WO2009073788A1 - Compositions and methods for treating menopausal females - Google Patents

Abstract

Compositions comprising vanilloid receptor ligands are used for treating human females experiencing symptoms of menopause. The vanilloid receptor ligand composition can be a sustained release formulation of the drug in order to control the release of the drug to the patient over an extended period of time. Methods of treating menopausal patients include administering compositions comprising a vanilloid receptor ligand.

Description

PATENT APPLICATION

COMPOSITIONS AND METHODS FOR TREATING MENOPAUSAL FEMALES

FIELD OF THE INVENTION

[0001] The invention relates to compositions and methods for treating symptoms of menopause in human females.

BACKGROUND OF THE INVENTION

[0002] Menopause is the transition period in a human female life cycle when her ovaries stop producing eggs, her body produces less estrogen and progesterone, and menstruation becomes less frequent, eventually stopping altogether. Menopause is a natural inevitable event of aging that normally occurs between the ages of 45 and 55. The symptoms of menopause are hot flashes and skin flushing, night sweats, insomnia, mood swings including irritability, depression and anxiety, irregular menstrual periods, spotting of blood in between periods, vaginal dryness and painful sexual intercourse, decreased sex drive, vaginal infections and urinary tract infections.

[0003] Treatments for menopausal symptoms in the past have included estrogen replacement therapy. General recommendations for hot flashes presently include wearing layered clothing, breathing slowly with awareness when the flash comes over you, and avoiding spicy foods and caffeinated beverages. Medications available to help with mood swings, hot flashes, and other symptoms include low doses of antidepressants such as paroxetine (Paxil), venlafaxine (Effexor), and fluoxetine (Prozac) or clonidine which is normally used to control high blood pressure.

[0004] Pre-menopause is a time period leading up a full year experienced by a mature female of having no menstrual periods. Thus the period of pre-menopause is defined only in terms of a date of menopause. Peri-menopause is the time period before pre-menopause, and may be defined by changes in hormone levels which can occur with or without any other symptoms. In general hormone levels and a woman's age help to define the precise stage of peri- menopause or pre-menopause, and may be able to distinguish one from the other, but in total as a woman progresses towards menopause she passes through these two time periods and throughout the whole process is said to be "menopausal." From woman to woman these time periods and her experiences in them will vary, and the symptoms indicating the pending, eventual or actual onset of menstrual cessation may vary widely from individual to individual. Once a full year without menstrual periods has been completed, the individual has "gone through" menopause and is then officially postmenopausal. Menopause is a defined as a single day following a complete year of no menstrual periods. Prior to the molecular cloning of VR1 , experimentation with capsaicin indicated the presence of a capsaicin sensitive receptor, which could increase the activity of sensory neurons in humans, rats and mice (Holzer, 1991; Dray, 1992, Szallasi and Blumberg 1996, 1999). The result of acute activation by capsaicin in humans was pain at injection site and in other species increased behavioral sensitivity to sensory stimuli (Szallasi and Blumberg, 1999). Capsaicin application to the skin in humans causes a painful reaction characterized not only by the perception of heat and pain at the site of administration but also by a wider area of hyperalgesia and allodynia, two characteristic symptoms of the human condition of neuropathic pain (Holzer, 1991). Topical or intradermal injection of capsaicin has also been shown to produce localized vasodilation and edema production (Szallasi and Blumberg 1999, Singh et al., 2001). This evidence indicates that capsaicin through its activation of VR1 can regulate afferent and efferent function of sensory nerves. Sensory nerve involvement in diseases could therefore be modified by molecules which affect the function of the vanilloid receptor to increase or decrease the activity of sensory nerves. VR1 gene knockout mice have been shown to have reduced sensory sensitivity to thermal and acid stimuli (Caterina et al., 2000)). Capsaicin and resinferatoxin

2 LHF-003 have been used for studies in in vivo models of disease (Holzer, 1991, Dray 1992, Szallasi and Blumberg 1999). Vanilloids are a class of natural and synthetic compounds that are characterized by the presence of a vanillyl (4-hydroxy 3-methoxybenzyl) group or a functionally equivalent group. Vanilloid Receptor (VR1), whose function is modulated by such compounds, has been widely studied and is extensively reviewed by Szallasi and Blumberg (The American Society for Pharmacology and Experimental Therapeutics, 1999, Vol. 51, No. 2.). A wide variety of Vanilloid compounds of different structures are known in the art, for example those disclosed in European Patent Application Numbers, EP 0347000 and EP 0401 903, UK Patent Application Number GB 2226313 and International Patent Application, Publication Number WO 92/09285. Particularly notable examples of vanilloid compounds or vanilloid receptor modulators are capsaicin or trans 8-methyl-N-vanillyl-6-nonenamide which is isolated from the pepper plant capsazepine (Tetrahedron, 53, 1997, 4791) and olvanil or -N-(4-hydroxy- 3-methoxybenzyl)oleamide (J. Med. Chem., 36, 1993, 2595). U.S. Pat. No. 3,424,760 and U.S. Pat. No. 3,424,761 both describe a series of 3- ureidopyrrolidines that are said to exhibit analgesic, central nervous system, and psychopharmacologic activities. These patents specifically disclose the compounds 1-(1-phenyl-3-pyrrolidinyl)-3-phenyl urea and 1-(1-phenyl-3- pyrrolidinyl)-3-(4-methoxyphenyl)urea respectively. International Patent Application, Publication Number WO 97/43255, discloses azetidinylurea derivatives as inhibitors of microsomal triglyceride transfer protein. International Patent Applications, Publication Numbers WO 02/08221 , WO 02/16317, WO 02/16318 and WO 02/16319 each disclose certain vanilloid receptor antagonists and their use in the treatment of diseases associated with VR1 activity. International Patent Applications, Publication Numbers WO 02/072536 and WO 02/090326, and International Patent Application, Publication Number WO 03/022809 disclose a series of urea derivatives and their use in the treatment of diseases associated with VR1 activity. Azetidinylurea derivatives in

LHF-003 particular azetidin-3-ylurea derivatives are disclosed in US Pub. 2006/0276447 to Fell, owned by Smithkline Beecham. Vanilloid compounds are characterized by:the presence of vanillyl group or a functionally equivalent group. Examples of several vanilloid compounds or vanilloid receptor, modulators are vanillin (4-hydroxy-3-methoxy- benzaldehyde), guaiacol (2-methoxy-phenol), zingeroone (4-/4-hydroxy-3- methoxyphenyl/-2-butanon), eugenol-(2-methoxy4-/2-propenyl/phenol), and capsaicin (8-methy-N-vanillyl-6-nonene-amide). Among others, capsaicin, the main pungent ingredient in "hot" chili peppers, is a specific neurotoxin that desensitizes C-fiber afferent neurons. Capsaicin interacts with vanilloid receptors (VR1), which are predominantly expressed in cell bodies of dorsal root ganglia (DRG) or nerve endings of afferent sensory fibers including C-fiber nerve endings [Tominaga M, Caterina M J, Malmberg A B, Rosen T A, Gilbert H Skinner K, Raumann B E, Basbaum A I, Julius D: The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron. 21 : 531-543, 1998]. The VR1 receptor was recently cloned [Caterina M J, Schumacher M A, Tominaga M, Rosen T A, Levine J D, Julius D: Nature 389: 816-824, (1997)] and identified as a nonselective cation channel with six transmembrane domains that is structurally related to the TRP (transient receptor potential) channel family. Binding of capsaicin to VR1 allows sodium, calcium and possibly potassium ions to flow down their concentration gradients, causing initial depolarization and release of neurotransmitters from the nerve terminals. VR1 can therefore be viewed as a molecular integrator of chemical and physical stimuli that elicit neuronal signals in a pathological conditions or diseases. There are abundant of direct or indirect evidence that shows the relation between VR1 activity and diseases such as pain, ischaemia, and inflammatory (e.g., WO 99/00115 and 00/50387). Further, it has been demonstrated that VR1 transduce reflex signals that are involved in the overactive bladder of patients who have damaged or abnormal spinal reflex pathways [De Groat W C: A neurologic basis for the overactive bladder. Urology 50 (6A Suppl): 36-52, 1997]. Desensitisation of the afferent nerves by

4 LHF-003 depleting neurotransmitters using VR1 agonists such as capsaicin has been shown to give promising results in the treatment of bladder dysfunction associated with spinal cord injury and multiple sclerosis. [(Maggi C A: Therapeutic potential of capsaicin-like molecules-Studies in animals and humans. Life Sciences. 51: 1777-1781 , 1992) and (DeRidder D; Chandiramani V; Dasgupta P; VanPoppel H; Baert L; Fowler C J: Intravesical capsaicin as a treatment for refractory detrusor hyperreflexia: A dual center study with long- term followup. J. Urol. 158: 2087-2092, 1997). Vanilloid receptor ligands (VR1 ligands) and uses therefore are well-known in the art. These ligands are structurally diverse, yet are all readily characterized by their ability to bind the vanilloid receptor 1 , Caterina et al., 1997. VR1 is the first cloned vanilloid receptor, however it is believed that other vanilloid receptors exist. The physiological sensitivity of mammals to vanilloid receptor ligands can be characterized as the ability of these ligands to activate vanilloid- sensitive neurons which express vanilloid receptors. Compounds that bind the vanilloid receptor 1 (VR1 ) have been proposed for use as analgesics for the treatment of pain of various genesis or aetiology, for example acute, inflammatory and neuropathic pain, dental pain and headache, particularly vascular headache such as migraine, cluster headache and mixed vascular syndromes as well as non-vascular, tension headache. They have also been proposed as anti-inflammatory agents for the treatment of inflammatory diseases or conditions, for example the treatment of arthritis and rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders (e.g. uvetis), inflammatory or unstable bladder disorders (e.g. cystitis and urinary incontinence), psoriasis and skin complaints with inflammatory components, as well as other chronic inflammatory conditions. It has been proposed to use VR1 ligands in the treatment of neuropathic pain and associated hyperalgesia and allodynia, e.g. trigeminal or herpetic neuralgia, diabetic neuropathy pain, causalgia, sympathetically maintained pain and deafferentation syndromes such as brachial plexus avulsion. They are proposed for use in the prophylactic or curative treatment of asthma, of

5 LHF-003 epithelial tissue damage or dysfunction, e.g. spontaneous lesions, of herpes simplex, and in the control of disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular e.g. for treating wounds, burns, allergic skin reactions, pruritis and vitiligo, for the prophylactic or curative treatment of gastrointestinal disorders such as gastric ulceration, duodenal ulcers, inflammatory bowel disease and diarrhea, gastric lesions induced by necrotising agents, for example ethanol or chemotherapeutic agents, hair growth, for the treatment of vasomotor or allergic rhinitis and for the treatment of bronchial disorders or bladder disorders, such as bladder hyper-reflexia. Amgen, Inc. has numerous publications of VR1 ligands, including patents

USPN 7,053,088 to Doherty, et al. (US Pub 2004/038969, USSN 10/445,170), USPN 7,148,221 to Doherty et al. (US Pub 2005/0277631), and USPN 7,144,888 to Doherty et al. (US Pub 2004/0082780, USSN 10/638,009). Other vanilloid receptor 1 ligands are also described in published patent applications US Pub 20060241296 to Doherty et al. (USSN 11/411,366), US Pub 20060235036 to Doherty et al. (USSN 11/406,437), US Pub 20060183745 to Bo et al. (USSN 11/354,650), US Pub 20060160872 to Norman et al. (USSN 11/337,188), US Pub 20060089360 to Norman et al. (USSN 11/256,427), US Pub 20060084640 to Gore et al. (USSN 11/251,445), US Pub 20060058308 to Norman et al (USSN 11/226,844), US Pub 20060030618 to Bo et al. (USSN 11/100,272), US Pub 20050277646 to Doherty et al. (USSN 11/195,303), US Pub 20050272931 to Bo et al. (USSN 11/099,978), US Pub 20050272777 to Doherty et al. (USSN 11/195,159), US Pub 20050267163 to Doherty et al. (USSN 11/195,302), US Pub 20050227986 to Bo et al. (USSN 11/100,077), US Pub 20050182067 to Balan et al. (USSN 11/056,534), US Pub 20050176726 to Wang et al. (USSN 11/056,568), US Pub 20050165049 to Hulme et al. (USSN 11/041 ,173), US Pub 20050165046 to Hulme et al. (USSN 11/041,169), US Pub 20050165032 to Norman et al. (USSN 11/041 ,174), US Pub 20050165028 to Norman et al. (LTSSN 11/040,668), US Pub 20050165015 to Ncube et al. (USSN 11/040,995), US Pub 20050153984 to Chen et al. (USSN 10/956,648), US Pub 20040157845 to Doherty et al. (USSN 10/775,980), US Pub

6 LHF-003 20040152690 to Balan et al. (USSN 10/688,246), and US Pub 20030195201 to Bo et al. (USSN 10/316,295), which have not issued yet as patents at the writing of this application. All these patent and published applications are entitled "Vanilloid Receptor Ligands and their use in treatments", and all are assigned to Amgen, Inc.

[00010] Other patent or publication documents describing VR1 ligands include oxazolyl compounds disclosed in US Pub 2006/0281799 to Gomtsyan et al. (Abbot laboratories), diaryl piperazines (US Pub. 2004/176443 to Bakthavatchalam et al.), Anandamide, an endogenous vanilloid receptor ligand is disclosed in US Pub. 2002/0019444 to Hogestatt et al, as well as structurally related lipids, such as AM404, 1-arachidonylglycerol, and 2-arachidonylglycerol. The VR1 ligands can include substituted pyrimidyl-4-ylamine analogues as disclosed in US Pub. 2006/0229308 to Blum et al., urea derivatives or salts thereof including those disclosed in US Pub. 20005/0119304 to Yura et al, owned by Bayer Pharmaceuticals, more urea derivatives and salts thereof in US Pub. 2005/0154230 to Yura et al. also owned by Bayer Pharmaceuticals, the urea derivatives and pharmaceutically acceptable salts or solvates thereof as disclosed in US Pub. 2006/0276447 to Fell et al., owned by SmithKline Beecham Corporation, and the urea derivatives disclosed in US Pub. 2006/0178397 to MacDonald, also owned by SmithKline Beecham Corporation. Other vanilloid ligands include amide chemicals disclosed in US Pub. 2005/0004133 to Makings et al., owned by Vertex Pharmaceuticals, including certain benzamides and amides.

[00011] Other patent documents that disclose vanilloid receptor 1 ligands include the following: USPN 7,112,685 to McDonnell et al., owned by Ortho-McNeill Pharmaceuticals, disclosing resinferatoxin derivatives (published also as US Pub. 2004/0230064), USPN 6,723,730 to Bakthavatchalam et al, owned by Neurogen Corporation disclosing diaryl piperazines and related compounds (published also in US Pub. 2002/0132853).

LHF-003 [00012] Still other VR1 ligands are described in USPN 6,476,076 to Lee et al. which discloses resinferatoxin pharmacophores, and pharmaceutical compositions comprising such analogues, owned by Pacific Corporation and Digital Biotech Co., Ltd. USPN 6,872,748 to Lee et al. owned by Digital Biotech Co., Ltd. also discloses other resinferatoxin pharmacophores, and pharmaceutical compositions comprising such analogues. USPN 6,984,647 to Dax et al., owned by Janssen Pharmaceutica discloses beta-aminotetralin derived ureas that are VR1 ligands. USPN 5,290,816 to Biumberg, owned by the U.S. government discloses resinferatoxin and analogues. USPN 4,939,149 to Biumberg also discloses resinferatoxin and analogues. USPN 7,183,411 to Codd et al. also discloses naphthol, quinoline, and isoquinoline-derived ureas that are VR1 ligands.

[00013] Other vanilloid receptor 1 ligands that can be used in the invention are also known as olvanil, piperine, zingerone, anandamide, 12- and 15-(S)- hydroperoxy-eicosatetraenoic acids, 5- and 15-(S)-hydroxyeicosatet- raenoic acids, phorbol 12-phenylacetate 13-acetate 20-homovanillate, 2 phorbol 12,13- didecanoate 20-homovanillate, leukotriene B(4), N-(3-acyloxy-2-benzylpropyl)- N'-dihydroxytetrahydrobenzazepine, and tetrahydroisoquinoline thiourea analogs.

[00014] Resinferatoxin, a diterpene, is approximately 1000 times more potent a VR1 agonist than capsaicin (methyl vanilyl nonenamide), and therefore may be administered in discreet quantities to great effect in some patients. Resinferatoxin has been described for its "thermoregulatory effects in mice" see de Vries and Biumberg, Life Sci. 1989:44(11):711-5). Resinferatoxin (100 mg/kg, s.c. in ferrets) an ultrapotent analogue of capsaicin, produced a decrease in core temperature (in ferrets), as has been reported for capsaicin. (Andrews PL, Bhandari P., Neuropharmacology 1993 Aug; 32(8): 799-806). Resinferatoxin can be made or isolated as described in USPN 7,053,088, USPN 7,148,221 and USPN 7,144,888.

LHF-003 [00015] Capsaicin (also known as methyl vanilyl nonenamide) is the main capsaicinoid in chile peppers, followed by dihydrocapsaicin. Both are vanilloid receptor ligands. These two compounds are about twice as hot as the minor capsaicinoids nordihydrocapsaicin, homodihydrocapsaicin, and homocapsaicin.

[00016] The VR1 ligands can be made by chemical synthesis or as described in the patents and publications disclosing a particular VR1 ligand.

[00017] In addition to chemical synthesis, capsaicin or capsaicinoids can be isolated from a species of capsicum. The capsaicin or capsaicinoid can be biosynthetically made by in vitro culturing of cells of a species of capsicum. The species of capsicum include capsicum annuum L., capsicum frutescens L., capsicum chinense, capsicum annum coraciforme, capsicum annum grossum, , capsicum chacoense, capsicum baccatum, capsicum eximium, capsicum pendulum, capsicum pubescens, capsicum minimum, capsicum abbreviatum, capsicum breviflorum, capsicum buforum, capsicum brasilianum, capsicum campylopodium, capsicum cardenasii, capsicum ciliatum, capsicum chlorocladium, capsicum coccineum, capsicum cordiforme, capsicum cornutum, capsicum dimorphum, capsicum dusenii, capsicum exile, capsicum eximium, capsicum fasciculatum, capsicum fastigiatum, capsicum galapagoensis, capsicum geminifolum, capsicum hookerianum, capsicum lanceolatum, capsicum leptopodum, capsicum luteum, capsicum microcarpum, capsicum minutiflorum, capsicum mirabile, capsicum parvifolium, capsicum praetermissum, capsicum schottianum, capsicum scolnikianum, capsicum stramonifolium, capsicum tetragonum, capsicum villosum, capsicum violaceum, and others.

[00018] Other studies and observations related to the function and activity of VR ligands are discussed in the following references: See Birder-L A. Kanai-A J. de-Groat- W C. Kiss-S. Nealen-M L. Burke-N E. Dineley-K E. Watkins-S. Reynolds-I J. Caterina-M J. (2001) Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. PNAS 98: 23: 13396 13401. CSchumacher, M. A., Tominaga, M., Rosen, T. A., Levine, J. D., and Julius, D, (1997). The

9 LHF-003 capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389: 816 824. Caterina-M J. Leffler-A. Malmberg-A B. Martin-W J. Trafton-J. Petersen-Zeitz K R. Koltzenburg-M. Basbaum-A I. Julius-D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science- (WASH-DC). 288: 5464: 306 313. Cortright-D N. Crandall-M. Sanchez-J F. Zou-T. Krause-J E. White-G (2001) The tissue distribution and functional characterization of human VR1. Biochemical and Biophysical Research Communications 281 : 5: 1183 1189. Dray, A., (1992). Therapeutic potential of capsaicin-like molecules. Life Sciences 51 : 1759 1765. Gauldie-S D. McQueen- D S. Pertwee-R. Chessell-I P. (2001) Anandamide activates peripheral nociceptors in normal and arthritic rat knee joints. British Journal of Pharmacology 132: 3: 617 621. Helliwell-R J A. McLatchie-L M. Clarke-M. Winter-J. Bevan-S. Mclntyre-P (1998) Capsaicin sensitivity is associated with expression of the vanilloid (capsaicin) receptor (VR1 ) mRNA in adult rat sensory ganglia. Neuroscience Lett. 250: 3: 177 180. Holzer, P. (1991) Capsaicin: Cellular targets, Mechanisms of Action and selectivity for thin sensory neurons. Pharmacological reviews 43: 2: 143 201 Hwang-S W. Cho-H. Kwak-J. Lee-S Y. Kang-C J. Jung-J. Cho-S. Min-K H. Suh-Y G. Kim-D. Oh-U. (2000) Direct activation of capsaicin receptors by products of lipoxygenases: Endogenous capsaicin-like substances. PNAS 97: 11: 6155 6160. Mezey-E. Toth-Z E. Cortright-D N. Arzubi-M K. Krause-J E. Elde-R. Guo-A. Blumberg-P M. Szallasi-A (2000) Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human. PNAS 97: 7: 3655 3660. Nozawa-Y. Nishihara-K. Yamamoto-A. Nakano-M. Ajioka-H. Matsuura-N.(2001) Distribution and characterization of vanilloid receptors in the rat stomach. Neuroscience Letters 309: 1: 33 36. Olah-Z. Karai-L. ladarola-M J. (2001) Anandamide activates vanilloid receptor 1 (VR1) at acidic pH in dorsal root ganglia neurons and cells ectopically expressing VR1. Journal of Biological Chemistry 276: 33, 31163 31170. Onozawa-K. Nakamura-A. Tsutsumi-S. Yao-J. Ishikawa-R. Kohama-K. (2000) Tissue distribution of capsaicin receptor in the various organs of rats. Proc.

10 LHF-003 Jpn. Acad. Ser. B, Phys.-Biol. Sci. 76: 5: 68 72. Premkumar-L S. Ahern-G P.

(2000) Induction of vanilloid receptor channel activity by protein kinase C. Nature (London) 408: 6815: 985 990. Singh-L K. Pang-X. Alexacos-N. Letourneau-R. Theoharides-T C. (1999) Acute immobilization stress triggers skin mast cell degranulation via corticotropin releasing hormone, neurotensin, and substance P: A link to neurogenic skin disorders. Brain Behav. Immun. 13: 3: 225 239. Szallasi, A. Blumberg-P M (1996) Vanilloid receptors: New insights enhance potential as a therapeutic target. Pain 68: 195 208. Szallasi-A. Blumberg-P M. (1999) Vanilloid (capsaicin) receptors and mechanisms. Pharmacol. Rev. 51: 2: 159 211. Szabo-T. Wang-J. Gonzalez-A. Kedei-N. LiIe- J. Treanor-J. Blumberg-P M. (2000) Pharmacological characterization of the human vanilloid receptor type-1 (hVR1). Society for Neuroscience Abstracts. 26:1 2: 634.18. Tominaga, M., Caterina, M. J., Malmberg, A. B., Rosen, T. A., Gilbert, H., Skinner, K., Raumann, B. E., Basbaum, A. I., and Julius, D., (1998). The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21: 531 543. Yiangou-Y. Facer-P. Dyer-N H C. Chan-C L H. Knowles- C. Williams-N S. Anand-P. (2001) Vanilloid receptor 1 immunoreactivity in inflamed human bowel. Lancet (North American Edition) 357: 9265: 1338 1339. Yiangou-Y. Facer-P. Ford-A. Brady-C. Wiseman-0. Fowler-C J. Anand-P.

(2001) Capsaicin receptor VR1 and ATP-gated ion channel P2X3 in human urinary bladder. BJU International 87: 9: 774 779. Wang-H. Bian-D. Zhu-D. Zajic-G. Loeloff-R. LiIe-J. WiId-K. Treanor-J. Curran-E. (2000) Inflammation- induced upregulation of VR1 in rat spinal cord and DRG correlates with enhanced nociceptive processing. Society for Neuroscience Abstracts 26:1 2: 632.15. VRI ligands including both agonists or antagonists have been proposed as analgesics for the treatment of pain of various genesis or etiology, for example acute, inflammatory and neuropathic pain, dental pain and headache, particularly vascular headache such as migraine, cluster headache and mixed vascular syndromes as well as non-vascular, tension headache. They have also been proposed as anti-inflammatory agents for the treatment of

11 LHF-003 inflammatory diseases or conditions, for example the treatment of arthritis and rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders (e.g. uveitis), inflammatory or unstable bladder disorders (e.g. cystitis and urinary incontinence), psoriasis and skin complaints with inflammatory components, as well as other chronic inflammatory conditions. They have been proposed for treatment of inflammatory pain and associated hyperalgesia and allodynia. VR1 ligands are also useful in the treatment of neuropathic pain and associated hyperalgesia and allodynia, e.g. trigeminal or herpetic neuralgia, diabetic neuropathy pain, causalgia, sympathetically maintained pain and deafferentation syndromes such as brachial plexus avulsion. They are also indicated for the use in the prophylactic or curative treatment of asthma, of epithelial tissue damage or dysfunction, e.g. spontaneous lesions, of herpes simplex, and in the control of disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular e.g. for treating wounds, burns, allergic skin reactions, pruritis and vitiligo, for the prophylactic or curative treatment of gastrointestinal disorders such as gastric ulceration, duodenal ulcers, inflammatory bowel disease and diarrhea, gastric lesions induced by necrotising agents, for example ethanol or chemotherapeutic agents, hair growth, for the treatment of vasomotor or allergic rhinitis and for the treatment of bronchial disorders or bladder disorders, such as bladder hyper-reflexia.

[00020] Any and all patents, patent applications, underlying priority documents, scientific papers, books and any other type of publication in any form whatsoever (printed, audio, multimedia, etc.) cited or referred to herein, or from which a claim to priority is made, are hereby incorporated by reference into the disclosure of this specification.

SUMMARY OF THE INVENTION

[00021] A method of treating hot flashes associated with menopause or perimenopause, comprising administering to a human female in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a

12 LHF-003 vanilloid receptor ligand, thereby reducing severity or frequency of said hot flashes.

[00022] The method wherein said vanilloid receptor ligand comprises a therapeutically effective amount of a means for vanilloid receptor ligand binding, thereby reducing severity or frequency of said hot flashes.

[00023] The method wherein said vanilloid receptor is vanilloid receptor 1.

[00024] The method wherein said vanilloid receptor ligand is selected from the group consisting of compounds of formula I, compounds of formula II, compounds of formula III, compounds of formula IV, compounds of formula V, compounds of formula Vl, compounds of formula VII, compounds of formula VIII, compounds of formula IX, compounds of formula X, compounds of formula Xl, compounds of formula XII, compounds of formula XIII, compounds of formula XIV, compounds of formula XV, compounds of formula XVI, compounds of formula XVII, compounds of formula XVIII, compounds of formula XIX, compounds of formula XX, compounds of formula XXI, compounds of formula XXII, compounds of formula XXIII, compounds of formula XXIV, compounds of formula XXV, compounds of formula XXVI, resinferatoxin (RTX), capsaicin, isovelleral, scutigeral, resinferanoids, capsaicinoids, unsaturated dialdehydes triprenyl phenols, capsazepine, terpenoid unsaturated dialdehydes, triprenyl phenols, n-bicyclic amides, substituted benzimidazoles, substituted nitrogen- containing heterocycles , compounds of a general structure of therapeutic benzimidazoles.substituted pyridines and pyrimidines, pyrimidine ethers, bis- bicyclic amides and compositions containing them, therapeutic benzimidazoles, oxazolyl compounds, diaryl piperazines.anandamide ligands, structurally related lipids to anandamide such as AM404, 1-arachidonylglycerol, and 2- arachidonylglycerol, substituted pyrimidyl-4-ylamine analogues and compositions containing them, amide chemicals including benzamides and amides, diaryl piperazines, resinferatoxin pharmacophores, beta-aminotetralin derived ureas, naphthol-derived ureas, quinoline-derived ureas, and isoquinoline-derived ureas.

[00025] The method comprising oral administration.

13 LHF-003 [00026] The method wherein said vanilloid receptor ligand is formulated in a sustained release dosage form. [00027] The method wherein said pharmaceutical composition is in an oral dosage form selected from the group consisting of a tablet and a capsule. [00028] The method wherein said oral dosage form is a sustained release dosage form. [00029] The method wherein said amount of vanilloid receptor ligand is at least 0.01 mg per administration. [00030] The method wherein said oral administration comprises administering at least

0.01 mg of a vanilloid receptor ligand in a single oral dosage form. [00031] A pharmaceutical composition comprising as an active agent a vanilloid receptor ligand formulated in a sustained release dosage form. [00032] The pharmaceutical composition wherein said active agent is a means for vanilloid receptor binding.

[00033] The pharmaceutical composition wherein vanilloid receptor ligand is selected from the group consisting of compounds of formula I, compounds of formula II, compounds of formula III, compounds of formula IV, compounds of formula V, compounds of formula Vl, compounds of formula VII, compounds of formula VIII, compounds of formula IX, compounds of formula X, compounds of formula Xl, compounds of formula XII, compounds of formula XIII, compounds of formula XIV, compounds of formula XV, compounds of formula XVI, compounds of formula XVII, compounds of formula XVIII, compounds of formula XIX, compounds of formula XX, compounds of formula XXI, compounds of formula XXII, compounds of formula XXIII, compounds of formula XXIV, compounds of formula XXV, compounds of formula XXVI, resinferatoxin (RTX), capsaicin, isovelleral, scutigeral, resinferanoids, capsaicinoids, unsaturated dialdehydes triprenyl phenols, capsazepine, terpenoid unsaturated dialdehydes, triprenyl phenols, n-bicyclic amides, substituted benzimidazoles, substituted nitrogen-containing heterocycles , compounds of a general structure of therapeutic benzimidazoles.substituted pyridines and pyrimidines, pyrimidine ethers, bis-bicyclic amides and

14 LHF-003 compositions containing them, therapeutic benzimidazoles, oxazolyl compounds, diaryl piperazines,anandamide ligands,structurally related lipids to anandamide such as AM404, 1-arachidonylglycerol, and 2- arachidonylglycerol.substituted pyrimidyl-4-ylamine analogues and compositions containing them, amide chemicals including benzamides and amides, diaryl piperazines, resinferatoxin pharmacophores, beta-aminotetralin derived ureas, naphthol-derived ureas, quinoline-derived ureas, and isoquinoline-derived ureas.

[00034] The pharmaceutical composition wherein said sustained release dosage form is an oral dosage form.

[00035] The pharmaceutical composition wherein said oral dosage form is selected from the group consisting of a tablet or a capsule. [00036] The pharmaceutical composition wherein an amount of said active agent of vanilloid receptor ligand in said sustained release dosage form is at least 0.01 mg.

[00037] Further embodiments of the invention are described herein.

DESCRIPTION OF THE FIGURES

[00038] FIG. 1 (having sheets labeled FIG. 1A, 1B, 1C, 1D and 1E) depicts VR1 ligands of formula I.

[00039] FIG. 2 (having sheets labeled FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2H) depicts VR1 ligands of formula II.

[00040] FIG. 3 (having sheets labeled FIG. 3A, 3B, 3C, 3D, 3E, 3F, and 3G), depicts VR1 ligands of formula III.

[00041] FIG. 4 (having sheets labeled FIG. 4A, 4B, 4C, 4D, 4E, 4F, and 4G) depicts VR1 ligands of formula IV.

[00042] FIG. 5 (having sheets labeled FIG. 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, and 5I) depicts VR1 ligands of formula V.

15 LHF-003 [00043] FIG. 6 (having sheets labeled FIG. 6A, 6B, 6C, 6D, 6E, 6F, 6G, 6H, and 61) depicts VR1 ligands of formula Vl.

[00044] FIG. 7 (having sheets labeled FIG. 7A, 7B, and 7C) depicts VR1 ligands of formula VII.

[00045] FIG. 8 (having sheets labeled FIG. 8A, 8B, 8C, 8D, and 8E) depicts VR1 ligands of formula VIII.

[00046] FIG. 9 (having sheets labeled FIG. 9A, 9B, 9C, and 9D) depicts VR1 ligands of formula IX.

[00047] FIG. 10 (having sheets labeled FIG. 10A, 10B, 10C, 10D, 10E, 10F, 10G, 10H, and 101) depicts VR1 ligands of formula X.

[00048] FIG. 11 (having sheets labeled FIG. 11 A, 11 B, 11 C, 11 D, 11E and 11 F) depicts VR1 ligands of formula Xl.

[00049] FIG. 12 (having sheets labeled FIG. 12A, 12B, 12C, and 12D) depicts VR1 ligands of formula XII.

[00050] FIG. 13 (having sheets labeled 13A, 13B, 13C, 13D, 13E, 13F, 13G, and 13H) depicts VR1 ligands of formula XIII.

[00051] FIG. 14 (having sheets labeled 14A and 14B) depicts VR1 ligands of formula XIV.

[00052] FIG. 15 (having sheets labeled FIG. 15A ad 15B) depicts VR1 ligands of formula XV.

[00053] FIG. 16 (having sheets labeled FIG. 16A, 16B, and 16C) depicts VR1 ligands of formula XVI.

[00054] FIG. 17 (having sheets labeled FIG. 17A, 17B, 17C, and 17D) depicts VR1 ligands of formula XVII.

[00055] FIG. 18 (having sheets labeled FIG. 18A and 18B) depicts VR1 ligands of formula XVIII.

16 LHF-003 [00056] FIG. 19 (having sheets labeled FIG. 19A, 19B, 19C, and 19D) depicts VR1 ligands of formula XIX.

[00057] FIG. 20 (having sheets labeled FIG. 2OA and 20B) depicts VR1 ligands of formula XX.

[00058] FIG. 21 (having one sheet labeled FIG. 21) depicts VR1 ligands of formula XXI.

[00059] FIG. 22 (having one sheet labeled FIG. 22) depicts VR1 ligands of formula XXII.

[00060] FIG. 23 (having sheets labeled FIG. 23A and 23B) depicts VR1 ligands of formula XXIII.

[00061] FIG. 24 (having sheets labeled FIG. 24A, 24B₁ 24C and 24D) depicts VR1 ligands of formulas XXIV, XXV, and XXVI.

DETAILED DISCLOSURE OF THE INVENTION

[00062] Presented here is a new use for vanilloid receptor ligands (VR ligands). The inventor has discovered that VR ligands, preferably VR1 ligands, can be used in the treatment of peri-menopausal, pre-menopausal and menopausal females. VR ligands are useful to treat, relieve, prevent or ameliorate one or more menopausal symptoms in human females experiencing some or all of the symptoms experienced by females in peri-menopause, pre-menopause or menopause. The symptoms generally include hot flashes, skin flushes, night sweats, mood swings, depression, and other central nervous system or neurologically-based reactions to the hormonal changes that come with the onset of the menopause phase of a woman's life. The menopause phase of a woman's life includes peri-menopause, pre-menopause and menopause.

[00063] As used herein the term "vanilloid receptor ligand" (VR ligand) denotes a molecule that can bind a vanilloid receptor. The term contemplates mostly agonists of the receptor, but also includes antagonists such as capsazepine which can compete with the agonists for binding the receptor. Presently, only one receptor has been identified and cloned (the vanilloid receptor 1 - VR1) but there is reason to believe that there is at least one other vanilloid receptor, and

17 LHF-003 maybe different activities and binding affinities of the vanilloid receptor or receptors in different tissues. More broadly the binding of vanilloid receptor ligands is defined as binding of the ligand to a vanilloid recpetor in vivo or in vitro. Typically, these receptors are found on neurons that are vanilloid- sensitive. receptors. Binding at vanilloid-sensitive neurons can indicate binding at a vanilloid receptor that is expressed at the neuron.

[00064] Binding of a vanilloid receptor ligand may occur at a site on the vanilloid receptor ligand such as the vanillyl site, but it has also been found that molecules which do not have vanillyl sites can still act as a vanilloid receptor ligand and bind a vanilloid receptor. Vanilloid receptor binding and the resulting activation is reviewed and detailed in a 110 page review on "Vanilloid (Capsaicin) Receptors and Mechanisms", Szallasi and Blumberg, Pharmacological Reviews vol. 51, Issue 2, 159-212, June 1999, herein incorporated by reference in its entirety. Many definitions and explanations of the state of the art of vanilloid receptor binding and activity as detailed in this review article pertain here.

[00065] As a group the vanilloid receptor ligands show differences in biological actions and mechanisms of action, even within their commonality of binding a vanilloid receptor at a vanilloid-sensitive neuron. The classic vanilloids are the capsaicinoids, including capsaicin. However, there are some ligands that activate vanilloid receptors which are structurally unrelated to typical vanilloids (e.g. sequiterpenes and others). Although generally considered typical vanilloid receptor ligands, even within the group of capsaicinoids, capsaicinoids differ from one another not only in their affinity for receptor binding, but also in activation kinetics. Other vanilloid receptor ligands include capsaicin congeners such as piperine, zingerone, eugenol, and guaiacol. Olvanil and nuvanil are synthetic vanilloid receptor ligands. In 1993 Walpole and Wrigglesworth determined that compounds with 3-alkoxy-4-substituted benzyl ring have the highest probability of being active vanilloid receptor ligands. Resinferatoxin (RTX) derivatives include RTX-amide, RTX-thiourea and RTX phorbol homovanillate derivatives. In addition there are vanilloid receptor

18 LHF-003 ligands that lack the 3-hydroxy 4-methoxyphenyl (vanillyl) functionality including sesquiterpene, related bioactive terpenoids, and terpenoids with unsaturated dialdehydes. Triprenyl phenols are similar to terpenoid unsaturated dialdehydes in that they don't have a vanillyl group by structure but still they bind a vanilloid receptor.

[00066] A preferred group of vanilloid receptor ligands are the classic ligands having a vanillyl site. A second preferred group of vanilloid receptor ligands are the vanilloid receptor ligands found endogenously in a mammal, or in plants or organisms, such as the capsaicin and resinferatoxin and molecules of these classes. A third preferred group of vanilloid receptor ligands are deritives, analogues, and metabolites of vanilloid receptor ligands. A fourth preferred group of vanilloid receptor ligands are the ligands which do not have a vanillyl group but which still bind the vanilloid receptor. A fifth preferred group are synthetic (chemically synthesized) vanilloid receptor ligands having a vanillyl group. A sixth preferred group are vanilloid receptor ligands that are derivatives of urea.

[00067] Accordingly, at a minimum, the vanilloid receptor ligands of the invention include the following: compounds of formula I shown in FIG. 1 (having sheets labeled FIG. 1A, 1B, 1C, 1D and 1 E), compounds of formula Il shown in FIG. 2 (having sheets labeled FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2H), compounds of formula III shown in FIG. 3 (having sheets labeled FIG. 3A, 3B, 3C, 3D, 3E, 3F, and 3G), compounds of formula IV shown in FIG. 4 (having sheets labeled FIG. 4A, 4B, 4C, 4D, 4E, 4F, and 4G), compounds of formula V shown in FIG. 5 (having sheets labeled FIG. 5A, 5B, 5C₁ 5D, 5E, 5F, 5G, 5H, and 51), compounds of formula Vl shown in FIG. 6 (having sheets labeled FIG. 6A, 6B, 6C, 6D, 6E, 6F, 6G, 6H, and 61), compounds of formula VII shown in FIG. 7 (having sheets labeled FIG. 7A, 7B, and 7C), compounds of formula VIII shown in FIG. 8 (having sheets labeled FIG. 8A, 8B, 8C, 8D, and 8E), compounds of formula IX shown in FIG. 9 (having sheets labeled FIG. 9A, 9B, 9C, and 9D), compounds of formula X shown in FIG. 10 (having sheets labeled FIG. 10A,

19 LHF-003 10B₁ 1OC, 10D, 10E, 10F, 10G, 10H, and 101), compounds of formula Xl shown in FIG. 11 (having sheets labeled FIG. 11A₁ 11B, 11C₁ 11D, 11E and 11F), compounds of formula XII shown in FIG. 12 (having sheets labeled FIG. 12A, 12B, 12C, and 12D), compounds of formula XiII shown in FIG. 13 (having sheets labeled 13A, 13B, 13C, 13D, 13E, 13F, 13G, and 13H), compounds of formula XIV shown in FIG. 14 (having sheets labeled 14A and 14B), compounds of formula XV shown in FIG. 15 (having sheets labeled FIG. 15A ad 15B), compounds of formula XVI shown in FIG. 16 (having sheets labeled FIG. 16A, 16B, and 16C), compounds of formula XVII shown in FIG. 17 (having sheets labeled FIG. 17A, 17B, 17C, and 17D), compounds of formula XVIII shown in FIG. 18 (having sheets labeled FIG. 18A and 18B), compounds of formula XIX shown in FIG. 19 (having sheets labeled FIG. 19A, 19B, 19C, and 19D), compounds of formula XX shown in FIG. 20 (having sheets labeled FIG. 2OA and 20B), the compounds of formula XXI shown in FIG. 21 (having one sheet labeled FIG. 21), the compounds of formula XXII shown in FIG. 22 (having one sheet labeled FIG. 22), the compounds of formula XXIII shown in FIG. 23 (having sheets labeled FIG. 23A and 23B), the compounds of formula XXIV, XXV, and XXVI shown in FIG. 24 (having sheets labeled FIG. 24A, 24B, 24C₁ and 24D).

In addition, the vanilloid receptors of the invention include molecules disclosed in USPN 7,053,088 including compounds of the formula

20 LHF-003

[00069] and compositions containing them, wherein R1 , Rd, R4 and Y are defined in USPN 7,053,088, which is specifically incorporated by reference in its entirety; USPN 7,148,221 including compounds of the formula

[00070] and compositions containing them, wherein R1 , Rd, J, R4 and Y are defined in USPN 7,148,221 , which is specifically incorporated by reference in its entirety;

[00071] USPN 7,144,888 including compounds of the formula

21 LHF-003

[00072] and compositions containing them, wherein R1, Rd, J, R4 and Y are defined in USPN 7,144,888 which is specifically incorporated by reference in its entirety;

[00073] US Pub. 2006/0241296 to Doherty et al including compounds of the formula

[00074] and compositions containing them, wherein R1, Rd, R4, Y and X are defined in US Pub. 2006/0241296 which is specifically incorporated by reference in its entirety;

[00075] ., US Pub. 2006/0235036 to Doherty et al. including compounds of the formula

22 LHF-003

[00076] and compositions containing them, wherein R1, Rd, R4, X, and Y are defined in US Pub. 2006/0235036 which is specifically incorporated by reference in its entirety;

[00077] US Pub. 2006/0183745 to Bo et al., including compounds having the formula

[00078]

[00079] and compositions containing them, wherein R1 , Rd, R4, X and Y are defined in US Pub. 2006/0183745 which is specifically incorporated by reference in its entirety; US Pub. 2006/0030618 to Bo et al. including compounds of the formula

23 LHF-003

[00080] wherein

R1, R2, A, R3, X, Y, and R4 are defined in US Pub 2006/0030618 which is specifically incorporated by reference in its entirety;

[00081] , US Pub. 2005/0277646 to Doherty et al. including compounds of the formula

[00082] and compositions containing them wherein R1 , Rd, R4, X and Y are defined in US Pub 2005/0277646 which is specifically incorporated by reference in its entirety,

[00083] US Pub. 2005/0272931 to Bo et al. including compounds of the formula

24 LHF-003

[00084]

[00085] and compositions containing them, wherein R1 , R2, A, R3, X, Y, and R4 are defined in US Pub 2005/027931which is specifically incorporated by reference in its entirety;, US Pub. 2005/0272777 to Doherty et al. including compounds of the formula

[00086]

[00087] and compositions containing them, wherein R1 , Rd, J, R4 and X and Y are defined in US Pub 2005/0272777 which is specifically incorporated by reference in its entirety; US Pub. 2005/0267163 to Doherty et al. including compounds of the formula

25 LHF-003

[00088]

[00089] and compositions containing them, wherein R1, Rd, X, Y, and R4 are defined in US Pub 2005/0267163 which is specifically incorporated by reference in its entirety, US Pub. 2005/0227986 to Bo et al. including compounds of the formula

[00090]

[00091] and compositions containing them, wherein R1, R2, A, R3, X, Y and R4 are defined in US Pub 2005/0227986 which is specifically incorporated by reference in its entirety; US Pub. 2005/0182067 to Balan et al. including compounds of the formula

26 LHF-003

[00092]

[00093] and compositions containing them, wherein R1 , R2, R2\ X1 , X2, R3, 2, Y, J and R4 are defined in US Pub 2005/0182067 which is specifically incorporated by reference in its entirety; US Pub. 2005/1065049 to Hulme et al., including compounds of the formula

[00094]

[00095] and compositions containing them, wherein R1 , Y, X, R2, and R3 are defined in US Pub. 2005/1065049 which is specifically incorporated by reference in its entirety; US Pub. 2005/0165032 to Norman et al., including compounds of the formula

27 LHF-003

[00096]

[00097] and compositions containing them, wherein R1, R2, R4, R5, Y1, Y2, Y3, Y4, J, and X are defined in US Pub. 2005/0165032 which is specifically incorporated by reference in its entirety; US Pub. 2005/0165015 to Ncube et al., including compounds of the formula

[00098]

[00099] and compositions containing them, wherein Y1, Y2, Y3, Y3, X, R1, R2 and J are defined by US Pub. 2005/0165015 which is specifically incorporated by

28 LHF-003 reference in its entirety; US Pub. 2005/0153984 to Chen et al., including compounds of the formula

[000100]

[000101] and compositions containing them, wherein R1 , R2, R4, J, X, Y and Z are defined in US Pub. 2005/0153984 which is specifically incorporated by reference in its entirety US Pub. 2004/0157845 to Doherty et al., including compounds of the formula

[000102]

[000103]and compositions containing them, wherein L, N, Y, X1 , Q1 , Q2, Q3, Q4, and R3 are defined in US Pub. 2004/0157845 which is specifically incorporated by reference in its entirety; and US Pub. 2003/0195201 to Bo et al., including compounds of the formula

29 LHF-003

[000104]

[000105] and compositions containing them, wherein R1 , R2, R3, R4, A, and X are defined in US Pub. 2003/0195201 which is specifically incorporated by reference in its entirety; resinferatoxin (RTX) and compositions containing them, capsaicin and compositions containing them, isovelleral and compositions containing them, scutigeral and compositions containing them, resinferanoids and compositions containing them, capsaicinoids and compositions containing them, unsaturated dialdehydes triprenyl phenols and compositions containing them, and active analogues of the unsaturated dialdehydes triprenyl phenols and compositions containing them, active analogues, derivatives and metabolites of resinferatoxin (RTX) and compositions containing them, active analogues, derivatives and metabolites of capsaicin and compositions containing them, active analogues, derivatives and metabolites of isovelleral and compositions containing them, active analogues, derivatives and metabolites of scutigeral and compositions containing them, resinferanoids and compositions containing them, capsaicinoids and compositions containing them, capsazepine, terpenoid unsaturated dialdehydes and compositions containing them, triprenyl phenols and compositions containing them; n-bicyclic amides such as those disclosed in US Pub. 2005/0165028 to Norman et al. which is specifically incorporated by reference in its entirety and compositions containing them, substituted

30 LHF-003 benzimidazoles such as those disclosed in US Pub. 2006/0160872 to Norman et al. which is specifically incorporated by reference in its entirety and compositions containing them, substituted nitrogen-containing heterocycles such as those disclosed in US Pub. 2006/0089360 to Norman et al. which is specifically incorporated by reference in its entirety and compositions containing them, therapeutic benzimidazoles such as those disclosed in US Pub. 2006/0084640 to Gore et al. which is specifically incorporated by reference in its entirety and compositions containing them, substituted pyridines and pyrimidines such as those disclosed in US Pub. 2006/0058308 which is specifically incorporated by reference in its entirety and compositions containing them, pyrimidine ethers such as those disclosed in US Pub. 2005/0176726 which is specifically incorporated by reference in its entirety and compositions containing them, bis-bicyclic amides such as those disclosed in US Pub. 2005/0165046 which is specifically incorporated by reference in its entirety and compositions containing them, therapeutic benzimidazoles such as those disclosed in US Pub. 2004/0152690 which is specifically incorporated by reference in its entirety and compositions containing them, oxazolyl compounds such as those disclosed in US Pub. 2006/0281799 which is specifically incorporated by reference in its entirety and compositions containing them, diaryl piperazines such as those disclosed in US Pub. 2004/176443 which is specifically incorporated by reference in its entirety and compositions containing them, anandamide ligands such as those disclosed in US Pub. 2002/0019444 which is specifically incorporated by reference in its entirety and compositions containing them, structurally related lipids to anandamide such as AM404, 1-arachidonylglycerol, and 2-arachidonylglycerol and compositions containing them, substituted pyrimidyl-4-ylamine analogues and compositions containing them, urea derivatives or salts thereof including such as those disclosed in US Pub. 20005/0119304 to Yura et al. which is specifically incorporated by reference in its entirety and compositions containing them, urea derivatives and salts thereof such as those disclosed in US Pub. 2005/0154230 to Yura et al. which is specifically incorporated by reference in

31 LHF-003 its entirety and compositions containing them urea derivatives and pharmaceutically acceptable salts or solvates thereof such as those disclosed in US Pub. 2006/0276447 to Fell et al. which is specifically incorporated by reference in its entirety and compositions containing them, urea derivatives such as those disclosed in US Pub. 2006/0178397 to MacDonald which is specifically incorporated by reference in its entirety and compositions containing them, amide chemicals such as those disclosed in US Pub. 2005/0004133 to Makings et al. including certain depicted and disclosed benzamides and amides which is specifically incorporated by reference in its entirety and compositions containing them, diaryl piperazines and related compounds such as thos disclosed in EP 1301484 which is specifically incorporated by reference in its entirety and compositions containing them, resinferatoxin pharmacophores such as those disclosed in USPN 6,476,076 which is specifically incorporated by reference in its entirety and compositions containing them, resinferatoxin pharmacophores such as those disclosed in USPN 6,872,748 which is specifically incorporated by reference in its entirety and compositions containing them, beta-aminotetralin derived ureas and compositions containing them, naphthol-derived ureas and compositions containing them, quinoline-derived ureas and compositions containing them, isoquinoline-derived ureas and compositions containing them.

[000106] The compositions comprising VR ligands may also comprise an additional active agent. Such agent can be, for example, an agent that addresses other symptoms of menopause, or tempers any adverse side effects that might occur from administration of the VR ligand. Such potential adverse side effects can be, for example, gastrointestinal irritation, usually temporary, during early doses of oral administration of capsaicin. An additional active agent can assert effects in concert with the VR ligand, or can work independently of the VR- ligand, manifesting independent effects on the patient.

[000107] According to the invention, VR ligand can be formulated in any standard oral dosage form appropriate. This includes immediate release or sustained

32 LHF-003 release dosage forms for oral administration. Sustained release is defined as a dosage form that releases the VR ligand into the patient's gastrointestinal tract or systemic body systems more slowly than a same amount of the VR ligand in an immediate release dosage form. Sustained release, extended release, modified release, delayed release, timed release and attenuated release are all synonyms of each other and of controlled release, and fit generally into the broad umbrella category defined by the term controlled release. Slight definitional distinctions may be carved out with a particular dosage form, for example, a modified release dosage form might contain a component that is immediate release and a component that is extended, delayed release, or sustained release so that the patient being administered the dosage form receives an essentially continuous input of VR ligand throughout the treatment protocol. However, sustained release formulations may, in one embodiment, begin releasing agent the minute the drug enters the patient, and can continue a continous input until the releasable agent is released, and thus all these terms relating to release can be considered to be describing essentially the same type of result in drug release, generally.

In addition to being administered to patients orally, the VR receptor ligands of the invention can also be administered in any other reasonable or acceptable mode. Generally all delivery modes can be divided into two categories, parenteral and gastro intestinal. Parenteral includes all modes that are not directed to the gastrointestinal tract. The gastrointestinal delivery modes are primarily oral, or anything by mouth that reaches the gastrointestinal tract, and can also include rectal delivery (e.g. with rectal suppositories, for example extended release suppositories), delivery directly to the stomach, e.g. by feeding tube, buccal delivery to the mucosal tissues in the mouth e.g. by lozenge or troche that dissolve in the mouth, or the standard, most common oral delivery of tablets, capsules, powder (as in a condiment with food), a suspension, syrup, gel or liquid that are swallowed and which the body absorbs through the gastrointestinal tract. Parenteral administraton can include

33 LHF-003 intravenous, intramuscular, subcutaneous, nasal, or intravaginal modes of delivery. Vaginal delivery, which may be quite appropriate for a treatment involving menopausal conditions - can be extended release vaginal suppositories, gels, foams or sponges administered intravaginally. Other parenteral modes include topical or transdermal administration using patches on thin-skinned areas of the patient. Parenteral administration can also include subcutaneous infusion, for example using a pump mechanism. Because some VR receptor ligands are known to be ingestible and are readily consumed as a food or spice in cayenne pepper, it is anticipated that the most preferred mode of delivery of the VR agonists is oral delivery, particularly using a sustained release component so that the patient receives an essentially constant input of VR ligand for the duration of treatment. The sustained release formulations of the invention (synonomous with the term controlled release) can be made by standard means.

Dosage of any particular VR ligand can be determined by those of skill in the art via routine trials to establish a preferred dose or dose range. Starting points to determine a therapeutically effective amount can be found in the above-cited patents and patent applications disclosing such ligands. Generally, a one time administration of a VR ligand to treat a menopausal woman will contain at leastθ.01 mg or more of the VR ligand, or at least 0.01 mg/kg per day administered to the patient. Accordingly also a single dosage unit (such as an oral dosage form, or a parenteral dosage form) will contain at least 0.1 mg of VR ligand, or the equivalent of at least 0.01 mg/kg/day administered to the patient. The dosage form, for example an oral dosage form such as a tablet or capsule, or another parenteral dosage form will preferably be a dosage form containing over 50% of the VR ligand in a sustained release formulation, so that some portion (typically at least 25%, more typically at least at least 50%) of the VR ligand is delivered to the patient slowly in a sustained manner over time. The balance of the VR ligand, if any, is in an immediate release form. The oral or parenteral dosage form can have 100% or nearly 100% of the VR ligand in a

34 LHF-003 sustained release form that attenuates delivery of the VR ligand to the patient over an extended period of time.

[000110] Making the oral or parenteral sustained release formulations of the invention involves combining or formulating the VR ligand with any number of exipients to slow the release of the VR ligand in the gastrointestinal tract or other systemic route of the patient.

[000111] The term "pharmaceutically acceptable" such as in the recitation of a pharmaceutically acceptable salt or excipient means a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition and administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term "pharmaceutically acceptable" is used to refer to a derivative (e.g., a salt) of an active agent, it is to be understood that the compound is pharmacologically active as well. When the term, "pharmaceutically acceptable" is used to refer to an excipient, it implies that the excipient has met the required standards of toxicological and manufacturing testing or that it is on the Inactive Ingredient Guide prepared by the FDA.

[000112] A "pharmaceutical composition" according to the invention is a composition that contains the active agent(s) of interest and, optionally, exipients which promote a desired in vivo release profile for the active agent(s) when administered either parenterally or to the gastrointestinal tract of the female experiencing the menopausal symptoms. Pharmaceutical compositions can comprise two or more active agents or excipients.

[000113] "Rate of release" as used herein is the rate and pattern of release of an active agent from the dosage form after administration to a patient. A release profile can be determined by measuring the plasma concentration of the active agent

35 LHF-003 in the patient after administration at two or more time points. The release rate can be quantified by the ratio dC/dT, where C is concentration and T is time.

[000114] n general, the term "therapeutically effective amount" refers to that amount of the VR ligand which is sufficient to reduce the severity and/or frequency of hot flashes associated with menopause or perimenopause when administered to a peri-menopausal, pre-menopausal or menopausal human female. A therapeutically effective amount also can reduce the likelihood of onset of hot flashes in an asymptomatic female.

[000115] Accordingly, a therapeutically effective amount will usually be at least 0.01 mg per administration or dosage form of a VR ligand in a pharmaceutical composition, subject for any particular compound of course to the routine trials discussed above. It is relatively straightforward to select a higher dose for a particular individual as needed, and to increase the dose until a desired effect is achieved in the individual. The dosage appropriate for a given individual is tied to the degree of effect desired in that individual.

[000116] Accordingly, a therapeutically effective amount per administration of VR ligand can be at least about 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg or 200 mg.,.

[000117]A therapeutically effective amount in a single dosage unit can also be at least about 0.01mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg or 200 mg.The dosage unit can be an oral dosage unit or a parenteral one.

36 LHF-003 The dosage unit can be formulated in an immediate release or in some form of controlled or sustained release dosage form.

[000118] An acceptable range of doses for the VR1 ligand can be from any of the above dosages up to about 30 mg/kg/day, preferably up to about 10 mg/kg/day, more preferably up to about 1 mg/kg/day. Alternatively, oral dosage forms can contain from any of the above doses up to about 2000 mg, or up to about 500 mg, or up to about 150 mg of active drug. Typical dosage ranges are expected to have a minimum selected from about 0.01 mg, 0.1 mg, 1 mg, 5 mg, 10 mg or 20 mg, and a maximum selected from about 30 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 400 mg, 500 mg or 1000 mg.

[000119] The preparation of pharmaceutical or pharmacological compositions are known to those of skill in the art in light of the present disclosure. General techniques for formulation and administration are found in "Remington: The Science and Practice of Pharmacy, Twentieth Edition," Lippincott Williams & Wilkins, Philadelphia, PA. Tablets, capsules, pills, powders, granules, dragees, gels, slurries, ointments, and suppositories, are examples of such formulations.

[00012O]To make a sustained release dosage form, exipients are used with the VR ligand to slow the release of the VR ligand into the gastrointestinal tract after administration of the dosage form. The excipients used to produce the formulation may include bulking agents, lubricants, glidants, anti-tack agents, and release controlling agents. Many such materials are found in "Remington: The Science and Practice of Pharmacy, Twentieth Edition," Lippincott Williams & Wilkins, Philadelphia, PA and commonly known to the skilled artisan. The specific excipients used will be determined by the requirements for administration of the dosage, including the targeted dosing frequency, slope of VR agonist release and absorption, and route of administration.

[000121] Exipients may include pharmaceutically acceptable carriers that include any and all solvents, dispersion media, coatings, antibacterial and antifungal

37 LHF-003 agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[000122] Excipients used for sustained release include agents that comprise such parts of a dosage form as a core, seal coating, sustained release coating, polymer to be mixed with the VR ligand or coating; and including throughout both water soluble and water insoluble agents. Additional excipients are also commonly used which do not contribute directly to the sustained release properties of the composition.

[000123] Liposomes, such as those described in U.S. Patent No. 5,422,120, WO

95/13796, WO 91/14445, or EP 524,968 B1 , may also be used as a carrier.

[000124] Additional methods for making sustained release formulations are described in, e.g., U.S.Patent Nos. 5,422,123; 5,601 ,845; 5,912,013; and 6,194,000, all of which are hereby incorporated by reference.

[000125] The patients to be treated are human females of an age or circumstance such that they are experiencing peri-menopause, pre-menopause, or menopause. These females can be symptomatic, experiencing any number of menopausal symptoms, or they may be asymptomatic. In asymptomatic patients, administration of VR ligands can be characterized as prophylactic administration, administering the VR ligand in anticipation of eventual symptoms. Prophylaxis using the VR ligands serves to condition the body to avoid the uncomfortable effects of the physiological progression towards menopause. The terms patient, human, female, person, individual, and subject are used synonamously to indicate the individual being administered the VR ligand.

38 LHF-003 [000126] The dosage regimen for treating a peri-menopausal, pre-menopausal or menopausal female with the compounds of this invention and/or compositions of this invention is based on a variety of factors, including the general health and physical condition of the female patient, and also including the severity of the condition, the frequency and intensity of the symptoms, the route of administration, responsiveness of the patient to the VR ligand, any tolerance that may develop with administration of the VR ligand over time, any fluxuation in the frequency or severity of symptoms, and the particular compound, composition or formulation employed for treatment or prophylaxis.

[000127] Whether an administration of the active ingredient (a VR ligand) has been effective is determined by whether the VR ligand as administered to a peri- menopausal, pre-menopausal, or menopausal human female treats, relieves, prevents, or ameliorates menopausal symptoms in the human female. . Generally, a woman will seek some form of treatment around the time of menopause where they are experiencing symptoms that cause discomfort or which are annoying. Upon a regimen incorporating administration of a VR ligand, the treatment or prophylaxis will be considered successful if the woman is relieved of at least one of her symptoms, and accordingly can function more like her "normal self and feel more comfortable or in charge of herself because of taking the VR ligand.

[000128] Thus, the dosage regimen can be determined routinely using standard methods. Daily dosage amounts are determined based on efficacy for a patient or a population. Dosage amounts of any VR ligand are expected to be at least 0.01 mg per administration. Dosage forms can comprise at least 0.01 mg in a single dosage form. As resiferatoxin is more potent than capsaicin the daily dosage required for efficacy for this VR ligand may be at least 0.0001 mg or greater. The pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to human female patients. The compounds can be formulated for administration in any variety of modes.

39 LHF-003 [000129] The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water. The daily parenteral dosage regimen will be at least 0.01 mg/kg of total body weight.

[000130] The VR ligand can be administered in any variety of daily or weekly administrations, for example 1X daily, 2X daily, 3X daily, 4X daily, and as needed when symptoms arise Weekly administrations may apply particularly to transdermal delivery of the VR ligand, where a transdermal patch containing VR ligand can deliver the ligand continuously to the patient for days and even up to one week or two weeks before needing to exchange the patch. The composition can also be administered at night before bed, in the morning, midday, and as-needed to ameliorate symptoms. The frequency of administration of a given dosage form may depend on whether or not the drug is formulated as a sustained release formulation, or an immediate release formulation.

[000131] The frequency of administration will depend on patient factors, the dosage form, and the responsiveness of the patient to treatment, among other considerations. For example, it is conceivable that the initial doses of the VR ligand will be high and frequently administered, and that once tolerance is developed, both the administration frequency and dose amount might be reduced to a maintenance level of VR ligand. Thus loading doses are contemplated as necessary to bring the patient to a minimum effective concentration of VR ligand as soon as possible.

[000132] Suppositories for rectal or vaginal administration of the VR ligand can be prepared by mixing the VR ligand with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina and release the VR ligand.

[000133] Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin (e.g., liniments, lotions,

40 LHF-003 ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose.

[000134] For administration, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration. The compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, acacia, gelatin, sodiunValginate, polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration. Alternatively, the compounds of this invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art. The carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.

[000135] The pharmaceutical compositions may be made up in a solid form (including granules, powders or suppositories) or in a liquid form (e.g., solutions, suspensions, or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc.

[000136] Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

41 LHF-003 [000137] Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

[000138] Compounds of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereoisomeric salts, by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active compounds of the invention can likewise be obtained by using active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.

[000139] Likewise, the compounds of this invention may exist as isomers, compounds of the same molecular formula but in which the atoms, relative to one another, are arranged differently. In particular, the alkylene substituents of the compounds of this invention, are normally and preferably arranged and inserted into the molecules as indicated in the definitions for each of these groups, being read from left to right. However, in certain cases, one skilled in the art will appreciate

42 LHF-003 that it is possible to prepare compounds of this invention in which these substituents are reversed in orientation relative to the other atoms in the molecule. That is, the substituent to be inserted may be the same as that noted above except that it is inserted into the molecule in the reverse orientation. One skilled in the art will appreciate that these isomeric forms of the compounds of this invention are to be construed as encompassed within the scope of the present invention.

[000140] The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. The salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methansulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 2- phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, and undecanoate. Also, the basic nitrogen-containing groups can be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.

[000141] Examples of acids that may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.

43 LHF-003 ] Also encompassed in the scope of the present invention are pharmaceutically acceptable esters of a carboxylic acid or hydroxyl containing group, including a metabolically labile ester or a prodrug form of a compound of this invention. A metabolically labile ester is one which may produce, for example, an increase in blood levels and prolong the efficacy of the corresponding non-esterified form of the compound. A prodrug form is one which is not in an active form of the molecule as administered but which becomes therapeutically active after some in vivo activity or biotransformation, such as metabolism, for example, enzymatic or hydrolytic cleavage. For a genera! discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, Apr. 11 , 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use. Esters of a compound of this invention, may include, for example, the methyl, ethyl, propyl, and butyl esters, as well as other suitable esters formed between an acidic moiety and a hydroxyl containing moiety. Metabolically labile esters, may include, for example, methoxymethyl, ethoxymethyl, iso-propoxymethyl, α-methoxyethyl, groups such as α-((C_rC₄)alkyloxy)ethyl, for example, methoxyethyl, ethoxyethyl, propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-1 ,3-dioxolen-4-ylmethyl groups, such as 5-methyl-2-oxo-1,3,dioxolen-4-ylmethyl, etc.; CrC₃ alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, etc.; acyloxymethyl groups, for example,

44 LHF-003 pivaloyloxymethyl, α-acetoxymethyl, etc.; ethoxycarbonyl-1 -methyl; or α- acyloxy-α-sυbstituted methyl groups, for example α-acetoxyethyl.

[000143] Further, the compounds of the invention may exist as crystalline solids which can be crystallized from common solvents such as ethanol, N₁N- dimethylformamide, water, or the like. Thus, crystalline forms of the compounds of the invention may exist as polymorphs, solvates and/or hydrates of the parent compounds or their pharmaceutically acceptable salts. All of such forms likewise are to be construed as falling within the scope of the invention.

[000144] While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.

[000145] The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

[000146] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

EXAMPLES

[000147] In order to study the effects of oral capsaicin upon a characteristic menopausal symptom, the hot flash, flush and/or night sweat, 10 red marbles and 10 black marbles were placed in a container where all marbles were accessible to a - reaching hand. For the period of about one month, the study female (age 48 ^ΛA , weight 120 pounds, 57" tall, in otherwise decent health) kept the marbles within easy access and completed the following study. Upon the hint of the

45 LHF-003 onset of a hot flash, flush or sweat, a marble would be selected randomly and blindly. A red marble dictated that capsaicin would be taken (in powder capsule form in cayenne pepper capsules of 450 mg of cayenne per tablet, Puritan Pride™ brand, with 8 oz. of water) and a black marble dictated taking just the water. Notes were made following the administration of the cayenne or control. The results are embodied in the table below. The general experience of the patient was that with the ingestion of cayenne, the flash, flush or sweat was "chased" away. It was not clear how much cayenne is actually needed to cause a positive effect, but in this study about 10 caps, or 4.5 g, or sometimes 20 caps (9 g) were administered upon the drawing of each red marble. A later brief and undocumented study indicated to the patient that perhaps only 2 caps (approximately 900 mg) were needed at an administration, but that 2 caps could be taken 5 times in a day to achieve a "protective" effect to the onset of any symptoms throughout the day. For the purposes of understanding the description of the symptoms and effects in the "Effect" column, a flash and a flush are just about the same thing - a flash being alittle more intense and localized and shorter, and a flush being a warmth throughout a larger region and less intense.

[000148] Table 1

46 LHF-003

47 LHF-003

48 LHF-003

49 LHF-003

50 LHF-003

[000149] Conclusions that were drawn from this study include that cayenne pepper can be rough on the stomach; and so perhaps ingestion with food is preferred where the condiment cayenne pepper powder is the formulation, although this is contradicted because there was some indication that ingestion on an empty stomach provided maximal and most expedient relief. Along these lines parenteral administration should also be explored.

[000150] Experiencially, a lower sustained dose taken (or delivered) more frequently and before symptoms are even evident achieved an optimal effect, without some of the gastrointestinal challenges presented with large doses of cayenne taken right when symptoms are coming on.

51 LHF-003 [00015I]A regimen to try may be a prophylactic regimen, administering the VR1 ligand before actual symptoms to provide a protection from the inevitable onset of the symptoms, a regimen that may work well if employing a sustained formulation of some amount of VR ligand by which a protective effect can be established; for example: either a sustained continual dose, or first a large sustained dose for a short period of time followed second by a lower sustained continual maintenance dose.

[000152] All references cited are incorporated in their entirety. Although the foregoing invention has been described in detail for purposes of clarity of understanding, it will be obvious that certain modifications may be practiced within the scope of the appended claims.

52 LHF-003

Claims

WHAT IS CLAIMED IS:

1. A method of treating hot flashes associated with menopause or perimenopause, comprising administering to a human female in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a vanilloid receptor ligand, thereby reducing severity or frequency of said hot flashes.

2. The method of claim 1 , wherein said vanilloid receptor ligand comprises a therapeutically effective amount of a means for vaniϋoid receptor ligand binding, thereby reducing severity or frequency of said hot flashes.

3. The method of claim 1 or 2, wherein said vanilloid receptor is vanilloid receptor 1.

4. The method of claim 3, wherein said vanilloid receptor ligand is selected from the group consisting of compounds of formula I₁ compounds of formula II, compounds of formula III, compounds of formula IV, compounds of formula V, compounds of formula Vl, compounds of formula VII, compounds of formula VIII, compounds of formula IX, compounds of formula X, compounds of formula Xl, compounds of formula XII, compounds of formula XIII, compounds of formula XIV, compounds of formula XV, compounds of formula XVI, compounds of formula XVII, compounds of formula XVIII, compounds of formula XIX, compounds of formula XX, compounds of formula XXI, compounds of formula XXII, compounds of formula XXIII, compounds of formula XXIV, compounds of formula XXV, compounds of formula XXVI, resinferatoxin (RTX), capsaicin, isovelleral, scutigeral, resinferanoids, capsaicinoids, unsaturated dialdehydes triprenyl phenols, capsazepine, terpenoid unsaturated dialdehydes, triprenyl phenols, n- bicyclic amides, substituted benzimidazoles, substituted nitrogen-containing heterocycles , compounds of a general structure of therapeutic benzimidazoles.substituted pyridines and pyrimidines, pyrimidine ethers, bis-bicyclic amides and compositions containing them, therapeutic benzimidazoles, oxazolyl compounds, diaryl piperazines,anandamide ligands.structurally related lipids to anandamide such as AM404, 1-arachidonylglycerol, and 2-

53 LHF-003 arachidonylglycerol, substituted pyrimidyl-4-ylamine analogues and compositions containing them, amide chemicals including benzamides and amides, diaryl piperazines, resinferatoxin pharmacophores, beta-aminotetralin derived ureas, naphthol-derived ureas, quinoline-derived ureas, and isoquinoline-derived ureas.

5. The method of claim 1 or 2 comprising oral administration.

6. The method of claim 3 comprising oral administration.

7. The method of claim 1 or 2, wherein said vanilloid receptor ligand is formulated in a sustained release dosage form.

8. The method of claim 1 or 2, wherein said pharmaceutical composition is in an oral dosage form selected from the group consisting of a tablet and a capsule.

9. The method of claim 8 wherein said oral dosage form is a sustained release dosage form.

10. The method of claim 1 or 2, wherein said amount of vanilloid receptor ligand is at least 0.01 mg per administration.

11. The method of claim 10, wherein said oral administration comprises administering at least 0.01 mg of a vanilloid receptor ligand in a single oral dosage form.

12. A pharmaceutical composition comprising as an active agent a vanilloid receptor ligand formulated in a sustained release dosage form.

13. The pharmaceutical composition of claim 12, wherein said active agent is a means for vanilloid receptor binding.

14. The pharmaceutical composition of claim 12 or 13, wherein vanilloid receptor ligand is selected from the group consisting of compounds of formula I, compounds of

54 LHF-003 formula II, compounds of formula III, compounds of formula IV, compounds of formula V, compounds of formula Vl₁ compounds of formula VII, compounds of formula VIII, compounds of formula IX, compounds of formula X, compounds of formula Xl, compounds of formula XII, compounds of formula XIII, compounds of formula XIV, compounds of formula XV, compounds of formula XVI, compounds of formula XVII, compounds of formula XVIII, compounds of formula XIX, compounds of formula XX, compounds of formula XXI, compounds of formula XXII, compounds of formula XXIII, compounds of formula XXIV, compounds of formula XXV, compounds of formula XXVI, resinferatoxi.n (RTX), capsaicin, isovelleral, scutigeral, resinferanoids, capsaicinoids, unsaturated dialdehydes triprenyl phenols, capsazepine, terpenoid unsaturated dialdehydes, triprenyl phenols, n-bicyclic amides, substituted benzimidazoles, substituted nitrogen-containing heterocycles , compounds of a general structure of therapeutic benzimidazoles.substituted pyridines and pyrimidines, pyrimidine ethers, bis-bicyclic amides and compositions containing them, therapeutic benzimidazoles, oxazolyl compounds, diaryl piperazines,anandamide ligands.structurally related lipids to anandamide such as AM404, 1-arachidonylglycerol, and 2- arachidonylglycerol, substituted pyrimidyl-4-ylamine analogues and compositions containing them, amide chemicals including benzamides and amides, diaryl piperazines, resinferatoxin pharmacophores, beta-aminotetralin derived ureas, naphthol-derived ureas, quinoline-derived ureas, and isoquinoline-derived ureas.

15. The pharmaceutical composition of claim 12 or 13, wherein said sustained release dosage form is an oral dosage form.

16. The pharmaceutical composition of claim 15, wherein said oral dosage form is selected from the group consisting of a tablet or a capsule.

17. The pharmaceutical composition of claim 15, wherein an amount of said active agent of vanilloid receptor ligand in said sustained release dosage form is at least 0.01 mg.

55 LHF-003