WO2010108103A1 - Azepan-2-one derivatives - Google Patents

Abstract

This invention relates to novel azepan-2-ones, their derivatives, and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a calcitonin gene -related peptide (CGRP) receptor antagonist.

Description

AZEPAN-2-ONE DERIVA TIVES

Related Application

[0001] The application claims priority to U.S. Provisional Application No. 61/161,678 filed March 19, 2009, which is incorporated by reference herein in its entirety.

Field of the Invention

[0002] This invention relates to novel azepan-2-ones, their derivatives, pharmaceutically acceptable salts, solvates, and hydrates thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a calcitonin gene-related peptide (CGRP) receptor antagonist.

Background of the Invention

[0003] Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor subject compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. A rapidly metabolized drug may also expose subjects to undesirable toxic or reactive metabolites.

[0004] Another ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites. As a result, some subjects receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that subjects receive a suboptimal amount of the active agent. In certain cases, modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound. [0005] In some select cases, a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. The FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverse effects and adds to the pill burden for HIV subjects who must already take a combination of different drugs. Similarly, the CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect. Quinidine, however, has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine at www.accessdata.fda.gov).

[0006] In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme's activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.

[0007] A potentially attractive strategy for improving a drug's metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP -mediated metabolism of a drug or to reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability . At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

[0008] Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, MI et al, J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res 1985, 14:1-40 ("Foster"); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9:101-09 ("Fisher")). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p. 35 and Fisher at p. 101).

[0009] The effects of deuterium modification on a drug's metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem. 1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.

[0010] Diseases and disorders that are known to involve CGRP or the activation of adenylyl cyclase caused by the binding of CGRP to its cell-surface receptor include migraine and cluster headache (Doods, Curr Opin Inves Drugs 2001, 2(9):1261-1268; Edvinsson et al, Cephalalgia 1994, 14:320-327); chronic tension type headache (Ashina et al, Neurology 2000, 14:1335-1340); pain (Yu et al, Eur J Pharm 1998, 347:275-282); chronic pain (Hulsebosch et al, Pain 2000, 86:163-175); neurogenic inflammation and inflammatory pain (Holzer, Neurosci 1988, 24:739-768; Delay-Goyet et al, Acta Physiol Scanda 1992, 146:537- 538; Salmon et al, Nature Neurosci 2001, 4(4):357-358); eye pain (May et al, Cephalalgia 2002, 22:195-196), tooth pain (Awawdeh et al, Int Endocrinol J 2002, 35:30-36), non insulin dependent diabetes mellitus (Molina et al, Diabetes 1990, 39:260-2651; vascular disorders; inflammation (Zhang et al, Pain 2001, 89:265), arthritis, asthma (Foster et al, Ann NY Acad Sci 1992, 657:397-404; Schini et al, Am J Physiol 1994, 267:H2483-H2490; Zheng et al, J Virol 1993, 67:5786-5791); shock, sepsis (Beer et al, Crit Care Med 2002, 30(8): 1794-1798); opiate withdrawal syndrome (Salmon et al, Nature Neurosci 2001, 4(4):357-358) morphine tolerance (Menard et al, J Neurosci 1996, 16(7):2342-2351); hot flashes in men and women (Chen et al, Lancet 1993, 342:49; Spetz et al, J Urology 2001, 166:1720-1723); allergic dermatitis (Wallengren, Contact Dermatitis 2000, 43(3): 137-143); encephalitis, brain trauma, ischemia, stroke, epilepsy, and neurodegenerative diseases (Roehrenbeck et al, Neurobiol of Disease 1999, 6:15-34); skin diseases (Geppetti and Holzer, Eds., Neurogenic Inflammation, 1996, CRC Press, Boca Raton, FL), neurogenic cutaneous redness, rosacea and erythema. [0011] MK-0974 also known as telcagepant, has the chemical name N-[6(S)-(2,3- difluorophenyl)-2-oxo-l-(2,2,2-trifluoroethyl)perhydroazepan-3(R)-yl]-4-(2-oxo-2,3- dihydro-lH-imidazo[4,5-δ]pyridin-l-yl)piperidine-l-carboxamide modulates the CGRP receptor.

[0012] Telcagepant is currently is phase III clinical trials in the United States for the treatment of migraine headaches.

[0013] Despite the reported beneficial activities of telcagepant in clinical trials, there is a continuing need for new compounds to treat the aforementioned diseases and conditions.

Summary of the Invention

[0014] The invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein each Z is independently selected from hydrogen and deuterium, R¹ is selected from CH₂CF₃, CHDCF₃, and CD₂CF₃, and ring A is a cyclohexylamine ring wherein 1 to 9 hydrogen atoms are optionally replaced with deuterium, wherein when R¹ is CH₂CF₃ and each Z is hydrogen, then ring A comprises at least one deuterium atom.

[0015] The invention also provides methods of making compounds of Formula I.

[0016] The invention further provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt therof, and a pharmaceutically acceptable carrier.

[0017] The invention also provides a method of treating a subject suffering from, or susceptible to, headache, cluster headache, chronic tension type headache, pain, chronic pain, neurogenic inflammation and inflammatory pain, neuropathic pain, eye pain, tooth pain, diabetes, non-insulin dependent diabetes mellitus, vascular disorders, inflammation, arthritis, asthma, shock, sepsis, opiate withdrawal syndrome, morphine tolerance, hot flashes, allergic dermatitis, encephalitis, brain trauma, epilepsy, neurodegenerative diseases, skin diseases, neurogenic cutaneous redness, rosacea or erythema, comprising the step of administering to the subject a composition of Formula I, or a pharmaceutically acceptable salt thereof. In an embodiment of the invention, the subject is suffering from or susceptible to migraine headache.

Definitions

[0018] The terms "ameliorate" and "treat" are used interchangeably and include both therapeutic and prophylactic treatment. Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease. The term should not be taken to imply that an animal or human is treated to total recovery.

[0019] "Disease" means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.

[0020] It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a preparation of telcagepant will inherently contain small amounts of deuterated isotopologues. The concentration of naturally abundant stable hydrogen and carbon isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this invention. See, for instance, Wada, E. et al, 1994, Seikagaku 66:15; Gannes, L.Z. et al, 1998, Comp. Biochem. Physiol. MoI. Integr. Physiol. 119:725.

[0021] In the compounds of this invention any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Also unless otherwise stated, when a position is designated specifically as "D" or "deuterium," the position is understood to have deuterium at an abundance of at least about 3000 times greater than the natural abundance of deuterium, which is 0.015% (45% deuterium incorporation).

[0022] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. [0023] In other embodiments, a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least about 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least about 4000 (60% deuterium incorporation), at least about 4500 (67.5% deuterium incorporation), at least about 5000 (75% deuterium incorporation), at least about 5500 (82.5% deuterium incorporation), at least about 6000 (90% deuterium incorporation), at least about 6333.3 (95% deuterium incorporation), at least about 6466.7 (97% deuterium incorporation), at least about 6600 (99% deuterium incorporation), or at least about 6633.3 (99.5% deuterium incorporation).

[0024] The term "isotopologue" refers to a species that differs from a specific compound of this invention only in the isotopic composition thereof.

[0025] The term "compound," when referring to a compound of this invention, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound. However, as set forth above the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0026] The invention also provides salts of the compounds of the invention.

[0027] A salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

[0028] The term "pharmaceutically acceptable," as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

[0029] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β- hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.

[0030] The compounds of the present invention may contain an asymmetric carbon atom, for example, as the result of deuterium substitution or otherwise. As such, compounds of this invention can exist as either individual enantiomers, or as racemic or scalemic mixtures of enantiomers. Accordingly, a compound of the present invention will include racemic and scalemic enantiomeric mixtures, as well as individual respective stereoisomers that are substantially free from another possible stereoisomer. The term "substantially free of other stereoisomers" as used herein means less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers and most preferably less than 2% of other stereoisomers, or less than 1% of other stereoisomers are present. Methods of obtaining or synthesizing an individual enantiomer for a given compound are well known in the art and may be applied as practicable to final compounds or to starting material or intermediates.

[0031] The term "stable compounds," as used herein, refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).

[0032] "D" refers to deuterium. "Stereoisomer" refers to both enantiomers and diastereomers. "Tert", " ^l ", and "t-" each refer to tertiary. "US" refers to the United States of America.

[0033] Throughout this specification, a variable may be referred to generally (e.g., "each Z") or may be referred to specifically (e.g., Z^la, Z^lb, Z², R^3a, etc.). Unless otherwise indicated, when a variable is referred to generally, it is meant to include all specific embodiments of that particular variable.

Therapeutic Compounds

[0034] The present invention provides a compound of Formula I:

, or a pharmaceutically acceptable salt thereof, wherein: each Z is independently selected from hydrogen and deuterium;

R¹ is selected from CH₂CF₃, CHDCF₃ and CD₂CF₃; and ring A is a cyclohexylamine ring wherein 1 to 9 hydrogen atoms are optionally replaced with deuterium, and wherein when R¹ is CH₂CF₃ and each Z is hydrogen, then ring A comprises at least one deuterium atom. [0035] In other embodiments of Formula I: a) R¹ is selected from CH₂CF₃ and CD₂CF₃; and/or b) each Z¹ is the same; and/or c) each Z³ is the same; and/or d) each Z⁴ is the same; and/or

[0036] In more specific embodiments, a compound of Formula I has the features of two or more of a) through e), above.

[0037] In one such embodiment, R¹ is selected from CH₂CF₃ and CD₂CF₃; each Z¹ is the same; each Z³ is the same; each Z⁴ is the same; and ring A is selected from A-I, A-2, A-3, A-4 and A-5. In certain aspects of this embodiment, Z² is hydrogen. In certain aspects of this embodiment, Z² is deuterium. In certain aspects of this embodiment, each Z¹ is hydrogen. In certain aspects of this embodiment, each Z¹ is deuterium. In certain aspects of this embodiment, each Z is hydrogen. In certain aspects of this embodiment, each Z is deuterium. In certain aspects of this embodiment, each Z⁴ is hydrogen. In certain aspects of this embodiment, each Z⁴ is deuterium.

[0038] In yet another embodiment, the compound is selected from any one of the compounds set forth in Table 1 (below):

Table 1 : Exemplary Embodiments of Formula I

and a pharmaceutically acceptable salt thereof.

[0039] In another set of embodiments, any atom not designated as deuterium in any of the embodiments set forth above is present at its natural isotopic abundance.

[0040] The synthesis of compounds of Formula I can be readily achieved by synthetic chemists of ordinary skill by reference to the Exemplary Synthesis and Examples disclosed herein. Relevant procedures and intermediates are disclosed, for instance in PCT publication Nos WO 2004/092168, WO2007/120590, WO2007/120589 and WO2007/120591; and in Paone, D.V. et al, 2007, J. Med. Chem. 50(23):5564-5567.

[0041] Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure. Exemplary Synthesis

[0042] A convenient method for synthesizing compounds of Formula I is depicted in Scheme 1.

[0043] Scheme 1. Preparation of Compounds of Formula I.

[0044] Scheme 1 depicts a general route to preparing compounds of Formula I. Acylation of appropriately deuterated amine 10 with 4-nitrophenyl chloroformate (11) in the presence of triethylamine provides carbamate 12. Reaction of carbamate 12 with appropriately deuterated amine 13 in the presence of triethylamine affords compounds of Formula I.

[0045] Scheme 2. Preparation of amine 10.

[0046] Scheme 2 depicts a preparation of amine 10, which is a useful starting material for Scheme 1. Commercially-available amine 20 is alkylated with appropriately-deuterated bromide 21 to provide secondary amine 22. Amine 22 is coupled with appropriately- deuterated carboxylic acid 23 using EDCI to afford amide 24. Coupling with commercially- available 2,3-difluorophenylboronic acid is achieved via PdC^dppfh'ClHtCb in aqueous DMF or via Pd(PPh₃)₄ in aqueous THF to provide amide 25. Cyclization via metathesis using the "Grubbs II" ruthenium catalyst,

yields lactam 26. Nitrogen deprotection with TFA affords lactam 27. Hydrogenation of 27 using either H₂ or D₂ gas in the presence of Pd/C and BOC₂O, followed by cis/trans isomer separation according to the method of Paone, et al, J Med Chem 2007, 50:5564-5567, yields enantiopure lactam 28. Alkylation with the appropriate electrophile R*-X (wherein X = halide, OSO₂CH₃, OSO₂CF₃, OSO₂C₆H₄CH₃, or OSO₂CCl₃) 29 affords lactam 30. BOC deprotection via treatment with TFA provides amine 10. Alternatively, metathesis may be performed directly on bromide 24 using the Grubbs II catalyst, followed by TFA debenzylation and coupling with 2,3- difluorophenylboronic acid using Pd(OAc)₂ and (m-NaSO₃Ph)₃P to afford lactam 27.

[0047] One example of an appropriately deuterated bromide 21 is known 2,3-

dibromo- 1 -propene-3 ,3-d2,

, (Comer, E et al, JACS 2004, 126(49): 16087-

16092) which is used to ultimately provide compounds of Formula I wherein each Z¹ is deuterium.

[0048] Scheme 3. Preparation of deuterated carboxylic acids 23.

44

43

[0049] Scheme 3 depicts the preparation of deuterated carboxylic acids 23, which are useful reagents for Scheme 2. Following the method of Rose JE et al, J Chem Soc, Perkin Trans 1 1992, 13:1563-5, commercially-available (S)-2,5-dihydro-3,6-dimethoxy-2- isopropylpyrazine (40) (Z⁵ = H) or known (S)-2,5-dihydro-3,6-dimethoxy-2- isopropylpyrazine-d2 40 (Z⁵ = D) is alkylated with an appropriately-deuterated bromide 41 to provide 42. Ring-opening with HCl affords enantiopure ester 43, which is treated with HCl followed by propylene oxide in ethanol to yield enantiopure carboxylic acid 44. CBZ- protection of the amine moiety with NaOH, NaHCO₃ and N-

(benzyloxycarbonyloxy)succinimide (CBZ-OSu) following the method of Ijzendoorn DR et al, Org Lett 2006, 8(2):239-242 affords carboxylic acids 23.

[0050] An example of an appropriately deuterated bromide 41 is known 3-bromo-l-

propene-3,3-d2,

(Pasto DJ et al, J Org Chem 1986, 51(3):412-13; or Kim, JK et al, J Org Chem 1979, 44(12): 1897-1904) which is used in Scheme 3 to ultimately provide compounds of Formula I wherein Z³ is hydrogen and each Z⁴ is deuterium. Another example of an appropriately deuterated bromide 41 is commercially-available allyl-2-dl bromide,

D

Br

2 _s which is used in Scheme 3 to ultimately provide compounds of Formula I wherein Z is deuterium and each Z is hydrogen. In yet another example, one skilled in the

art will appreciate that commercially available allyl-d5 bromide

(4I)₅ could also be used as bromide XVI to ultimately provide compounds of Formula I wherein Z³ is deuterium and each Z⁴ is deuterium.

[0051] Scheme 4. Preparation of amine 13.

[0052] Commercially-available pyridine-2,3-diamine 50 is reductively alkylated with appropriate ly-deuterated ketone 51 using either sodium triacetoxyborohydride or sodium triacetoxyborodeuteride to afford pyridine 52. Treatment with carbonyldiimidazole (CDI) affords cyclized urea 53. BOC cleavage with HCl in MeOH provides amine 13.

[0053] Scheme 5. Preparation of Perdeuterated Ketone 51-ds.

60 61 51 -d₈

[0054] Commercially-available 4-hydroxypyridine-d5 (60) is reduced with deuterium gas in the presence of ruthenium on carbon according to the general procedures of Schaefgen, JR et al, J Polymer Sci 1959, 40:377-87. BOC protection of the resulting amine with BOC₂O in aqueous THF according to the procedures of Kreidler, B et al, Eur J Org Chem 2005, 24:5339-5348, affords carbamate 61. Oxidation with tetrapropylammonium perruthenate (TPAP) following the method of Ren, S et al, Synthesis and Applications of Isotopically Labelled Compounds, Proc Int Symp, 8th, Boston, MA, United States, June 1-5, 2003 (2004), Meeting Date 2003, 473-476, provides ketone 51-d₈.

[0055] Scheme 6. Preparation of ketone 51-(3,5-)d4.

Known benzyl-protected amine 62 (Majchrzak, MW et al, Spectroscopy 1983, 2(3): 190-197) is simultaneously debenzylated and BOC protected via hydrogenation over Pd/C in the presence OfBOC₂O according to the procedures of Ren, S et al, Synthesis and Applications of Isotopically Labelled Compounds, Proc Int Symp, 8th, Boston, MA, United States, June 1- 5, 2003 (2004), Meeting Date 2003, 473-476. Oxidation of alcohol 63 with tetrapropylammonium perruthenate (TPAP) and N-methylmorpholine-N-oxide (NMO) following the same literature reference affords ketone 51-(3,5-)d₄. [0056] Scheme 7. Preparation of ketone 51-f2,6-)d4.

[0057] Known, commercially-available phosphine oxide (64) is treated with sodium hydride and HMPT in THF, followed by addition of formaldehyde-d2, to afford beta- ketoester 65 according to the general methods of Van den Goorbergh, JAM et al, Tet Lett 1980, 21(37):3621-4. Mannich reaction with formaldehyde-d2 and benzylamine, followed by decarboxylation with HCl, provides benzyl-protected amine 66 according to the procedures of Nakatsuka, I et al, J Label Comp Radiopharm 1981, 18(4):495-506. Simultaneous debenzylation and BOC protection via hydrogenation over Pd/C in the presence OfBOC₂O according to the methods of Japanese patent application JP 2001089447 affords ketone 51- (2,6-)d₄.

[0058] Alternatively, ketone 51-(2,6-)d₄ may be prepared from formaldehyde-d2 following the general methods of Ren, S et al, Synthesis and Applications of Isotopically Labelled Compounds, Proc Int Symp, 8th, Boston, MA, United States, June 1-5, 2003 (2004), Meeting Date 2003, 473-476.

[0059] The specific approaches and compounds shown above are not intended to be limiting. The chemical structures in the schemes herein depict variables that are hereby defined commensurately with chemical group definitions (moieties, atoms, etc.) of the corresponding position in the compound formulae herein, whether identified by the same variable name (i.e., Z^la, Z^lb, Z², Z³, etc.) or not. The suitability of a chemical group in a compound structure for use in the synthesis of another compound is within the knowledge of one of ordinary skill in the art.

[0060] Additional methods of synthesizing compounds of Formula I and their synthetic precursors, including those within routes not explicitly shown in schemes herein, are within the means of chemists of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the applicable compounds are known in the art and include, for example, those described in Larock R, Comprehensive Organic Transformations, VCH Publishers (1989); Greene TW et al., Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley and Sons (1999); Fieser L et al., Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and Paquette L, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

[0061] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.

Compositions

[0062] The invention also provides pyrogen-free pharmaceutical compositions comprising an effective amount of a compound of Formula I (e.g., including any of the formulae herein), or a pharmaceutically acceptable salt of said compound; and a pharmaceutically acceptable carrier. The carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.

[0063] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0064] If required, the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions may be enhanced by methods well-known in the art. One method includes the use of lipid excipients in the formulation. See "Oral Lipid- Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences)," David J. Hauss, ed. Informa Healthcare, 2007; and "Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples," Kishor M. Wasan, ed. Wiley-Interscience, 2006.

[0065] Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this invention optionally formulated with a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See United States patent 7,014,866; and United States patent publications 2006/0094744 and 2006/0079502.

[0066] The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques). Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000).

[0067] Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0068] In certain embodiments, the compound is administered orally. Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a nonaqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.

[0069] In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

[0070] Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

[0071] Compositions suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[0072] Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

[0073] The pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

[0074] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, e.g.: Rabinowitz, J.D. and Zaffaroni, A.C., U.S. Patent 6,803,031, assigned to Alexza Molecular Delivery Corporation.

[0075] Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For topical application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.

[0076] Application of the subject therapeutics may be local, so as to be administered at the site of interest. Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.

[0077] Thus, according to yet another embodiment, the compounds of this invention,may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters. Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.

[0078] According to another embodiment, the invention provides a method of coating an implantable medical device comprising the step of contacting said device with the coating composition described above. It will be obvious to those skilled in the art that the coating of the device will occur prior to implantation into a mammal.

[0079] According to another embodiment, the invention provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this invention. Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non- degradable, diffusible polymer capsules and biodegradable polymer wafers.

[0080] According to another embodiment, the invention provides an implantable medical device coated with a compound or a composition comprising a compound of this invention, such that said compound is therapeutically active.

[0081] According to another embodiment, the invention provides an implantable drug release device impregnated with or containing a compound or a composition comprising a compound of this invention, such that said compound is released from said device and is therapeutically active.

[0082] Where an organ or tissue is accessible because of removal from the subject, such organ or tissue may be bathed in a medium containing a composition of this invention, a composition of this invention may be painted onto the organ, or a composition of this invention may be applied in any other convenient way.

[0083] In another embodiment, a composition of this invention further comprises a second therapeutic agent. The second therapeutic agent may be selected from any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered with a compound having the same mechanism of action as telcagepant. Such agents include those indicated as being useful in combination with telcagepant, including but not limited to, those described in WO 2004/092168.

[0084] Preferably, the second therapeutic agent is an agent useful in the treatment or prevention of a disease or condition selected from a compound useful in treating a subject suffering from or susceptible to one or more of the following conditions or diseases: headache; migraine, cluster headache; chronic tension type headache; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; eye pain; tooth pain; diabetes; non-insulin dependent diabetes mellitus; vascular disorders; inflammation; arthritis; asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; ; encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skin diseases; neurogenic cutaneous redness, rosacea and erythema; and other conditions that may be treated or prevented by antagonism of CGRP receptors.

[0085] For example, the compounds of the present invention may be used in conjunction with an anti inflammatory or analgesic agent or an anti-migraine agents such as ergotinine or 5-HTi agonists especially a 5-HT_1BAD agonist, for example sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan, and rizatriptan; a cyclooxygenase inhibitor, such as a selective cyclooxygenase 2 inhibitor, for example rofecoxib, etoricoxib, celecoxib, valdecoxib or parecoxib; a non-steroidal anti-inflammatory agent or a cytokine-suppressing anti-inflammatory agent, for example with a compound such as aspirin, ibuprofen, ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept, tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate, olsalazine or sulfasalazine and the like; or a steroidal analgesic. Similarly, the instant compounds may be administered with a pain reliever such as acetaminophen, phenacetin, codeine, fentanyl, sufentanil, methadone, acetyl methadol, buprenorphine or morphine.

[0086] Additionally, the present compounds may be used in conjunction with an interleukin inhibitor, such as an interleukin-1 inhibitor; an NK-I receptor antagonist, for example aprepitant; an NMDA antagonist; an NR2B antagonist; a bradykinin-1 receptor antagonist; an adenosine Al receptor agonist; a sodium channel blocker, for example lamotrigine; an opiate agonist such as levomethadyl acetate or methadyl acetate; a lipoxygenase inhibitor, such as an inhibitor of 5 -lipoxygenase; an alpha receptor antagonist, for example indoramin; an alpha receptor agonist; a vanilloid receptor antagonist; an mGluR5 agonist, antagonist or potentiator; a GABA A receptor modulator, for example acamprosate calcium; nicotinic antagonists or agonists including nicotine; muscarinic agonists or antagonists; a selective serotonin reuptake inhibitor, for example fluoxetine, paroxetine, sertraline, duloxetine, escitalopram, or citalopram; a tricyclic antidepressant, for example amitriptyline, doxepin, protriptyline, desipramine, trimipramine, or imipramine; a leukotriene antagonist, for example montelukast or zafϊrlukast; an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide.

[0087] Also, the present compounds may be used in conjunction with ergot alkaloids, for example ergotamine, ergonovine, ergonovine, methylergonovine, metergoline, ergoloid mesylates, dihydroergotamine, dihydroergocornine, dihydroergocristine, dihydroergocryptine, dihydro-I-ergocryptine, dihydro-Φ-ergocryptine, ergotoxine, ergocornine, ergocristine, ergocryptine, I-ergocryptine, Φ-ergocryptine, ergosine, ergostane, bromocriptine, or methysergide.

[0088] Additionally, the present compounds may be used in conjunction with a beta- adrenergic antagonist such as timolol, propanolol, atenolol, or nadolol, and the like; a MAO inhibitor, for example phenelzine; a calcium channel blocker, for example flunarizine, nimodipine, lomerizine, verapamil, nifedipine, prochlorperazine or gabapentin; neuroleptics such as olanzapine and quetiapine; an anticonvulsant such as topiramate, zonisamide, tonabersat, carabersat or divalproex sodium; an-angiotensin II antagonist' for example losartan and candesartan cilexetil;an angiotensin converting enzyme inhibitor such as lisinopril; or botulinum toxin type A.

[0089] The present compounds may be used in conjunction with a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextromethorphan; a diuretic; a prokinetic agent such as metoclopramide or domperidone, and a sedating or non-sedating antihistamine.

[0090] In one embodiment the present compounds are used in conjunction with an anti-migraine agent, such as: an ergotamine; a 5-HTi agonist, especially a 5-HT_1BAD agonist, in particular, sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan and rizatriptan; or a cyclooxygenase inhibitor, such as a selective cyclooxygenase-2 inhibitor, in particular, rofecoxib, etoricoxib, celecoxib, meloxicam, valdecoxib or parecoxib.

[0091] In another embodiment, the invention provides separate dosage forms of a compound of this invention and one or more of any of the above-described second therapeutic agents, wherein the compound and second therapeutic agent are associated with one another. The term "associated with one another" as used herein means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).

[0092] In the pharmaceutical compositions of the invention, the compound of the present invention is present in an effective amount. As used herein, the term "effective amount" refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat the target disorder.

[0093] The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described in Freireich et al, (1966) Cancer Chemother. Rep 50: 219. Body surface area may be approximately determined from height and weight of the subject. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N. Y., 1970, 537.

[0094] In one embodiment, an effective amount of a compound of this invention can range from about 0.01 to 500 mg per kg subject body weight per day which can be administered in single or multiple doses. Suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, or may be administered once or twice per day.

[0095] When treating, preventing, controlling, ameliorating, or reducing the risk of headache, migraine, cluster headache, or other diseases for which compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, or from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams or from about 50 milligrams to about 300 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.

[0096] Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co- usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician.

[0097] For pharmaceutical compositions that comprise a second therapeutic agent, an effective amount of the second therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent. Preferably, an effective amount is between about 70% and 100% of the normal monotherapeutic dose. The normal monotherapeutic dosages of these second therapeutic agents are well known in the art. See, e.g., Wells et al, eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are incorporated herein by reference in their entirety.

[0098] In one embodiment of the invention, where a second therapeutic agent is administered to a subject, the effective amount of the compound of this invention is less than its effective amount would be where the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art. Methods of Treatment

[0099] In another embodiment, the invention provides a method of modulating the activity of a calcitonin gene-related peptide (CGRP) receptor antagonist in a cell, comprising contacting the cell with one or more compounds of Formula I herein.

[0100] According to another embodiment, the invention provides a method of treating a subject suffering from, or susceptible to, a disease that is beneficially treated by telcagepant comprising the step of administering to said subject an effective amount of a compound, or a pharmaceutically acceptable salt of said compound, or a composition of this invention. Such diseases are well known in the art and are disclosed in, WO2004/092168.

[0101] Such diseases include, but are not limited to, headache; migraine, cluster headache; chronic tension type headache; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; eye pain; tooth pain; diabetes; non-insulin dependent diabetes mellitus; vascular disorders; inflammation; arthritis; asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; ; encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skin diseases; neurogenic cutaneous redness, rosacea and erythema.

[0102] In one particular embodiment, the method of this invention is used to treat a subject suffering from or susceptible to a disease or condition selected from headache, including migraine and cluster headache.

[0103] In another particular embodiment, the method of this invention is used to treat a subject suffering from or susceptible to migraine headache.

[0104] Methods delineated herein also include those wherein the subject is identified as in need of a particular stated treatment. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).

[0105] In another embodiment, any of the above methods of treatment comprises the further step of co-administering to the subject one or more second therapeutic agents. The choice of second therapeutic agent may be made from any second therapeutic agent known to be useful for co-administration with telcagepant. The choice of second therapeutic agent is also dependent upon the particular disease or condition to be treated. Examples of second therapeutic agents that may be employed in the methods of this invention are those set forth above for use in combination compositions comprising a compound of this invention and a second therapeutic agent.

[0106] The term "co-administered" as used herein means that the second therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an second therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In such combination therapy treatment, both the compounds of this invention and the second therapeutic agent(s) are administered by conventional methods. The administration of a composition of this invention, comprising both a compound of the invention and a second therapeutic agent, to a subject does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this invention to said subject at another time during a course of treatment.

[0107] Effective amounts of these second therapeutic agents are well known to those skilled in the art and guidance for dosing may be found in patents and published patent applications referenced herein, as well as in Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and other medical texts. However, it is well within the skilled artisan's purview to determine the second therapeutic agent's optimal effective-amount range.

[0108] In one embodiment of the invention, where a second therapeutic agent is administered to a subject, the effective amount of the compound of this invention is less than its effective amount would be where the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.

[0109] In yet another aspect, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention in a subject of a disease, disorder or symptom thereof delineated herein. Evaluation of Metabolic Stability

[0110] Microsomal Assay: Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC (Lenexa, KS). β-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl₂), and dimethyl sulfoxide (DMSO) are purchased from Sigma- Aldrich.

[0111] Determination of Metabolic Stability: 7.5 mM stock solutions of test compounds are prepared in DMSO. The 7.5 mM stock solutions are diluted to 12.5-50 μM in acetonitrile (ACN). The 20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl₂. The diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate. A lO μL aliquot of the 12.5-50 μM test compound is added to the microsomes and the mixture is pre-warmed for 10 minutes. Reactions are initiated by addition of pre-warmed NADPH solution. The final reaction volume is 0.5 mL and contains 0.5 mg/mL human liver microsomes, 0.25-1.0 μM test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCl₂. The reaction mixtures are incubated at 37 ⁰C, and 50 μL aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 μL of ice-cold ACN with internal standard to stop the reactions. The plates are stored at 4 ⁰C for 20 minutes after which 100 μL of water is added to the wells of the plate before centrifugation to pellet precipitated proteins. Supernatants are transferred to another 96-well plate and analyzed for amounts of parent remaining by LC-MS/MS using an Applied Bio-systems API 4000 mass spectrometer. The same procedure is followed for telcagepant and the positive control, 7-ethoxycoumarin (1 μM). Testing is done in triplicate.

[0112] Data analysis: The in vitro ti/₂s for test compounds are calculated from the slopes of the linear regression of % parent remaining (In) vs incubation time relationship, in vitro t i_/2 = 0.693/k k = -[slope of linear regression of % parent remaining(ln) vs incubation time]

[0113] Data analysis is performed using Microsoft Excel Software.

[0114] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. It should be understood that the foregoing discussion and examples merely present a detailed description of certain preferred embodiments. It will be apparent to those of ordinary skill in the art that various modifications and equivalents can be made without departing from the spirit and scope of the invention.

Claims

What is claimed is:

1. A compound of Formula I :

, or a pharmaceutically acceptable salt thereof, wherein: each Z is independently selected from hydrogen and deuterium;

R¹ is selected from CH₂CF₃, CHDCF₃ and CD₂CF₃; and ring A is a cyclohexylamine ring wherein 1 to 9 hydrogen atoms are optionally replaced with deuterium, wherein when R¹ is CH₂CF₃ and each Z is hydrogen, then ring A comprises at least one deuterium atom.

2. The compound of claim 1, wherein: a. R¹ is selected from CH₂CF₃ and CD₂CF₃; b. each Z¹ is the same; c. each Z³ is the same; d. each Z⁴ is the same; and

e. ring A is selected from

(A-I), (A-2),

(A-5).

3. The compound of claim 2, wherein each Z is hydrogen.

4. The compound of claim 2, wherein each Z² is deuterium.

5. The compound of any one of claims 2-4, wherein each Z¹ is hydrogen.

6. The compound of any one of claims 2-4, wherein each Z¹ is deuterium.

7. The compound of any one of claims 2-6, wherein each Z is hydrogen.

8. The compound of any one of claims 2-6, wherein each Z³is deuterium.

9. The compound of any one of claims 2-8, wherein each Z⁴ is hydrogen.

10. The compound of any one of claims 2-8, wherein each Z⁴ is deuterium.

11. The compound of claim 2, selected from any one of the compounds set forth in the table below:

and pharmaceutically acceptable salts thereof.

12. The compound of any one of claims 1-11, wherein any atom not designated as deuterium is present at its natural isotopic abundance.

13. A pyrogen-free pharmaceutical composition comprising a compound of any one of claims 1-12 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

14. A compound of any one of claims 1-12 or a composition of claim 13 for use in the treatment of a disease or condition selected from headache; migraine, cluster headache; chronic tension type headache; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; eye pain; tooth pain; diabetes; non-insulin dependent diabetes mellitus; vascular disorders; inflammation; arthritis; asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; ; encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skin diseases; neurogenic cutaneous redness, rosacea and erythema.

15. The compound or composition of claim 14 for the treatment of migraine headache.