (s, 3H), 5.10 (s, 2H), 5.60 (s, 1 H), 5.76 (s, 1 H), 7.39-7.35 (m, 5H), 8.96 (s, 1 H);13C-NMR (DMSO-de) 6 52.3, 65.9, 127.8, 128.1 , 128.3, 128.8, 133.3, 136.3, 153.5, 163.7.

[0126] (Z)-Methyl 3-(4-amino-3,5-dimethylphenyl)-2-(benzyloxycarbonyl)acrylate. A 2 L round bottom flask was charged 4-iodo-2,6-dimethylbenzenamine hydrochloride salt (55 g, 194 mmoles), methyl 2-(benzyloxycarbonyl)acrylate (59.2 g, 252 mmoles), tetrabutylammonium chloride (59.2 g, 213 mmoles), palladium (II) acetate (4.34 g, 19.4 mmoles), and tetrahydrofuran (1 .2 L, degassed by a flow of nitrogen for 30 min). The mixture was stirred so that a suspension was formed and then degassed by a flow of nitrogen for 30 min. Triethylamine (1 10 mL, 789 mmoles) was added and the resulting mixture was heated at reflux for 3 h. After cooling to room temperature, the reaction mixture was filtered through a pad of celite, washed with tetrahydrofuran (2x100 mL), and concentrated. The residue was dissolved in dichloromethane, washed with water (3x) and brine (2x), dried over sodium sulfate, and concentrated. Flash chromatography (silica gel, using 1 :9 ethyl acetate / dichloromethane) gave a tan solid. The solid was recrystallized from warm methanol (210 mL) and water (100 mL). The mixture was held at room temperature overnight, then at 0°C for 2 h, and finally at -15°C for 2 h. The resulting solid was filtered, washed with ice cold 1 :1 methanol / water, and dried under high vacuum overnight to give 44.7 g (65 percent) as a light tan solid which was a mixture of Z / E isomers (73:27).1H-NMR (DMSO-d6) 6, 2.05 (s, 6H), 3.61 (s, 0.8H), 3.68 (s, 2.2H), 5.00 (s, 0.54H), 5.13 (s, 1.46H), 5.24 (s, 2H), 7.40-7.21 (m, 8H), 8.51 (s, 0.27 H), 8.79 (s, 0.73H);13C-NMR (DMSO-d6) 6 17.8, 51.7, 65.3, 119.4, 120.0, 120.3, 127.3, 127.7, 128.3, 130.9, 135.8, 137.2, 146.9, 154.7, 166.0.

[0127] (R)-Methyl 3-(4-amino-3,5-dimethylphenyl)-2-(benzyloxycarbonyl)propanoate. A flame-dried 2-liter (L) Parr hydrogenation bottle was charged with (Z)-methyl 3-(4- amino-3,5-dimethylphenyl)-2-(benzyloxycarbonyl)acrylate (84.5 g, 239 mmoles), dichloromethane (300 mL), and methanol (300 mL). The bottle was swirled so that a light brown suspension was formed. The mixture was degassed using a flow of nitrogen for 30 min. To this was quickly added (-)-1 ,2-bis((2R,5R)-2,5-diethylphospholano)- benzene(cyclooctadiene) rhodium (I) tetrafluoroborate ([(2R,5R)-Et-DuPhosRh]BF4) (2.1 1 g, 3.20 mmoles). The bottle was immediately attached to a Parr Hydrogenator. After 5 cycles of hydrogen (60 psi (414 kPa)) and vacuum, the bottle was pressurized to 65 psi (448 kPa) and the suspension was agitated at room temperature for 16 h. The reaction had become homogeneous. The reaction mixture was concentrated, and the resulting residue purified by flash chromatography (silica gel, 1 :9 ethyl acetate / dichloromethane) to give 82.9 g (98 percent).1H-NMR (DMSO-de) 6 2.04 (s, 6H), 2.65 (dd, J=13.4, 9.8 Hz, 1 H), 2.82 (dd, J=13.7, 5.2Hz, 1 H), 3.62 (s, 3H), 4.15-4.10 (m, 1 H), 4.41 (s, 2H), 5.00 (s, 2H), 6.68 (s, 2H), 7.37-7.28 (m, 5H), 7.70 (d, J=7.9 Hz, 1 H);13C-NMR (DMSO-d6) 6 17.7, 35.9, 51.7, 56.1 , 65.3, 120.4, 124.0, 127.5, 127.7, 128.2, 128.3, 136.9, 142.6, 155.9, 172.5.

[0128] (R)-Methyl 2-(benzyloxycarbonyl)-3-(7-methyl-1H-indazol-5-yl)propanoate. (R)- Methyl 3-(4-amino-3,5-dimethylphenyl)-2-(benzyloxycarbonyl)propanoate (50.0 g, 140 mmoles) was weighed into a flame-dried 5 L three neck round bottom flask, followed by the addition of toluene (2.4 L) and glacial acetic acid (120 mL, 2.1 moles). The mixture was mechanically stirred to form a clear solution, and then potassium acetate (103 g, 1 .05 moles) was added. To the resulting white suspension, iso-amyl nitrite (20.7 mL, 154 mmoles) was added dropwise at room temperature, and the resulting mixture was stirred at room temperature for 16 h. Saturated sodium bicarbonate (1 L) was added, followed by the careful addition of solid sodium bicarbonate to neutralize the acetic acid. The mixture was extracted with a mixture of dichloromethane (2 L) and brine (1 .5 L). After separation, the aqueous layer was extracted with dichloromethane (500 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. Solvents were removed to afford a tan solid, which was washed with hexanes (2 L) and toluene (150 mL). The solid was recrystallized from hot acetone (260 mL) and hexanes (700 mL). The slightly cloudy mixture was allowed to cool to room temperature slowly, then to 0°C for 1 .5 h, and finally to -15°C for 1 .5 h. The resulting solid was filtered and washed with ice-cold acetone / hexanes (1 :1 , 200 mL) to afford 39.1 g (76 percent yield). Analytical HPLC showed >98 percent UV purity. The enantiomeric excess (ee) was determined to be 99.8 percent (conditions: Chiralpak AD column, 4.6x250 millimeters (mm), 10 pm; A=ethanol, B=0.05 percent diethylamine / heptane; 85 percent B @1 .0 mL / min. for 55 min. The retention times for R was 44.6 min and for S was 28.8 min)1H- NMR (DMSO-de) 5 2.48 (s, 3H), 2.93 (dd, J=13.4, 10.7 Hz, 1 H), 3.10 (dd, J=13.7, 4.9 Hz, 1 H), 3.63 (s, 3H), 4.32-4.27 (m, 1 H), 4.97 (s, 2H), 7.03 (s, 1 H), 7.24-7.22 (m, 2H), 7.29-7.27 (m, 3H), 7.41 (s, 1 H), 7.83 (d, J=8.2Hz, 1 H), 7.99 (s, 1 H), 13.1 (s, 1 H);13C- NMR (DMSO-de) 6 16.7, 36.5, 51 .8, 56.0, 65.3, 1 17.6, 1 19.6, 122.7, 127.2, 127.4, 127.6, 128.2, 129.3, 133.4, 136.8, 139.2, 155.9, 172.4. Mass spec.: 368.16 (MH)+.

[0129] (R)-Methyl 2-amino-3-(7-methyl-1 H-indazol-5-yl)propanoate. A Parr hydrogenation bottle was charged with (R)-methyl 2-(benzyloxycarbonyl)-3-(7-methyl- 1 H-indazol-5-yl)propanoate (1 1 .0 g, 29.9 mmoles) and methanol (75 mL). The suspension was purged with nitrogen and treated with palladium (10 percent on charcoal, 700 mg). The bottle was shaken under hydrogen (15 psi (103 kPa)) overnight. The mixture was filtered through a pad of celite to remove the catalyst. Concentration of the eluent gave 7.7 g (quant.) as an oil which was used without further purification.1H- NMR (CD3OD) 5 2.54 (s, 3H), 2.98 (dd, =13.5, 7.0 Hz, 1 H), 3.09 (dd, =13.5, 5.9 Hz, 1 H), 3.68 (s, 3H), 3.75 (dd, J=7.0, 6.2Hz, 1 H), 7.01 (s, 1 H), 7.39 (s, 1 H), 7.98 (s, 1 H). Mass spec.: 232.34 (M-H)-.

[0130] (R)-methyl 3-(7-methyl-1 H-indazol-5-yl)-2-(4-(2-oxo- 1 ,2-dihydroquinolin-3- yl)piperidine-1-carboxamido)propanoate. To a solution of (R)-methyl 2-amino-3-(7- methyl-1 H-indazol-5-yl)propanoate hydrochloride (7.26 g, 27.0 mmoles) in dimethylformamide (50 mL) at room temperature was added N,N'-disuccinimidyl carbonate (7.60 g, 29.7 mmoles) followed by triethylamine (1 1 .29 mL, 81 mmoles). The resulting mixture was stirred for 30 min and treated with 3-(piperidin-4-yl)quinolin-2( 1 H)- one (6.77 g, 29.9 mmoles) in portions. The reaction was allowed to stir for 24 h. The mixture was concentrated, dissolved in ethyl acetate, and washed sequentially with water, brine, and 0.5 normal (N) HCI (2x). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography (silica gel, 20:1 ethyl acetate / methanol) to give 1 1 .9 g (78 percent).1H-NMR (CD3OD) 5 13.0 (s, 1 H), 1 1.8 (s, 1 H), 7.98 (s, 1 H), 7.63 (d, J=7.6 Hz, 1 H), 7.57 (s, 1 H), 7.45-7.41 (m, 2H), 7.27 (d, J=8.2Hz, 1 H), 7.16 (t, J=7.9 Hz, 1 H), 7.03 (s, 1 H), 6.85 (d, J=7.9 Hz, 1 H), 4.31 -4.26 (m, 1 H), 4.10-4.08 (m, 2H), 3.60 (s, 3H), 3.07- 3.01 (m, 2H), 2.93-2.88 (m, 1 H), 2.77-2.67 (m, 2H), 2.48 (s, 3H), 1.78-1.72 (m, 2H), 1 .34-1 .26 (m, 2H). Mass spec.: 488.52 (MH)+.

[0131] (R)-3-(7-methyl- 1 H-indazol-5-yl)-2-(4-(2-oxo- 1 ,2-dihydroquinolin-3-yl)piperidine- 1 -carboxamido)propanoic acid. A solution of (R)-methyl 3-(7-methyl-1 H-indazol-5-yl)-2- (4-(2-oxo-1 ,2-dihydroquinolin-3-yl)piperidine-1 -carboxamido)propanoate (5.50 g, 11.3 mmoles) in tetrahydrofuran (50 mL) and methanol (10 mL) was cooled to 0 degrees centigrade To this was added a cold (0°C) solution of lithium hydroxide monohydrate (0.95 g, 22.6 mmoles) in water (20 mL), dropwise over 15 min. The reaction was stirred at room temperature for additional 3 h. The mixture was concentrated to remove the organic solvents. The resulting residue was dissolved in a minimum amount of water, cooled to 0°C, and treated with cold (0°C) 1 N HCI until pH 2 was attained. The resulting solid was collected by filtration, washed with cold water and ether, and then dried overnight under high vacuum to give 5.0 g (94 percent) as a white solid.1H-NMR (DMSO-de) 6 13.05 (bs, 1 H), 1 1 .77 (s, 1 H), 7.98 (s, 1 H), 7.62 (d, J=8.0 Hz, 1 H), 7.55 (s, 1 H), 7.44 (d, J=8.2Hz, 1 H), 7.42 (s, 1 H), 7.27 (d, J=8.2Hz, 1 H), 7.16 (t, J=7.6 Hz, 1 H), 7.05 (s, 1 H), 6.65 (d, J=7.9 Hz, 1 H), 4.27-4.22 (m, 1 H), 4.10-4.07 (m, 2H), 3.12-3.07 (m, 1 H), 3.03-2.99 (m, 1 H), 2.93-2.88 (m, 1 H), 2.77-2.66 (m, 2H), 2.47 (s, 3H), 1 .77- 1 .74 (m, 2H), 1 .34-1 .27 (m, 2H). Mass spec.: 474.30 (MH)+.

[0132] (R)-N-(3-(7-methyl- 1 H-indazol-5-yl- 1-(4-(1 -methylpiperidin-4-yl)piperazin- 1 -yl)- 1 - oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1 -carboxamide (I). A flask was charged with (R)-3-(7-methyl-1 H-indazol-5-yl)-2-(4-(2-oxo-1 ,2-dihydroquinolin-3- yl)piperidine-1 -carboxamido)propanoic acid (2.9 g, 6.11 mmoles), triethylamine (3.00 mL, 21 .5 mmoles), 1-(1-methylpiperidin-4-yl)piperazine (1 .23 g, 6.72 mmoles), and dimethylformamide (10 mL). The resulting solution was treated with 2-(1 H- benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (2.26 g, 7.03 mmoles) in portions. The reaction was allowed to stir at room temperature overnight. The mixture was concentrated under vacuum to remove dimethylformamide. The crude product was dissolved in 7 percent methanol in dichloromethane and purified by flash chromatography using 7 percent methanol in dichloromethane containing 2 percent of aqueous ammonium hydroxide as eluent. The pure fractions were collected, and solvent was removed under vacuum. The desired product was crystallized from hot acetone to give Compound I in 77 percent yield. Analytical HPLC showed 99.0 percent UV purity at 230 nm. The enantiomeric excess (ee) was determined to be >99.9 percent (conditions: Chiralpak AD column, 4.6x250 mm, 10 micro m; eluent: 70 percent (0.05 percent diethylamine) / heptane / 30 percent ethanol; @1 .0 mL / min. for 45 min. The retention times were 18.7 min for R and 28.1 min for S).1H-NMR (500 MHz, DMSO-de) 5 ppm 13.01 (s, 1 H), 11.76 (s, 1 H), 7.96 (s, 1 H), 7.62 (d, J=7.10 Hz, 1 H), 7.60 (s, 1 H), 7.42 (m, 1 H), 7.36 (s, 1 H), 7.26 (d, J=8.25 Hz, 1 H), 7.14 (m, 1 H), 7.00 (s, 1 H), 6.69 (d, J=8.25 Hz, 1 H), 4.78 (q, J=7.79 Hz, 1 H), 4.14 (d, J=12.37 Hz, 2H), 3.54 (dd, J=9.16, 4.58 Hz, 1 H), 3.24 (m, 1 H), 3.11 (m, 1 H), 2.97 (m, 1 H), 2.89 (m, 2H), 2.69 (m, 4H), 2.32 (m, 1 H), 2.21 (m, 1 H), 2.07 (m, 4H), 1 .95 (t, J=8.25 Hz, 1 H), 1 .87 (m, =11 .28, 11 .28, 3.55, 3.44 Hz, 1 H), 1 .76 (t, =12.03 Hz, 2H), 1 .68 (t, =11 .11 Hz, 2H), 1 .53 (t, J=8.25 Hz, 1 H), 1 .32 (m, 4H), 1 .16 (m, 2H);13C-NMR (DMSO-d6) 6 16.80, 27.30, 30.51 , 30.51 , 30.67, 35.50, 38.04, 41 .74, 44.00, 44.16, 45.35, 45.78, 48.14, 48.39, 51 .45, 54.76, 54.76, 60.61 , 114.53, 117.79, 119.29, 119.34, 121 .57, 122.78, 127.46, 127.79, 129.29, 129.79, 133.31 , 133.72, 136.98, 137.41 , 139.12, 156.50, 161 .50, 170.42. Accurate mass analysis: m / z 639.3770, [MH]+, DELTA=-0.2 ppm. Optical rotation: -27.36° @ 589 nm, concentration of 4.71 mg / mL in methanol.

[0133] Example 2: Preparation of Form 2 of (F?)-A / -(3-(7-methyl-1 / - / -indazol-5-yl)-1 -(4-(1 - methylpiperidin-4-yl)piperazin-1 -yl)-1 -oxopropan-2-yl)-4-(2-oxo-1 ,2-dihydroquinolin-3- yl)piperidine-1 -carboxamide (Compound I, Form 2)

[0134] A Form 2 seed was formed by adding 200 mg of Compound I monohydrochloride anhydrous from Example 1 to 5 mL of acetone in a 25 mL glass vial and slurrying at 25°C for 3 days.

[0135] 2.5 mL of each ethanol and acetone were then added to a 25 mL glass vial with a mini stir bar. 200 mg of Compound I monohydrochloride anhydrous were added and stirred for 5 minutes. Approximately 1% of Form 2 seed was added and the sample was slurried at 45°C for 3 days. The solid form from this procedure was obtained by cooling the slurry to room temperature (about 21 °C) and isolating the solid by filtration in a microcentrifuge tube with 0.45 micron nylon filter for about 30 seconds. The solid form was characterized by PXRD analysis and assigned as Form 2 (Compound I, Form 2).

[0136] Powder X-Ray Diffraction for Form 2

[0137] Powder X-ray diffraction analysis was conducted using a Bruker AXS D8 Endeavor diffractometer equipped with a Copper (Cu) radiation source. The divergence slit was set at 11 mm continuous illumination. Diffracted radiation was detected by a PSD-Lynx Eye detector, with the detector PSD opening set at 4.111 degrees. The X-ray tube voltage and amperage were set to 40 kV and 40 mA respectively. Data was collected at the Cu wavelength (CuKd = 1 .54060 A) in the Theta-Theta goniometer from 3.0 to 39.993 degrees 2-Theta (20) using a step size of 0.016 degrees and a step time of 0.4 second. The antiscatter screen was set to a fixed distance of 1 .5 mm. Samples were rotated during data collection. Samples were prepared by placing them in a silicon low background sample holder and rotated during collection. Data were collected using Bruker DIFFRAC Plus software and analysis was performed by EVA diffract plus software. The collected powder pattern of Compound I monochloride acetone solvate was compared to the simulated powder pattern from the crystal structure. The PXRD data file was not processed prior to peak searching. Using the peak search algorithm in the DIFFRAC.EVA 5.0 software, peaks selected with a threshold value of 1 were used to make preliminary peak assignments. To ensure validity, adjustments were manually made; the output of automated assignments was visually checked, and peak positions were adjusted to the peak maximum. Peaks with relative intensity of > 3% were generally chosen. Lower intensity peaks were included for low angles if considered to be characteristic of the form. Typically, the peaks which were not resolved or were consistent with noise were not selected. A typical error associated with the peak position from PXRD stated in USP up to + / - 0.2° 2-Theta (USP-941 ).

[0138] The PXRD pattern for Compound I, Form 2 is provided in FIG. 1 , and the corresponding peak list is provided in Table 1 , where a variability of ±0.2° 2-theta is assigned to these peaks. This pattern was confirmed with single crystal X-ray crystallography. The characteristic powder pattern obtained from the single crystal structure is provided in FIG. 2, and crystallographic information is provided in Table 2, where * indicates the peaks considered to be characteristic of Form 2.

[0139] 20

[0140] Example 3: Preparation of the amorphous of (F?)- / V-(3-(7-methyl-1 / - / -indazol-5-yl)-1 -(4-

[0141] (1 -methylpiperidin-4-yl)piperazin-1 -yl)-1 -oxopropan-2-yl)-4-(2-oxo-1 ,2-dihydroquinolin-3- yl)piperidine-1 -carboxamide (Compound I, Form 3) 21 .7 mg of Compound I monohydrochloride anhydrous from Example 1 was added to an HPLC vial containing 920 microliters of ethanol and 80 microliters of acetone with flea stir bar. The sample was capped and slurried at 45°C for 1 day. Approximately 10 microliters of slurry were removed, and the solvent was evaporated at ambient conditions, which produced a glassy material of Form 3 that was confirmed to be amorphous via XRD.

[0142] Powder X-Ray Diffraction for Form 3

[0143] Powder X-ray diffraction analysis was conducted using a Bruker AXS D8 Endeavor diffractometer equipped with a Copper (Cu) radiation source. The divergence slit was set at 11 mm continuous illumination. Diffracted radiation was detected by a PSD-Lynx Eye detector, with the detector PSD opening set at 4.111 degrees. The X-ray tube voltage and amperage were set to 40 kilovolts (kV) and 40 milliamps (mA) respectively. Data was collected at the Cu wavelength (CuKd = 1 .54060 A) in the Theta- Theta goniometer from 3.0 to 39.993 degrees 2-Theta using a step size of 0.016 degrees and a step time of 0.4 second. The antiscatter screen was set to a fixed distance of 1 .5 mm. Samples were rotated during data collection. Samples were prepared by placing them in a silicon low background sample holder and rotated during collection. Data were collected using Bruker DIFFRAC Plus software and analysis was performed by EVA diffract plus software.

[0144] The PXRD pattern for Compound I, Form 3 is provided in Figure 3 and is consistent with an amorphous material.

[0145] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application for all purposes.

[0146] It will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims.

Claims

CLAIMSWhat is claimed is:1 . A crystalline form of zavegepant, wherein the crystalline form is a crystalline monohydrochloride acetone solvate.

2. The crystalline form of Claim 1 , wherein the crystalline form has a powder x-ray diffraction pattern comprising 2-theta values of (CuKa radiation, wavelength of 1.54056 A) 9.4 ± 0.2 and 12.1 ± 0.2.

3. The crystalline form of any of the preceding claims, wherein the crystalline form has a powder x-ray diffraction pattern comprising 2-theta values of (CuKa radiation, wavelength of 1 .54056 A) 9.4 ± 0.2 and 12.1 ± 0.2 and at least one of 13.1 ± 0.2, 13.5 ± 0.2, 16.7 ± 0.2, 17.0 ± 0.2, 18.4 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 20.9 ± 0.2, 21 .4 ± 0.2, 22.9 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.0 ± 0.2, 27.1 ± 0.2, and 27.6 ± 0.2.

4. The crystalline form of any of the preceding claims, wherein the zavegepant is present in the crystalline form of the monohydrochloride acetone solvate in an amount of greater than or equal to 85 wt% based on the total weight of the zavegepant.

5. A method of producing the crystalline form of any of the preceding claims, comprising forming a mixture comprising zavegepant and a solution comprising acetone; adding a zavegepant seed to the mixture; forming a slurry from the mixture; and separating the crystalline form from the slurry.

6. A method of producing a monohydrochloride anhydrous form of Compound I, comprising desolvating the crystalline form of any of Claims 1 to 4 to form the monohydrochloride anhydrous form.

7. An amorphous form of the hydrochloride salt of zavegepant.

8. The amorphous form of Claim 7, wherein the zavegepant is present in the amorphous form in an amount of greater than or equal to 85 wt% based on the total weight of the zavegepant.

9. A method of producing the amorphous form of Claim 8, comprising mixing zavegepant in an acetone solution to form a mixture; forming a slurry from the mixture; separating the zavegepant from the slurry; and desolvating the zavegepant to form the amorphous form of the zavegepant.

10. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the crystalline forms of any of Claims 1 to 4 or the amorphous form of the zavegepant of any of Claims 7 to 8; and a pharmaceutically acceptable carrier.

11. A method of treating a CGRP related disorder comprising administering the pharmaceutical composition of Claim 10 to a patient.

12. The method of Claim 11 , wherein the CGRP related disorder is migraine.

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