TW200526227A - Methods of treating vasomotor symptoms - Google Patents

Abstract

The present invention relates to selective adrenergic α2B antagonists alone, selective adrenergic α2B antagonists in combination with norepinephrine reuptake inhibitors (NRI) (as a single compound or as a combination of two or more compounds), or selective adrenergic α2B antagonists in combination with dual norepinephrine reuptake inhibitors/serotonin reuptake inhibitors (NRI/SRI) (as a single compound or as a combination of two or more compounds) and methods of their use in the treatment of vasomotor symptoms.

Description

200526227… IX. Description of the invention: The priority claimed in this application is: (a) US application No. 10 / (filed on October 12, 2004), which claims US application No. 60/5 10,897 ( Filed on October 14, 2003), (b) US · Application No. 10 / 685,8 1 2 (filed on October 14, 2003); and (c) International Application No. (The corpses were applied for on October 15, 2003), and all of them are disclosed in this article for reference. [Technical field to which the invention belongs] The present invention relates to the use of a compound and a composition of a compound for adjusting orthopinephrine concentration to treat (especially) vasomotor symptoms (VMS). In particular, the present invention relates to compounds having adrenal α 2B antagonist activity to modulate the adrenaline system and the use of the composition of the compounds. [Prior art] Vasoconstriction symptoms (VMS) are related to menopause flushing and night sweats. They are the most common symptoms associated with menopause. 60% to 80% occur in women who have menopause naturally or surgically. VMS appears to be an adaptive response to the central nervous system (CNS), a degenerative sex steroid. According to the information, the most effective treatment for VMS is hormone-based treatment, including estrogens and / or some progesterone hormones. Hormonal treatment is very effective in alleviating VMS, but it is not suitable for all women . It is widely recognized that VMS is caused by changes in sex steroid concentrations and can disrupt and disable men and women. Menopause flushing can last for more than 30 minutes, and its frequency changes from several times a week to one. 200526227 1 ··· Many times the 'menopause flushing experienced by the patient is a rapid sense of rapid spread from the face to the chest and back and then spread Hotness throughout the body is often accompanied by a large amount of sweating, which can occur several times within an hour, and usually occurs at night. Insomnia caused by flushing and sweating during menopause during the night can cause insomnia. Observed psychological and emotional symptoms such as restlessness, fatigue, irritability, insomnia, depression, memory decline, headache, anxiety, nervousness or loss of concentration, It was judged to be caused by menopause flushing and insomnia after night sweats (ATrama a /., / W: Mwrp / i}; eta L ·, 3rd I nt fl Symposium on Recent Advances in Urological Cancer Diagnosis and Treatment-Proceedings, Paris, France: SCI: 3-7 (1992). Menopausal flushing may be even more severe for women who treat breast cancer for several reasons: (1) Many survivors of breast cancer are given tamoxifen. Common side effects are flushing during menopause; (2) many women who treat breast cancer endure premature menopause due to chemotherapy; (3) women with a history of breast cancer are usually not allowed to use estrogens because of the potential Sexual recurrence Wa / ·, 2000, "? 5 (5 (9247 Canton 2059-2063) 〇 Men also experience menopausal flushing after steroid hormone (androgen) decline, exact In terms of age-related decline in androgen (Katovich, eta l., Proceedings of the Society for Experimental Biology & Medicine, 1990, 193 (2): 129-35), and Horr related to the treatment of prostate cancer In the most extreme cases of deficiency (Berendsen, et al ·, European Journal of Pharmacology, 200526227 1 · *, 200i, " 9 (7) ·· 4 7-54), one third of these patients will Experiences persistent and often severe enough to cause significant discomfort and inconvenience. The clear mechanism of VMS is unknown, but it is often thought to indicate a mechanism that interferes with normal and stable thermoregulation and vasomotor activity ( Kronenberg et al., &Quot; Thermoregulatory Physiology of Menopausal Hot Flashes: A Review, Can. J. Physiol. Pharmacol., 1 987, 65: 1312-1324). In fact, estrogen therapy (such as estrogen replacement therapy) slows down Symptoms confirm the association between these symptoms and a lack of estrus hormones. For example, the menopause phase in life is associated with a wide range of other acute symptoms described above, and these symptoms are usually estrogens-responsive. It has been suggested that estrogens can stimulate the activity of the adrenaline (NE) and / or serotonin (5-HT) system (/ · P / iarmaco / ogy ά Ejcper / menia / rhMpeWid 7 9S6, 2 3 6 (3) 646-652), it is speculated that estrogens regulate NE and 5-HT concentrations to provide stabilization of the thermoregulatory center of the hypothalamus, from the downstream path of the hypothalamus via the brain stem / spinal cord and adrenal glands to the skin and maintain general skin temperature Are closely related. The effects of NE and 5-HT reuptake inhibitors are known to attack the CNS and peripheral nervous system (PNS). The disease physiology of VMS is regulated by central and peripheral mechanisms. Therefore, the interaction between CNS and PNS can be used to estimate the efficacy of SRI / NRIs that have a dual role in treating temperature regulation disorders. In fact, compared to the doses used to treat depressive behavior, the physiological aspects of VMS and CNS / PNS involving VMS are considered to be lower doses (Lopr / nzi, da / ·, Lancei, 2000, 356: 2059-2063; Stearns et al.t JAMA, 2003 f 200526227

1 1 · I 2S9: 2S2 7-2S34). The interaction of CNS / PNS in the physiology of VMS disease and the information present in this document are used to support the claimed adrenaline system as a target for treating VMS. Although patients with VMS are most often treated with hormone therapy (oral, subcutaneous, or implanted), some patients cannot tolerate estrogens (Berendsen, Maturitas, 20000, 36 (3) : 155-164, Fink etal, JVaiMre, 7996, 306). In addition, hormone replacement therapy is often not recommended for women or men who have or are at risk for hormone-sensitive cancers such as breast or prostate cancer. Therefore, non-hormonal therapies such as Prozac Fluoxetine, pai: oxetine [SRIs], and clonidine) were evaluated clinically. WO9944601 discloses a method for reducing flushing of men and women during menopause by administering Prozac. Other options have been studied in the treatment of menopausal flushing, including steroids, alpha-antagonists and / 3-blockers, with varying degrees of success (Wa / d / nger α / ·, 200 0, 36 (3 ): 165-168) 〇 The report states that a 2-adrenal receptors play a role in temperature regulation disorders (Freedman et al., Fertility & Sterility, 2 000, 74 (1): 2 0-3), etc. Receptors are located in the anterior and posterior synapses and regulate the inhibitory role in the central and peripheral nervous systems. There are four separate adrenal α 2 receptor subtypes, Liangzhu α 2Α, α 2B, a 2C, and a < 2 / ·, TIPS, 1994, 15: 119; French, Pharmacol · The r. F 1995, 68: 775). Fortunately, β reports that non-selective a 2-adrenergic receptor yohimbine causes redness, and a 2-adrenoreceptor competitor clonidine mitigates the effect of yohimbine (Katovichy et α / ., Proceedings of the Society for 200526227 1 1 *

Experimental Biology & Medicine, 1990, 193 (2): 12 9-35, Freedman et al., Fertility & Sterility, 2000, 74 (1): 20-3) 〇 Clonidine has been used to treat menopausal flushing . However, the use of this treatment may require high doses to alleviate menopausal flushing as described herein and known in the related art, with concomitant several unintended side effects. While maintaining stable body temperature regulation, it provides multiple aspects of natural body regulation and the interaction between CNS and PNS. Various aspects of therapy and pathways can improve target vasomotor symptoms. The present invention focuses on methods for these and other important uses . SUMMARY OF THE INVENTION The present invention provides a method for treating a patient suffering from vasomotor symptoms. In one aspect, the present invention relates to a method for treating vasomotor symptoms in a desired patient, comprising the following steps: administering to the patient comprises the following composition: an effective amount of an active ingredient selected from at least one necessary choice Adrenal α 2B receptor antagonist or a pharmaceutically acceptable salt thereof. In another aspect, the invention relates to a method for treating vasomotor symptoms in a desired patient, comprising the steps of: administering the patient to a composition comprising: an effective amount of at least one selective adrenal α 2B receptor Or a pharmaceutically acceptable salt thereof; and an effective amount of at least one orpine adrenaline reuptake inhibitor (NRI) or a pharmaceutically acceptable salt thereof. -9- 200526227 ,. In another aspect, the present invention is a method for treating vasomotor symptoms in a desired patient, comprising the following steps: administering the patient to the composition comprising: at least one choice of an effective amount Adrenal α 2B receptor antagonist or a pharmaceutically acceptable salt thereof; and an effective amount of at least one dual ortho adrenergic reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) or a pharmaceutically acceptable Salt. In another aspect, the present invention relates to a pharmaceutical composition comprising: an active ingredient consisting of at least one necessary selective adrenal α 2B receptor antagonist or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable Acceptable vehicle. In another aspect, the present invention relates to a medicinal composition comprising: at least one selective adrenal α 2B receptor antagonist or a pharmaceutically acceptable salt thereof; at least one orpine adrenaline reuptake inhibitor (NRI) or Its pharmaceutically acceptable salts; and at least one pharmaceutically acceptable carrier. In another aspect, the present invention relates to a medicinal composition comprising: at least one selective adrenal α 2B receptor antagonist or a pharmaceutically acceptable salt thereof; at least one orpine adrenaline reuptake inhibitor / serotonin Absorption inhibitor (NRI / SRI) or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier. Detailed description of the invention-10- 200526227 Adrenal α 2 receptor antagonists are known to cause menopausal flushing. Surprisingly, we have discovered a selective adrenal α 2 β receptor antagonist when administered alone A dose-dependent alleviation of naloxone-induced flushing with or when administered together with NRI compounds. Furthermore, we have found that the efficacy of N RI is made possible when administered in combination with an adrenal (X 2 β receptor antagonist). It is believed that the present invention describes the treatment, relaxation, inhibition and / or prevention of blood vessels There is a considerable breakthrough in the field of diastolic instability and / or symptoms. The present invention provides a method for treating patients suffering from vasomotor symptoms by restoring reduced activity of orthopinephrine, in the hypothalamus or brain stem The positive adrenaline activity can be increased by: (i) blocking the activity of adrenal α2B receptors with antagonists, and / or (ii) blocking the activity of NE transporters. More particularly, the present invention provides treatment A method for patients with vasomotor symptoms, which comprises administering a selective adrenal cx2B antagonist alone, and an adrenaline reuptake inhibitor (N RI) (a single compound or a combination of two or more compounds)倂) A combination of selective adrenal α2B 掊 inhibitors, and a dual orpine adrenaline reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) (a single compound or a combination of two or more compounds) Ii) Selective adrenal α2B antagonists. The present invention also includes a pharmaceutical composition comprising, as an active ingredient, a selective selective adrenal α2B 掊 antagonist, and the selectivity of combination with a normal adrenaline reuptake inhibitor. Adrenal α2B antagonist (NRI) (either a single compound or a combination of two or more compounds), or with a dual ortho-adrenergic reuptake inhibitor / serotonin reuptake inhibitor 200526227 agent (NRI / SRI) (a A single compound or a combination of two or more compounds) A selective adrenal α2B antagonist. The following definitions are provided to fully understand the terms and abbreviations used in the present invention. As used herein and in the scope of the attached patent application In addition, unless the context clearly indicates, the word of a single type includes the meaning of plural. Therefore, for example, the meaning of "an antagonist" includes the plural of the antagonist, and the meaning of "a compound" includes familiarity with the term. One or more compounds known to the skilled person and their equivalents, etc. The unit of measurement, technique, property or compound in the description. The abbreviations should be as follows: "min" means minutes, "h" means hours, "// L" means microliters, "mL" means milliliter, "mM" means millimolar concentration, "M" means molar concentration, " "mmole" means millimoles, "cm" means centimeter, "SEM" means standard deviation of mean 値, and "IU" means international unit. "△ It" and △ TST indicate normalization before naloxone-induced flushing1 The change in the tail skin temperature at the base of τ ST at 5 minutes, "ED50 °" means a 50% soothing dose that produces the observed condition or response (50% represents the maximum end point). "Tail skin temperature" is referred to as TST. "Positive "Adrenaline transporter" is referred to as NET. "Human adrenaline transporter" is referred to as hNET. "Serotonin Transporter" is referred to as SERT. "Human serotonin transporter" is abbreviated as hSERT. "Nephroadrenaline reuptake inhibitor" is abbreviated as NRI. "Selective ortho-adrenergic reuptake inhibitor" is abbreviated as SNRI. "Serotonin reuptake inhibitor" is abbreviated as SRI. 200526227 "Selective Serotonin Reuptake Inhibitor" is abbreviated as SSRI. "Nephrine" is abbreviated as NE. "Serotonin" is referred to as 5-HT. "Subcutaneous" is abbreviated sc. "Intraperitoneal" is referred to as ip. "Oral" is abbreviated as p0. "High performance liquid chromatography" is referred to as HPLC. The terms "vasomotor symptoms", "syndromes of vasomotor instability" and "vasomotor disorders" include (but are not limited to) menopausal flushing (flushing), insomnia, and sleep disturbances, particularly caused by temperature regulation disorders , Upset, irritability, excessive sweating, night sweats, fatigue, etc. The term “menopausal flushing” is a technically recognized term that refers to transient imbalances in body temperature, especially rapid skin flushing, which usually occurs with the patient's sweating. The term “menopausal flushing” can be used interchangeably with terms such as vasomotor symptoms, vasomotor instability, vasomotor disorders, night sweats, vasomotor disorders, and hot flushes. As used herein, the term "pre-menopause" means before the menstrual period. As used herein, "menopause period" means that the menopause period is in progress, and "postmenopause period" as used herein means after the menopause period. The term “premature menstrual period” or “unnatural menstrual period” refers to ovarian failure caused by unknown causes, which can occur before the age of 40, and may be related to smoking, living at high altitudes, or poor nutrition. Unnatural menstrual periods can be caused by oophorectomy, chemotherapy, radiation from the pelvis, or in any way damaging the ovarian blood supply. -13- 200526227 "Ovariectomy" as used herein means the removal of one or two ovaries, and according to Mercenthaler et al., Maturitas, 1998; 30 (3): 307-316 # ίτ 0 used in this article The "selective adrenal α2B receptor antagonist" refers to an adrenal α2B receptor antagonist compound, which preferentially binds to an adrenal α2B receptor over an adrenal α2A receptor or an adrenal a2C receptor, and may Selective adrenal a2B receptor antagonists, measured by the ratio of in vitro or in vivo 1C 50 0 値 of antagonist activity on adrenal α2B receptors, divided by IC5G 値, which is adrenergic activity of adrenal Ct2A or C The ratio to any adrenal a2 receptor antagonist is greater than 1, preferably greater than 2, more preferably greater than 5, more preferably greater than 10, and more preferably greater than 50. The most preferred is about greater than 100. As used herein, "orpinephrine reuptake inhibitors" are compounds that alter the concentration of orthopinephrine (NE) by inhibiting NE absorption through the central and / or peripheral neurological system and / or peripheral system neurons. And its selectivity with SERT: NET activity (measured by EC50% or by% specific binding to NE uptake by human transporters) is at least about 1: 1. Preferably, the selection rate of SERT: NET does not exceed about 1000: 1. Preferably, the selection rate of SERT: NET is greater than about 2: 1. More preferably, the selection rate of SERT: NET is greater than about 5: 1. Even better, the selectivity of SERT: NET is greater than about 10: 1. The phrase "substantially free of serotonin reuptake inhibitor (SRI) activity" means that the selectivity with SERT: NET activity (measured by EC5G 値 or by% specific binding to NE absorption by human transporters) is greater than about 2: 1 of adrenal gland 200526227 hormone reuptake inhibitor, preferably, greater than about 5: 1, and more preferably, greater than about 10: 1. As used herein, the terms "adrenaline reuptake inhibitor / serotonin reuptake inhibitor" and "(NRI / SRI)" mean a single having the dual activities of a serotonin reuptake inhibitor and an orpinephrine reuptake inhibitor. Compounds. As used herein, a compound having dual activity is a compound having dual effects. As used herein, the term "treatment" includes preventive (eg, preventive), therapeutic, or palliative treatment, and "treating" as used herein also includes preventive, curative, or palliative treatment. As used herein, "administering" means directly administering a compound or a composition of the invention, or administering a prodrug, derivative, or analogue that will form an equivalent amount of an active compound or substance in the body. As used herein, the term "effective amount" means an effective amount at a dose and is used as necessary to achieve the desired result. In particular, an "effective amount" means an amount of a compound or a composition of compounds that increases the concentration of norepinephrine to partially or fully compensate for the availability of steroids that are insufficient in patients suffering from vasomotor symptoms. Different hormonal concentrations will affect the required amount of the compounds of the present invention. For example, due to higher hormonal concentrations in the premenopausal phase, lower amounts of the compound may be required in the premenopausal phase. It is important to note that the effective amount of the ingredients of the present invention will vary according to each patient, not only depending on the particular compound, ingredient or composition selected, route of administration, and efficacy of the ingredient (single or one or more combination drugs) Combination) and the desired response induced in the individual, and based on the severity of the disease condition or symptom to be alleviated, hormone concentration, age, sex, individual weight, patient location-15-200526227 The stage, the severity of the pathological symptoms to be treated, the factors such as drugs or special diets that will be treated at the same time for special patients, and other factors recognized by those skilled in the art, are administered to the attending physician in a final and appropriate dose. Dosage therapy can be adjusted to provide an improved therapeutic response. A therapeutically effective amount is also the amount by which a therapeutically beneficial response exceeds the toxic or harmful response of any ingredient. Preferably, the number of flushes during menopause can be reduced by administering the compound of the present invention in one dose and once compared to the number of flushes during menopause before the start of treatment. Compared to the severity of flushing during menopause before starting treatment, this treatment also helps to reduce the overall severity or the intensity distribution of any menopause flushing that is still felt. "Ingredients," "medicines," or "pharmaceutically active agents" or "active agents" or "drugs" as used interchangeably herein means that a compound or several compounds or compositions of matter are administered to an organism (human or animal) Through the local and / or systemic effects, the desired pharmacological and / or physiological effects are caused. The ingredients in this text may include ortho-adrenergic reuptake inhibitory activity, or a combination of ortho-adrenergic reuptake inhibitory activity and ortho-adrenergic reuptake inhibitory activity. In addition, the ingredients herein may include ortho-adrenergic reuptake inhibitory activity and adrenal α2B receptor antagonist activity. The term "modulation" means the ability to enhance or inhibit the functional properties of a biological activity or process, such as receptor binding or signal activity, which enhances or inhibits the occurrence of occasional special events, such as activation of signal transduction pathways, and / or may only Shown in some cell types. Modulators intentionally include any compound, such as an antibody, small molecule, peptide, oligopeptide, polypeptide or protein, preferably a small molecule or peptide. • 16- 200526227 Concomitant treatment means the administration of-* one or more therapeutic agents or compounds to treat the treatment symptoms or disorders disclosed in the present invention, such as menopause flushing, sweating, temperature-related symptoms or disorders, etc. This administration includes co-administration of these therapeutic agents or compounds in the same manner, for example, as a single compound with NRI / adrenal α2B receptor antagonist activity, or a plurality, for each NRI, NRI / SRI, or adrenal Sexual & receptor antagonist compounds (including individual compounds administered in a single dosage unit). In addition, this administration also includes the use of various types of therapeutic agents in the same way. In other cases, the system of treatment is based on the treatment of symptoms or disorders described herein, which will provide the beneficial effects of drug combination. The term "patient" or "patient" means animals including humans, which can be treated with the composition and / or the method of the present invention. The word "patient" or "patient" is intended to mean both males and females, except where gender is specified. Therefore, the term "patient" includes any mammal that can benefit from the treatment or prevention of vasomotor disorders, such as Humans, especially if they are female, are in the period before, during or after menopause. Furthermore, the term patient includes female animals that include humans, and among humans, not only the elderly who have passed menopause. Women, and women who have undergone hysterectomy or have suppressed estrogen production for other reasons, such as people who have been undergoing prolonged administration of adrenal corticosteroids, people with Gushing's syndrome, or those with hypogonadism. However, the term "patient" does not It is not intended to be restricted to women. As used herein, the term "side effects" means additional effects on the medicament or measurement used, such as the harmful effects of the drug, especially if it is intended to be beneficial through administration Other tissues or organ systems, such as -17- 200526227 high doses of NRIs or NRI / SRI compounds alone The term "side effects" means symptoms such as vomiting, nausea, sweating, and flushing ^ al., Journal of Clinical Psychiatry, 1984, 45 (10 Pt 2): 3-9). "Inhibitors" as used herein The term "intentionally includes any compound 'such as an antibody, small molecule, peptide, oligopeptide, polypeptide or protein, preferably a small molecule or peptide, which presents a partial, complete, competitive on mammals And / or inhibitory effects, preferably for human adrenaline reabsorption, or serotonin reabsorption and oradrenaline reabsorption, thereby reducing or blocking (preferably reducing) some or all of the endogenous positive Biological effects of epinephrine reabsorption or serotonin reabsorption and orpinephrine reabsorption. As used herein, the term "pharmaceutically acceptable salts" means prepared from pharmaceutically acceptable non-toxic acids, including inorganic salts And organic salts. Suitable non-organic salts include inorganic and organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphor sulfonic acid, citric acid, ethylene sulfonic acid, fumaric acid, glucuronic acid, bran Amino acid Hydrobromic acid, hydrochloric acid, 2-hydroxyethanesulfonic acid, lactic acid, malic acid, phenylglycolic acid, methanesulfonic acid, mucidic acid, nitric acid, piperic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluene Acid expansion and the like are preferably hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid, and the most preferable is hydrochloric acid salt. In addition, the compound of the present invention may exist in a non-soluble and soluble form of a pharmaceutically acceptable solvent , Pharmaceutically acceptable solvents such as water, ethanol, etc. Generally speaking, for the purpose of forming the present invention, a soluble form is considered to be equivalent to a non-soluble form. -18- 200526227 As used herein, the term "prodrug" means to It can be converted into adrenal α2B receptor antagonists, NRIs, and NRI / SRIs through metabolic methods (such as hydrolysis) in vivo. For example, different types of prodrugs well known in the art have been discussed below:

Elsevier (1985); Widde r, et al · (ed.)} Methods in Enzymolo gy tv ol. 4 f Academic Press (1985) »Krogsgaard-Larsen, et al. T (ed), Design and Application of Prodrugs," Textbook of Drug Design and Development, Chapter 5, 113-191 (1991), Bundgaa rd, et al. Y Journal of Drug Deliver Reviews, 1992, 8: 1-38, Bundgaard, J. of Pharmaceutical Sciences, 19 8 8, 77: 285 etseq · \ and Higuchi and Stella (eds ·) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975) ° In one aspect, the present invention is a method for treating vasomotor symptoms in a desired patient, including the following Steps: Administering the patient comprises the following composition: An effective amount of an active ingredient, which essentially consists of at least one selective adrenal α2B receptor antagonist or a pharmaceutically acceptable salt thereof. In another aspect, the present invention A method for treating vasomotor symptoms in a desired patient, comprising the steps of: administering the patient to a composition comprising: an effective amount of at least one selective adrenal α2B receptor An antagonist or a pharmaceutically acceptable salt thereof; and 200526227 an effective amount of at least one ortho adrenergic reuptake inhibitor (NRI) or a pharmaceutically acceptable salt thereof. In some specific examples, the adrenaline reuptake inhibitory Agent (NRI) is administered concurrently with a selective adrenal α2B receptor antagonist. In other specific examples, a normal adrenergic reuptake inhibitor (NRI) and a selective adrenal α2B receptor antagonist are administered continuously. In some specific examples, the selective adrenal α2B receptor antagonist and the adrenergic reuptake inhibitor (NRI) are a single compound. In some specific examples, the selective adrenal α2B receptor antagonist and the adrenal gland NRIs are separate compounds. In some preferred embodiments, the oradrenaline reuptake inhibitors do not substantially possess serotonin reuptake inhibitor (SRI) activity. In other aspects, the present invention The invention relates to a method for treating vasomotor symptoms in a desired patient, comprising the following steps: administering the patient comprises the following composition: an effective amount of at least one selectivity Adrenal α2B receptor antagonist or a pharmaceutically acceptable salt thereof; and an effective amount of at least one double ortho-adrenergic reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) or a pharmaceutically acceptable salt thereof class. In some specific examples, a norpinephrine reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) is administered simultaneously with a selective adrenal α2B receptor antagonist. In some other specific examples, a normal adrenergic reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) and a selective adrenal α2B receptor antagonist are continuously administered. -20- 200526227 In some specific examples, the selective adrenal α2B receptor antagonist and the adrenaline reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) are single compounds. In some specific examples, the selective adrenal α2B receptor antagonist and the adrenergic reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) are separate compounds. In another aspect, the invention relates to a pharmaceutical composition comprising: an active ingredient consisting essentially of at least one selective adrenal cx2B receptor antagonist or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable Vehicle. In another aspect, the present invention relates to a pharmaceutical composition comprising: at least one selective adrenal (X2B receptor antagonist or a pharmaceutically acceptable salt thereof); at least one orpine adrenaline reuptake inhibitor (NRI) or Its pharmaceutically acceptable salts; and at least one pharmaceutically acceptable carrier. In another aspect, the present invention relates to a pharmaceutical composition comprising: at least one selective adrenal α2B receptor antagonist or a pharmaceutically acceptable thereof Salt; at least one norepinephrine reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier. Appropriate selective adrenal α2B receptor antagonists include, but are not limited to, 2- (1-ethyl-2-imidazolyl) methyl-1,4-benzodioxane (imiloxan), 2-[(2, 3-dihydro-1,4-benzobisfluorene-2-yl) methyl] -1-ethyl 200526227 -1H-imidazole, 2- [2- [4- (2-methoxyphenyl) -1-Hydroxypyridyl] ethyl] -4,4-dimethyl-1,3 (2H, 4H) -isoquinolinedione (ARC 239), or a mixture thereof or a pharmaceutically acceptable salt. Mi Kexon is a better selective adrenal α2B receptor antagonist. Suitable ortho-adrenergic reuptake inhibitors (NRI) include, but are not limited to, maprotiline; reboxetine; nopa Norpramine, desipramine; nisoxetine; tomoxetine; amoxapine; doxepin; lofepramin ); Amitapalene (amitryptyline); 1- [1- (3-fluorophenyl) -2- (4-methyl-1-hexahydropyridyl) ethyl] cyclohexanol; 1-Π -(3-chlorophenyl) -2- (4-methyl-buhexahydropyridyl) ethyl] cyclohexanol; 1- [2- (4-methyl-1-hexahydropyridyl) -1-[3- (trifluoromethyl) -phenyl] ethyl] cyclohexanol; 1- [1- (4-methoxyphenyl) -2- [4-methyl-1-hexahydro Pyridyl] ethyl] cyclohexanol; [1- (3-chlorophenyl) -2- [4- (3-chlorophenyl) -1-hexahydropyridyl] ethyl] cyclohexanol ; 1- [1- (3-methoxyphenyl) -2- [4-phenylmethyl] -1-hexahydropyridyl] ethyl} cyclohexanol; 1- [2- (3- Chlorophenyl) 1-hexahydropyridylmethoxyphenyl] ethyl] cyclohexanol; 1- [2- [4- (6-chloro-2 -pyridyl) -1-hexahydropyridine Aryl] -l- [3-methoxyphenyl] ethyl] cyclohexanol; 1- [2- [4- (phenylmethyl)]-1-hexahydropyrene] -1- [3- (trifluoromethyl) phenyl] ethyl] cyclohexanol; 1- [1- (3-methoxyphenyl) -2- [4- [3- (trifluoromethyl) -benzene []-[Hexahydropyridyl] ethyl] cyclohexanol; Π- (4-fluorophenyl) -2- [4- (phenylmethyl) -1-hexahydropyridyl] ethyl] Cyclohexanol; -methoxyphenyl) -2- [4- [3- (trifluoromethyl) -phenyl] -buhexyl] ethyl] cyclopentanol; fluorophenyl)- 2- [4- (phenylmethyl) -1_hexahydropyridyl] ethyl] cyclohexanol; 1- [2- (dimethylamino) -1- (3-trifluoromethylphenyl ) Ethyl] cyclohexanol; 200526227 l- [l- (3-fluorophenyl) -2- (4-methyl-1-hexahydropyridyl) ethyl] cyclohexanol; 1- [1- (3-chlorophenyl) -2- (dimethylamino) ethyl] cyclohexanol; 1- [2-dimethylaminotrifluoromethylphenyl) ethyl} cyclohexanol; 1- [1- (3-chlorophenyl) -2-hexahydropyridin-1-yl-ethyl] -cyclohexanol; or a mixture thereof or a pharmaceutically acceptable salt. Preferred NRIs include desipramine and 1- [1- (3-chlorophenyl) -2- (4-methyl-1-hexahydropyridyl) ethyl] cyclohexanol, especially pure 1 R and S image isomers of [1- (3-chlorophenyl) -2- (4-methyl-1-hexahydropyridyl) ethyl] cyclohexanol, dimethylamine derivatives may be Synthesized as follows, such as 115-eight-4,535,186, the disclosure of which is incorporated herein by reference in its entirety. Hexamidine derivatives can be synthesized, for example, as described in US-A-4,8 26,844, the disclosure of which is incorporated herein by reference in its entirety. Suitable dual adrenergic reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) compounds are venlafaxine, O-desmethyl-venlafaxine (DVS-23 3 or CDV) , Milnacipran, duloxetine and their combination and pharmaceutically acceptable salts. In the case of a dual-acting NRI / SRI compound, the compound may exhibit more than SRI, approximately equivalent to NRI and SRI activity, or preferably greater than NRI activity. In the present invention, adrenal α2B receptor antagonists, NRIs, and NRI / SRIs can be prepared in the form of pharmaceutically acceptable salts, solvents, and prodrugs. Some compounds of the present invention may include a palmar center, and such compounds may exist as stereoisomers (ie, isomers). The present invention includes all such stereoisomers and any mixtures thereof, including external Racemic mixtures, racemic mixtures of stereoisomers and substantially pure stereoisomers are included within the scope of the present invention -23-200526227. The term "substantially pure" as used herein means at least about 90%, preferably at least about 95%, and most preferably at least about 98% relative to other possible stereoisomers. For stereoisomers. Preferred mirror isomers can be separated from racemic mixtures by methods known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of palm salts, or by the methods described herein Preparation, see for example in / acgwd Μ α /., Enantiomers, Racemates and Resolutions (Wiley

Inter science y New York, 1981); Wi l enf SH, et al ·, Tetrahedron, 3 3: 2725 (1977); Eli el f EL. Stereochemistry of Carbon Compounds, (McGraw-Hill, NY, 1962) ·, Wilen , SH · Tables of Resolving Agents and Optical Resolutions, p. 268 (EL Eli el f Ed, f University of Notre Dame Press y Notre

Dame, IN 1972) 〇 The composition of the present invention comprises, as active ingredients, a single selective adrenal cx2B antagonist, a selective adrenal α2B antagonist, and an adrenaline reuptake inhibitor (NRI) (a single compound or two A combination of one or more compounds), or a selective adrenal α2B antagonism with a dual orpine adrenergic reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) (a single compound or two or more compounds Of the combination) of the combination. The composition of the present invention also includes at least one pharmaceutically acceptable carrier, adjuvant, and / or excipient, etc., which are well known in the art (all herein referred to as "pharmaceutically acceptable carriers"), for example, in the following Said: Dan and βοΑ: Ejcc / p / enis, second edition, American Pharmaceutical Association, 1994 (herein referred to as a reference). -24- 200526227 Selective adrenal α2B antagonist compounds can be administered alone or in combination with a norepinephrine reuptake inhibitor (NRI) or norepinephrine reuptake inhibitor / serotonin reuptake inhibitor compound (NRI / SRI ) Combined to treat patients, the dosage range of about 0.1 to about 500 mg per day per day is sufficient to reduce and / or substantially reduce the number and / or severity of menopausal flushing. The preferred range is about per day. From 1 to about 300 mg, the optimal daily dose is from about 10 to about 200 mg per day. Orthoadrenaline reuptake inhibitors (NRI) can be administered to patients in combination with selective adrenal α2B antagonist compounds, with daily dosages ranging from about 0.1 mg / day to about 500 mg / day Sufficient to reduce and / or substantially reduce the number and / or severity of menopausal flushing, a preferred range is about 1 mg / day to about 300 mg / day, and the optimal daily dose is about 1 mg / day Daily to about 200 mg / day. Treatment with adrenaline reabsorption inhibitor / serotonin reabsorption inhibitor compound (NRI / SRI) and selective adrenal α2B antagonist compound can be administered to patients in a daily dose range from about 0.1 each time. mg / day to about 200 mg / day is sufficient to reduce and / or substantially reduce the number and / or severity of menopausal flushing, preferably in the range of about 1 mg / day to about 100 mg / day, most preferably The daily dose is about 10 mg / day to about 50 mg / day. The selective adrenal oc2B antagonist compound of the present invention is treated alone or in combination, for example, a pharmaceutical composition containing a selective adrenal α2B antagonist is combined with a norepinephrine reuptake inhibitor (NRI), or a selective adrenal The α2B antagonist can be combined with a dual norepinephrine reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) in any dosage form, such as those described in this document 200526227, and can also be administered in different ways, such as Described in this article. In a preferred embodiment, the combined product of the present invention is formulated together in a single dosage form (that is, combined together in a single capsule, tablet, powder, or liquid, etc.). When the combined products are not formulated together in a single dosage form, a selective adrenal α2B antagonist is combined with a normal adrenaline reuptake inhibitor (NRI), or a selective adrenal α2B antagonist is doubled with a double adrenal Absorption inhibitors / serotonin reuptake inhibitors (NRI / SRI) are combined and can be administered the same or simultaneously (ie, together), or in any order. When not administered at the same or at the same time, that is, when administered continuously, it is preferable to administer a selective adrenal α2B antagonist in combination with a normal adrenaline reuptake inhibitor (NRI), or a selective adrenal α2B antagonist The combined double ortho-adrenergic reuptake inhibitors / serotonin reuptake inhibitors (NRI / SRI) are separated by less than about one hour, preferably less than about 30 minutes, and more preferably less than about 15 minutes, and Optimally about 5 minutes. The pharmaceutical composition of the present invention is prepared according to an acceptable pharmaceutical process, such as the following: Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Ge e n a r o t Mack Publishing, whn, PA. A pharmaceutically acceptable carrier is one that is formulated with other ingredients and is biologically acceptable. The compounds and compositions of the present invention can be administered orally or parenterally, simply or in combination with traditional pharmaceutical carriers, and acceptable solid carriers can include one or more substances, which can also be used as flavoring agents, lubricants, etc. Agents, solubilizers, suspending agents, fillers, slip aids, compression aids, adhesives or lozenges, or sealants. In powders, the carrier is a finely divided solid which is mixed with a finely divided active ingredient. The active ingredient in the sediment is mixed with a carrier having the necessary compression properties in an appropriate ratio of -26- 200526227 and compacted in the desired model and size. Powders and lozenges preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactic acid, dextrin, starch, animal gum, cellulose, methyl cellulose , Sodium methylol cellulose, polyvinyl pyrrolidine, low melting point rhenium, and ion exchange resins. Liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs. The active ingredients of the present invention can be dissolved or suspended in pharmaceutically acceptable liquid carriers, such as water, organic solvents, a mixture of the two, or medicine Acceptability by or fat. Liquid carriers may contain other suitable pharmaceutical additives such as co-solvents, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, pigments, viscosity modifiers, stabilizers, or osmotic adjustment agents. Agent. Suitable examples of liquid carriers for oral or parenteral administration include water (especially those containing the above-mentioned additives, such as avidin derivatives, preferably sodium methylol cellulose), alcohols (including monohydroxy alcohols) And polyhydric alcohols, such as glycerol, and their derivatives, and oils, such as fractionated cocoa butter and peanut oil. Carriers for parenteral administration can also be oleyl esters, such as ethyl oleate and isopropyl myristate. Sterile liquid carriers can be used in sterile liquids to form compositions for parenteral administration. versus. The liquid pharmaceutical composition is a sterile solution or suspension, and can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. The sterile solution can also be administered intravenously. Oral administration can be in the form of a liquid or solid composition. The preferred pharmaceutical composition is in a unit dosage form, such as a lozenge, a capsule, a powder, a solution, a suspension, an emulsion, a granule or a suppository. In these types, the composition is a unit dose containing an appropriate amount of the active ingredient that is sub-dispersed; the unit dosage type can be a packaged composition, such as a small package powder, a small potion bottle, -27- 200526227 ampoule, prefilled Syringes or sachets containing liquid. The unit dosage form may be, for example, a capsule or lozenge thereof, or it may be a packaged form of any such composition in an appropriate amount. Generally speaking, the active ingredient (selective adrenal α2B antagonist, NRI or NRI / SRI or a pharmaceutically acceptable salt thereof) is present at a concentration of about 0.1% to about 90% by weight based on the total weight of the pharmaceutical composition And, if a pharmaceutically acceptable carrier is present, its concentration is about 0.1% to about 90% by weight based on the total weight of the pharmaceutical composition. Preferably, the active ingredient (selective adrenal ct2B antagonist, NRI or NRI / SRI or a pharmaceutically acceptable salt thereof) is present at a concentration of about 1% to about 90% by weight based on the total weight of the pharmaceutical composition, And if a pharmaceutically acceptable carrier is present, its concentration is from about 1% to about 90% by weight based on the total weight of the pharmaceutical composition. More preferably, the active ingredient (selective adrenal α2B antagonist, NRI or NRI / SRI or a pharmaceutically acceptable salt thereof) is present at a concentration of about 5% to about 90% by weight based on the total weight of the pharmaceutical composition, And, if a pharmaceutically acceptable carrier is present, its concentration is about 5% to about 90% by weight based on the total weight of the pharmaceutical composition. More excellent 'active ingredients (selective adrenal α2B antagonists, NRI or NRI / SRI or their pharmaceutically acceptable salts) are present at a concentration of about 10% to about 90% by weight based on the total weight of the pharmaceutical composition %, And if a pharmaceutically acceptable carrier is present, its concentration is from about 10% to about 90% by weight based on the total weight of the pharmaceutical composition. Very excellent, active ingredients (selective adrenal α2B antagonists, NRI or NRI / SRI or their pharmaceutically acceptable salts) are present at a concentration of about 25% to about 90% by weight based on the total weight of the pharmaceutical composition 'And if a pharmaceutically acceptable 200526227 carrier is present, its concentration is from about 25% to about 90% by weight based on the total weight of the pharmaceutical composition. The route of administration can be any route that effectively transports the active ingredient to the appropriate or intended site of action, such as oral, nasal, pulmonary, transdermal, such as passive or iontophoretic delivery, or parenteral, such as rectal, retention , Subcutaneous, intravenous, intraurethral, intramuscular, intranasal, eye drops or ointment. Some compounds of the present invention may include a palmar center, and such compounds may exist as stereoisomers (ie, isomers). The present invention includes all such stereoisomers and any mixtures thereof, including external Racemic mixtures, racemic mixtures of stereoisomeric structures and substantially pure stereoisomers are included within the scope of the invention. The term "substantially pure" as used herein means at least about greater than 90 mole%, preferably at least about greater than 95 mole%, and most preferably at least about relative to other possible stereoisomers. More than 98 mole% of the desired stereoisomer. Preferred mirror isomers can be separated from racemic mixtures by methods known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of palm salts, or prepared by the methods described herein See, for example, Jacques, eta l., Enantiomers, Racemates and Resolutions (Wiley Intersciencef New York, 1981); Wilen, S.H. etal, Tetrahedron, 33: 2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds, (McGraw-Hill, NYf 1962) \ Wilen, SH

Table s of Resolving Agents and Optical Resolutions, p. 2 68 (EL Eli el, Ed.f University of Notre Dame Press, Notre Dame, IN 1972) 〇-29- 200526227 The route of administration can effectively transport active adrenaline Any route of absorption inhibitor, or serotonin reabsorption inhibitor and adrenaline reabsorption inhibitor to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal, such as passive or iontophoretic delivery, or Parenteral, such as rectum, stagnation, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, eye drops or ointment. Furthermore, the administration of the adrenaline reuptake inhibitor and the serotonin reuptake inhibitor may be administered at the same time or simultaneously. [Embodiments] The present invention is further illustrated in the following examples, in which all parts and percentages are by weight, and the degree is Celsius unless otherwise stated. It must be understood that, when specific examples are pointed out as being preferred, these examples are merely illustrative. From the following discussion and these examples, those skilled in the art can determine the basic characteristics of the present invention, and without departing from the spirit and scope, can make various changes and modifications to the invention to adapt to different uses and situations. General method reagents: Miloxan is commercially available (TocrisCookson Inc, Ellisville, MO), and desipramine can be prepared by the method described in US Pat. No. 3,454,554. The following reagents are commercially available: Morphine Bio Base granules (Murty Pharmaceuticals, Lexington, KY), ketamine (Phoenix Pharmaceuticals, Belmont, CA) and naloxone (Research Biochemicals International ·, St. Louis, MO) 〇 Dose: All doses are prepared in mg / For the principle of kg, the compound is dissolved in sterile water or 2.0% Tween / methylcellulose, and injected subcutaneously (Sc) or intraperitoneally (ip), and the following doses are used: Miloxan (1, 10, 15 and 30 mg / kg), 200526227 Dexipramine (0.01, 1.0, 10, and 30 mg / kg), Kitaject (Phoenix, Phoenix Pharmaceuticals, Belmont, CA) with slight stabilization without causing tail skin temperature The determined dose (40 mg / kg) was injected intramuscularly on the hind legs. Animals: Ovrectomy Sprague-Dawley rats (180-220 g) were obtained from a vendor (Taconic, Germantown, NY) and kept individually in a constant temperature 25 ° C room under a 12-hour day / night cycle. For the microdialysis experiment, male Sprague-Dawley rats (275-350 g) were obtained from Charles River (Wilmington, MA) and kept in groups until surgery. Animals were raised on any standard rat feed and decanted water. Morphine-dependent mode: Ovariectomized rats are injected once daily with 8-9 minutes to minimize the immediate response, and the compound is administered on the test day. On the 4th day of administration, morphine dependence was induced by subcutaneous implantation of two slow-release morphine particles (75 mg / pellet) in the scapular region of the back. This model was based on the established morphine-dependent naloxone-induced flushing Example, which is reversible by estrogens (ATaiov / c / z " a /., Proc ~

Society for Experimental Biology & Medicine, 1990. 193 (2) p. 729-35). Four to six days after implantation, morphine withdrawal is induced with an opioid antagonist (naloxone), which causes a transient increase in TST. In a typical experiment, rats are injected with their final dose of test compound 40 to 60 minutes before naloxone injection, with a slight quiescence of life, and will be connected to the MacLab data detection system. The thermostat was glued to the base of the tail, and the skin temperature of the tail was continuously collected for 35 minutes to establish the base temperature. Then naloxone was administered, and the TST was measured for another 35-60 minutes (total record time 70-95 minutes). 200526227 Telemetry mo die: This model has been established in a previously reported standard procedure describing the regulation of estrogen in the daytime TST model (Beren heart α Μ. Α /., 20C »i). Before more than 24 hours, rats with full cycles reduced TST during active (dark) and continued to increase TST during inactive (light). In OVX rats, the TST rises for more than a continuous 24 hour period, so the decrease in TST during activity (darkness) is usually lost, so the ability of compounds to restore this reduced TST during activity can be tested. The temperature and physical activity transmitter (PhysioTel TA1 OTA-F40, Data Sciences International) was implanted subcutaneously into the scapular region of the back, and the tip of the temperature probe was subcutaneously embedded in the base of the tail for more than 2.5 cm. After the 7-day recovery period, continuous readings of TST readings were used to investigate differences. Tail skin temperature readings were collected for each animal every 5 minutes over a 10-second sampling period. On the day before the test day, the average basic TST of each animal was calculated from the temperature readings recorded during the average 12-hour active (dark) period. In these studies, the animals were dosed approximately 1 hour before the start of the dark cycle. . In vivo microdialysis: preparations before using a microdialysis procedure have been reported (hyr Hd ·, 2002), anesthesia using 2-3% halothane (Fluothane; Zeneca, Cheshire, UK), ears and anterior teeth The fixed table (David Kopf, Tnjunga, CA) placed the animals according to the structure of each body. Using the following coordinates, the microdialysis catheter (CMN12; CMA Microdialysis, Stockholm, Swede η) was directed to the preoptic area of the hypothalamus: the cranium. Anterior front of the cardia-0.4 mm, midline side-1.0 mm, and ventral dura mater-6 · 9 mm (ρ α λ: ί η d Υ9θ (ί). Two stainless steel screws (Small Parts, Roanoke , VA) and dentist acrylic (Plastics One, Roanoke, 200526227 VA), the catheter was fixed to the cranium. After surgery, the animals were individually kept in acrylic cages (45 cm sq.) For about 24 hours, and started Free feeding and decoction. Microdialysis probes (CMA / 12; 20 kD cut-off) were purchased from CMA / Microdialysis and consisted of a 2-mm active membrane (OD 0.5 mm) and a 14-mm stainless steel shaft (〇 D 0.64mm), according to the manufacturer's instructions, the probe was artificial CSF (aCSF; 125 mM N aC, 3 mM KC, 0.75 mM MgSCU and 1.2 mM CaCl2, pH 7.4). On the day of the experiment, the microdialysis probe was inserted into the hypothalamus through a catheter, and aCSF was perfused at a slow rate of 1 # Ι / min. The probes were given a 3-hour period after the probe was inserted, during which the microdialysate was collected every 20 minutes in a plastic tube (CMA) placed in a CMA / 142 microfiltration collector. Six microdialyses were collected before drug injection. The samples were confirmed to be stable. Subsequently, the animals received injections of miloxan (10 mg / kg, ip) or excipients, and microdialysate samples were collected for at least 3 hours after the injection. After the experiment, the animals were euthanized, and Confirm the probe configuration on the tissue. The microdialysate (10 # 1) containing NE and 5-HT was separated by HPLC (C18 ODS3 column, 150 X 3.0 mm, Metachem, Torrance, CA), and 0.65V was used. Detection of voltage and Ag / AgCl reference electrode by ANTEC electrochemical detector (ANTEC, Netherlands). Mobile phase (0 · 15 M NaH2P04, 0.25 mMEDTA, 1.75 mM 1-octanesulfonic acid, 2% isopropanol and 4 % Methanol, ρΗ = 4 · 8) with Jasco PU1580 HPLC Lipu (Jasco Ltd, Essex, UK), 0.5 ml / mm Low-rate distribution, neurochemical data was compared with external standard curves, and all data was obtained using Atlas software products (Thermo Lab systems, Beverley, MA) using a PC. 200526227 Statistical analysis: In order to analyze changes in TST induced by naloxone in morphine-induced rats, all data were analyzed using repeated measures ANOVA for the two factors of "treatment" and "time", regardless of the test population There are no significant differences in response, and the model is suitable for testing. The administration of naloxone was designated as time 0, and then the data was analyzed every 5 minutes, with the average of the first three readings, and used as the baseline TST data. All data were analyzed as △ TST (for each time point-the baseline TST ), The majority control 値 (LSD p- 値) at each time point between treatment groups was used for analysis. When the maximum change in TST is observed, the effect of the relief of flushing during menopause is assessed through the statistical difference in the peak response time after 15 minutes of naloxone, and a customized SAS-excel (SAS Institute, Cary, NC) application to determine ED50 値, the logical dose shift is shown in LTST, the maximum 値 flush (LXTST after 15 minutes of naloxone) is used for analysis, and the minimum 値 is fixed at 0, ED50 値A customized JMP application was presented at a dose of a test compound that relieves 50% of naloxone-induced flushing by a statistician at the Biometrics Department (Wyeth Research, Collegeville, PA). Using an average of 12 temperature readings taken every 5 minutes during the recording period, the hourly TST 値 calculated for each animal was used to analyze the compound's assessment of the ability to return to a normal low amount of TST in the telemetry mode. In order to analyze the △ TST in the long-distance measurement mode, the binomial factor of the repeated measurement ANOVA is used. The mode used for analysis is LSTST = GRP (group) + HR (hour) + GRP * HR + BASELINE. Therefore, if two If the groups have the same baseline, the least squares average presented is the expected average, and the post-hoc test of the hourly GRP * HR sample is the t-test of the difference between groups per hour. For the sake of caution, 200526227, results other than p- 値 < 0.025 are not considered significant. All analyses were performed using SAS PROC MIXED (SAS, Carey, NC). Analyze the neurochemical effects of miloxan by repeated measurement (time) standard deviation squared two-way analysis (AN OV A), average the fmol concentrations of NE and 5-HT during the reference sample period, and this term is expressed as 1〇 〇%, and then the sample was expressed as a percentage of the baseline before injection (% of the baseline). Post-hoc analysis was performed using Bonferroni / Dunns adjustments for multiple comparisons. All statistical estimates were made using the PC's Statview application software (Abacus Concepts Inc., Berke 1 ey, CA). Example 1: In rats using the naloxone-induced flushing mode, the effect of selective adrenal α2B receptor antagonists on mitigating vasomotor instability is in addition to the following, in the morphine-dependent rat mode Next, follow the method of use described in the general method section: 1 hour before naloxone administration, rats are injected subcutaneously with vehicle (2% Tween / 0.5% methyl cellulose) or dissolved in 2% Tween / ( Tociris with K5% methylcellulose, and each subcutaneously administered K0, 10, and 30 mg / kg, the results are shown in Figure 1, at the maximum flushing (15 minutes after naloxone; △ ° C TST (mean 値 + SEM), ED5G 値 evaluated at 15 mg / kg, Sc, miloxen relieves naloxone-induced flushing in a dose-dependent manner. Example 2: Rats in naloxone-induced flushing mode In addition, the effect of selective adrenal α2B receptor antagonists on mitigating vasomotor instability is in addition to the following, in the remote measurement rat mode, as described in the general method section: Rats are injected subcutaneously (2% Tween / 0.5% methylcellulose) or subcutaneously 3 0 or 60 mg / kg dissolved in 200526227 2% Tween / 0.5% methylcellulose (Tocris). The effect of miloxan is measured by evaluating the following parameters in this model ... The sustained effect, the maximum change in TST, and the duration of the Miloxon effect, the average change in TST, the results are shown in Figure 2. In the OVX-induced thermoregulation disorder remote measurement mode (remote measurement mode), the phase Compared with the vehicle control group, Miloxan (adrenal α2B receptor antagonist) returned to normal TST of 30 mg / kg, sc, * represents ρ < 0.05. Example 3: Has the activity of adrenal α2B receptor antagonist and The effects of NRI-active compounds are in addition to the following, in the morphine-dependent rat mode, as described in the General Methods section: at maximum flushing (15 minutes after naloxone; △ ° C TST, average値 + SEM) 40 minutes before, rats were injected subcutaneously with vehicle (2% Tween / 0.5% methyl cellulose), or subcutaneously injected with 15 mg / kg miloxan, or subcutaneously injected with 1 mg / kg dissolved in 2% Tween / 0.5% methylcellulose desipramine The combination of Miloxan and Dexipramine effectively alleviates induced flushing, and the results are shown in Figure 3. In the MD mode of naloxone-induced flushing, an adrenal α2B receptor antagonist (miloxan ) Additional effects in combination with NRI (Dexipamin). Example 4: Neurochemistry of NE and 5-HT concentrations in selective anterior ct2B receptor antagonists in the preoptic lobe region of the hypothalamus of rats Effect Under in vivo microdialysis, follow the method of use described in the general method section: Intraperitoneal injection of excipients (water) or 10 mg / kg miloxan in rats, and NE and 5-HT concentrations via microdialysis And monitoring by HPLC technology, at 60 200526227 minutes after injection, the rapid administration of Miloxin significantly increased the NE concentration in the preoptic lobe area of the hypothalamus of rats. Conversely, in the same rat, miloxan treatment did not affect 5-HT concentration. When ranges of physical properties (such as molecular weight) or chemical properties (such as chemical formula) are used herein, they are intended to include specific examples of combinations and subcombinations of all ranges. The disclosures of patents, patent applications, and publications cited or described herein are hereby incorporated by reference in their entirety. Those skilled in the art will recognize that many variations and modifications can be made to the preferred embodiments of the invention, and that these changes and modifications can be made without departing from the spirit of the invention. Therefore, when falling within the true spirit and scope of the present invention, the scope of the attached patent application is intended to include all such equivalent variations. [Brief description of the drawings] The present invention can be better understood by the following detailed description and the drawings that form a part of this case. Figure 1 shows the dose response of miloxan (an adrenal α 2B receptor antagonist) in the morphine-dependent morphine-dependent rat model of menopause (MD mode); miloxan ED5G 値 = 15 mg / kg , Sc, * indicates p < 0.05 compared to the vehicle control group (see Example 1). Figure 2 shows the administration of miropexan (an adrenal α 2B receptor antagonist) in 2 doses (30 and 60 mg / kg, sc) in a rat model of ovariectomy-induced thermoregulation. The result (see Example 2). Figure 3 shows a microdialysis study of the effects of miloxan, an adrenal α 2B receptor antagonist, at extracellular concentrations of NE and 5-ΗΤ in the preoptic lobe region of the inferior parietal mast. Results; Miloxan 10 mg / kg, ip, * indicates P < 0.05 compared to the vehicle control group (see Example 3). -37-

Claims (1)

200526227 10. Scope of patent application: 1. A method for treating vasomotor symptoms in a patient in need, comprising the following steps: administering to the patient contains the following composition: an effective amount of an active ingredient, which basically consists of Composition of at least one selective adrenal α2B receptor antagonist or a pharmaceutically acceptable salt thereof. 2. The method according to item 1 of the scope of patent application, wherein the selective adrenal α2B receptor antagonist is 2- (1-ethyl-2-imidazolyl) methyl-1,4-benzodinoxane ( Miloxan; imiloxan), 2-[(2,3-dihydro-1,4-benzodifluoren-2-yl) methyl] -1-ethyl-1fluoren-imidazole, 2- [2- [4- (2-methoxyphenyl) -1-hexahydropyridyl] ethyl] -4,4-dimethyl-1,3 (211,4 to -isoquinolinedione (ARC 239 ), Or a mixture thereof or a pharmaceutically acceptable salt thereof. 3. The method according to item 2 of the patent application scope, wherein the selective adrenal α2B receptor antagonist is miloxox or a pharmaceutically acceptable salt thereof. 4. A A method of treating vasomotor symptoms in a patient in need, comprising the steps of: administering the patient to a composition comprising: an effective amount of at least one selective adrenal (x2B receptor antagonist or a pharmaceutically acceptable Salts; and an effective amount of at least one norepinephrine reuptake inhibitor (NRI) or a pharmaceutically acceptable salt thereof. 5. The method according to item 4 of the scope of patent application, wherein the norrepinephrine reuptake inhibitor (NRI) and this Selective adrenal α2B receptor antagonists are administered simultaneously. -38- 200526227, * 6. The method according to item 4 of the patent application, wherein the orpinephrine reuptake inhibitor (NRI) and the selective adrenal The α2B receptor antagonist is continuously administered. 7 · The method according to item 4 of the patent application, wherein the selective adrenal oca receptor antagonist and the orpinephrine reuptake inhibitor are single compounds. 8 · If applied The method according to item 4 of the patent, wherein the ortho-adrenergic reuptake inhibitor does not substantially have serotonin resorption inhibitor (SRI) activity. 9 · The method according to item 4 of the patent application, wherein the selective adrenal Receptor antagonists are 2- (1-ethyl-2-imidazolyl) methyl-14-benzoxanthine (miloxan), 2-[(2,3-dihydro-l, 4-benzene Hexamidine-2-yl) methyl] -buethyl-1H-imidazole, 2- [2- [4- (2-methoxyphenyl) -1-hexahydropyridyl] ethyl]- 4,4-Dimethyl-1,3 (211,411) -isoquinolinedione (eight 1 ^ 2 3 9), or a mixture thereof or a pharmaceutically acceptable salt. 1 〇 As the 9th item in the scope of patent application Fang Wherein the selective adrenal α2B receptor antagonist is miloxan or a pharmaceutically acceptable salt thereof. 11. The method according to item 4 of the patent application, wherein the orpinephrine reuptake inhibitor (NRI) Maprotiline; reboxetine; norpramine, desipramine; nisoxetine; atomoxetine; amosa Amoxapine; doxepin; lofepramin; amitryptyline; l- [l- (3-fluorophenyl) -2- (4-methyl- Buhexahydropyridyl) ethyl] cyclohexanol; 1- [1- (3-chlorophenyl) -2- (4-methyl-buhexahydropyridyl) ethyl] cyclohexanol; 200526227 ^ [2- (4-methyl-1-hexahydropyridyl) -1- [3- (trifluoromethyl) -phenyl] ethyl] cyclohexanol; 1- [1- (4-methyl Oxyphenyl) -2- [4-methyl-1-hexahydropyridyl] ethyl] cyclohexanol; [1- (3-chlorophenyl) -2- [4- (3-chloro Phenyl) -1-hexahydropyridyl] ethyl] cyclohexanol; 1-Π- (3-methoxyphenyl) -2- [4-phenylmethyl] -1-hexahydropyridine Group] ethyl} cyclohexanol; 1- [2- (3-chlorophenyl) 1-hexahydropyridyl] -1- [ 3-methoxyphenyl] ethyl] cyclohexanol; 1- [2- [4- (6-chloro-2-pyridyl) -1-hexahydropyridyl] -W3-methoxybenzene Group] ethyl] cyclohexanol; 1- [2- [4- (phenylmethyl)]-1-hexahydropyridyl] -1- [3 -_ (trifluoromethyl) phenyl] ethyl] Cyclohexanol; 1- [1- (3-methoxyphenyl) -2- [4- [3- (trifluoromethyl) -phenyl] -1-hexahydropyridyl] ethyl] ring Hexanol; 1- [1- (4-fluorophenyl) -2- [4- (phenylmethyl) -1-hexahydropyridyl] ethyl] cyclohexanol; 1- [1- (3 -Methoxyphenyl) -2- [4- [3- (trifluoromethyl) -phenylb1-hexahydropyridyl] ethyl] cyclopentanol; 1- [1- (4-fluoro Phenyl) -2- [4- (phenylmethyl) -1-hexahydropyridyl] ethyl] cyclohexanol; 1- [2- (dimethylamino) -1- (3-trifluoro Methylphenyl) ethyl] cyclohexanol; 1- [1- (3-fluorophenyl) -2- (4-methyl-1-hexahydropyridyl) ethyl] cyclohexanol; 1- [1- (3-chlorophenyl) -2- (dimethylamino) ethyl] cyclohexanol; 1- [2-dimethylamino] -1- (3-trifluoromethylphenyl ) Ethyl} cyclohexanol, 1- [1- (3-chlorophenyl) -2 -hexaaminopyrene-I-yl-ethyl] _cyclohexanol; or mixtures or pharmaceutically acceptable salts thereof class. 12. The method according to item 11 of the scope of patent application, wherein the repinephrine reuptake inhibitor is desipramine. 13. The method according to item 1 of the patent application range, wherein the orpinephrine reuptake inhibitor is Bu [1- (3-chlorophenyl) -2- (4-methyl-buhexahydropyridyl) Ethyl] cyclohexanol or a pharmaceutically acceptable salt thereof. -40- 200526227 14. The method according to item 13 of the patent application, wherein the orpinephrine reuptake inhibitor is 1- [1- (3-chlorophenyl) -2- (4-methyl-1-hexan The pure mirror isomer of hydropyridyl) ethyl] cyclohexanol. 1 5. A method of treating vasomotor symptoms in a patient in need, comprising the steps of: administering the patient to a composition comprising: an effective amount of at least one selective adrenal α2B receptor antagonist or A pharmaceutically acceptable salt thereof; and an effective amount of at least one dual norepinephrine reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) or a pharmaceutically acceptable salt thereof. 16. The method according to item 15 of the scope of patent application, wherein the dual adrenergic reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) and the selective adrenal cx2B receptor antagonist are administered simultaneously versus. 17. The method according to item 15 of the patent application, wherein the dual adrenergic reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) and the selective adrenal α2B receptor antagonist are administered continuously. 18. The method according to item 15 of the patent application, wherein the selective adrenal α2B receptor antagonist and the dual orpine adrenergic reuptake inhibitor / serotonin reuptake inhibitor are single compounds. 19. The method according to item 15 of the scope of patent application, wherein the selective adrenal α2B receptor antagonist is 2- (1-ethyl-2-imidazolyl) methyl-1,4-benzodi. Alkanes (miloxan), 2-[(2,3-dihydro-1,4-benzobisfluorene-2-yl) methyl] -buethyl-1H-imidazole, 2- [2- [4- (2-Methoxyphenyl) -1-hexahydropyridine 200526227, · · Trapyl] ethyl] -4,4-dimethyl-1,3 (211,411) -isoquinolinedione (eight 110 239), or a mixture thereof or a pharmaceutically acceptable salt. 20. The method according to item 19 of the scope of patent application, wherein the selective adrenal (x2B receptor cleansing agent is Miloxan or a pharmaceutically acceptable salt thereof. 2 1. As the item 15 of scope of patent application The method, wherein the dual oradrenaline reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) is venlafaxine, 0-desmethyl-venlafaxine (DVS-233 or CDV ), Milnacipran, duloxetine, or mixtures or pharmaceutically acceptable salts thereof. 22. The method according to any one of claims 1, 4, or 15 in the scope of patent application, wherein Symptoms of vasomotor symptoms are menopause flushing. 23 · If the method of applying for the scope of patent application No. 22, the patient is a human. 24 · If the method of applying for the scope of patent application No. 23, wherein the human is female. 25. If applying The method of the scope of the patent No. 24, wherein the woman is in the menopause period -w · 刖 ° 26. The method of the scope of the patent application No. 24, wherein the woman is at the menopause period. 27 · If the method of the scope of the patent application No. 24, The woman was after menopause. 28 · Ru Shen The method according to item 23 of the patent, wherein the human being is a male. 29. The method according to item 28 of the patent application, wherein the male is menopause naturally, chemically, or surgically. 30. A pharmaceutical composition, which It contains: -42- 200526227 an active ingredient consisting essentially of at least one selective adrenal α2B receptor antagonist pharmaceutically acceptable salt; and at least one pharmaceutically acceptable carrier. 3 1. As in the 30th of the scope of patent application Item of the pharmaceutical composition, wherein the selective adrenal α2B receptor antagonist is 2- (1-ethyl-2-imidazolyl) methylbenzodinoxane (miloxan), 2-[(2, 3-dihydro-1,4-benzodinoyl) methyl] -1-ethyl-1H-imidazole, 2- [2- [4- (2-methoxyphenyl) hydropyridyl] Ethyl] -4,4-dimethyl-1,3 (2H, 4H) -isoquinoline (ARC 2 3 9), or a mixture thereof or a pharmaceutically acceptable salt. 3 2. As the scope of patent application No. 3 1 The pharmaceutical composition of clause, wherein the selective adrenal α2B receptor antagonist is Miloxan or a pharmaceutically acceptable class thereof. 3 3. A pharmaceutical composition comprising: at least one selective adrenal gland α2B receptor antagonist or a pharmaceutically acceptable salt thereof; at least one norepinephrine reuptake inhibitor (NRI) or a pharmaceutically acceptable salt thereof: and at least one pharmaceutically acceptable carrier. 3 4. As claimed in the patent application The pharmaceutical composition according to item 33, wherein the selective adrenal α2B receptor antagonist is 2- (1-ethyl-2-imidazolyl) methylbenzodioxane (miloxan), 2-[( 2,3-dihydro-1,4-benzodifluorenyl) methyl] -1-ethyl-1fluorene-imidazole, 2- [2- [4- (2-methoxyphenyl) hydropyridine Group] ethyl] -4,4-dimethyl-1,3 (2Η, 4Η) -isoquinoline (ARC 2 3 9), or a mixture thereof or a pharmaceutically acceptable salt. Or its kidney-1,4- spell-2--1 -hexadiketone kidney salt can be connected to kidney-1,4-well-2_-1-hexadionone 200526227 35 The pharmaceutical composition according to item 34, wherein the selective adrenal ot2B receptor antagonist is miloxox or a pharmaceutically acceptable salt thereof. 36. The pharmaceutical composition according to item 33 of the patent application scope, wherein the orpinephrine reuptake inhibitor (NRI) is maprotiline; reboxetine; nopamin, dexipamin; nisoxetine; Tomoxetine; amosapine; doxepin; lofipramine; amitaparin; 1- [1- (3-fluorophenyl) -2- (4-methyl-l-hexahydro Pyridyl) ethyl] cyclohexanol; l- [l- (3-chlorophenyl) -2- (4-methyl-1-hexahydropyridyl) ethyl] cyclohexanol; 1- [ 2- (4-methyl-1-hexahydropyridyl) -1- [3- (trifluoromethyl) -phenyl] ethyl] cyclohexanol; l- [l- (4-methoxy Phenyl) -2- [4-methyl-1-hexahydropyridyl] ethyl] cyclohexanol; 1- [1- (3-chlorophenyl) -2- [4- (3-chlorobenzene Group) -1-hexahydropyridyl] ethyl] cyclohexanol; 1- [1- (3-methoxyphenyl) _2- [4-phenylmethyl] -1-hexahydropyridyl ] Ethyl} cyclohexanol; 1- [2- (3-chlorophenyl) 1-hexahydropyridyl] -1-p-methoxyphenyl] ethyl] cyclohexanol; 1- [2 -[4- (6 -Chloro-2-fluorenylpyridyl) -1-hexaazepine D-pyridyl] -1- [3-methoxyphenyl] ethyl] cyclohexanol; 1- [2- [4- (phenylmethyl)]-1-hexahydropyridyl] -1- [3- (trifluoromethyl) phenyl] ethyl] cyclohexanol; 1- [1 -(3-methoxyphenyl) -2- [4- [3- (trifluoromethyl) -phenyl] -1-hexahydropyridyl] ethyl] cyclohexanol; 1- [1- (4-fluorophenyl) -2- [4- (phenylmethyl) -1-hexahydropyridyl] ethyl] cyclohexanol; 1- [1- (3-methoxyphenyl)- 2- [4- [3- (trifluoromethyl) -phenyl] -1-hexahydropyridyl] ethyl] cyclopentanol; 1- [1- (4-fluorophenyl) -2- [ 4- (phenylmethyl) -1-hexahydropyridyl] ethyl] cyclohexanol; 1- [2- (dimethylamino) -1- (3-trifluoromethylphenyl) ethyl ] Cyclohexanol; 1- [1- (3-fluorophenyl) -2- (4-methyl-1-hexahydropyridyl) ethyl] cyclohexanol 200526227 alcohol; l- [l- (3- Chlorophenyl) -2- (dimethylamino) ethyl] cyclohexanol; l- [2-dimethylaminol·l- (3-trifluoromethylphenyl) ethyl} cyclohexanol Alcohol; l- [l- (3-chlorophenyl) -2-hexahydropyr-1-yl-ethylcyclohexanol; or a mixture thereof or a pharmaceutically acceptable salt thereof. 37. The pharmaceutical composition according to item 36 of the application, wherein the orprenaline reuptake inhibitor is desipramine. 38. The pharmaceutical composition according to item 36 of the application, wherein the orprenaline reuptake inhibitor is 1- [1- (3-chlorophenyl) -2- (4-methyl-1-hexahydropyridine Trapyl) ethyl] cyclohexanol or a pharmaceutically acceptable salt thereof. 39. The pharmaceutical composition according to item 38 of the scope of patent application, wherein the orpinephrine reuptake inhibitor is W1- (3-chlorophenyl) -2- (4-methyl-buhexyl) Is the pure mirror isomer of cyclohexanol. 40. A pharmaceutical composition, comprising: at least one selective adrenal α2B receptor antagonist or a pharmaceutically acceptable salt thereof; at least one orpinephrine reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier. 41. The pharmaceutical composition according to item 40 of the application, wherein the selective adrenal ct2B receptor antagonist is 2- (1-ethyl-2-imidazolyl) methyl-1,4-benzodi Evane (Miloxen), 2-[(2,3-dihydro-1,4-benzodioxo-2-yl) methyl] -1-ethyl-1H-imidazole, 2- [2 -[4- (2-methoxyphenyl) -1-hexahydropyridyl] ethyl] -4,4-dimethyl-1,3 (211,411) -isoquinolinedione (ARC 2 3 9), or a mixture thereof or a pharmaceutically acceptable salt. 200526227 42. The pharmaceutical composition according to item 41 of the patent application scope, wherein the selective adrenal α2B receptor antagonist is miloxan or a pharmaceutically acceptable salt thereof. 43. The pharmaceutical composition according to item 41 of the scope of patent application, wherein the dual ortho adrenaline reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) is venlafaxine, 0-desmethyl-methyl Lafaxine (DVS-23 3 or CD V), Minapril, Duloxetine or a mixture thereof or a pharmaceutically acceptable salt. 44. An article of manufacture comprising: at least one selective adrenal (x2B receptor antagonist or a pharmaceutically acceptable salt thereof); and at least one ortho-adrenergic reuptake inhibitor (NRI) or ortho-adrenergic reuptake inhibitor / Serotonin reabsorption inhibitor (NRI / SRI) or a pharmaceutically acceptable salt thereof; used to treat vasomotor symptoms in patients in need, as a combined preparation for simultaneous, separate or continuous use. 45 · If applying for a patent The product according to item 44, wherein the selective adrenal α2B receptor antagonist is 2- (1-ethyl-2-imidazolyl) methyl-1,4-benzodioxane (miloxan), 2-[(2,3-dihydro-1,4-benzobisfluorene-2-yl) methyl] -1-ethyl-1H-imidazole, 2- [2- [4- (2-methyl Oxyphenyl) -1-hexahydropyridyl] ethyl] -4,4-dimethyl-1,3 (211,411) -isoquinolinedione (eight feet € 239), or a mixture thereof Or pharmaceutical salts. 46. The product according to item 44 of the patent application, wherein the selective adrenal α2B receptor antagonist is miloxan or a pharmaceutically acceptable salt thereof. 47. Such as the scope of patent application 44 To any of 46 Products, wherein the orpinephrine reuptake inhibitor (NRI) is Maprotiline; Reboxetine; -46- 200526227 Noparmin, Dexipamin; Nisoxetine; Tomoxetine; Amo Shapin; Doxepin; Lofipamin; Amitapalene; 1-[1-(3-fluorophenyl) -2-(4-methyl-1-hexahydropyridyl) ethyl] Cyclohexanol; 1- [1- (3-chlorophenyl) -2- (4-methyl-1 -hexahydropyridyl) ethyl] cyclohexanol; 1-[2-(4-methyl -1 -hexahydropyridyl) -1- [3- (trifluoromethyl) _phenyl] ethyl] cyclohexanol; [1- (4-methoxyphenyl) -2- [4 -Methyl-1-hexahydropyridyl] ethyl] cyclohexanol; 1- [1- (3-chlorophenyl) -2- [4- (3-chlorophenyl) -1-hexahydropyridine Aryl] ethyl] cyclohexanol; bU-y-methoxyphenyl) _2- [4-phenylmethyl] -1-hexahydropyridyl] ethyl} cyclohexanol; 1- [2 -(3-chlorophenyl) 1-hexahydropyridyl] -W3-methoxyphenyl] ethyl] cyclohexanol; 1- [2- [4- (6-chloro-2-pyridyl) ) -1-hexahydropyridyl] -1- [3-methoxyphenyl] ethyl] cyclohexanol; 1- [2- [4- (phenylmethyl)]-1-hexahydropyridine Aryl] -1- [3- (trifluoromethyl) phenyl] ethyl] cyclohexanol; 1- [1- (3-methoxy Group) -2- [4- [3- (trifluoromethyl) -phenyl] -1-hexahydropyridyl] ethyl] cyclohexanol; bH-M-fluorophenyl) -2_ [4- (Phenylmethyl) -1-hexahydropyridyl] ethyl] cyclohexanol; H- (3-methoxyphenyl) -2- [4- [3- (trifluoromethyl) _benzene [Yl] -1-hexahydropyridyl] ethyl] cyclopentanol; fluorophenyl) -2- [4- (phenylmethyl) -1-hexahydropyridyl] ethyl] cyclohexanol; 1- [2- (dimethylamino) -1- (3-trifluoromethylphenyl) ethyl] cyclohexanol; 1- [1- (3-phenylphenyl) -2- (4-methyl 1-Hexahydropyridyl) ethyl] cyclohexanol; 1-Π- (3-chlorophenyl) -2- (dimethylamino) ethyl] cyclohexanol; 1- [2 -Dimethylamino] -1- (3-trifluoromethylphenyl) ethyl} cyclohexanol; 1- [1- (3-chlorophenyl) -2-hexahydropyridine-butyl- Ethyl] -cyclohexanol; or a mixture thereof or a pharmaceutically acceptable salt. -47- 200526227 48. The product according to any one of items 44 to 46 in the scope of application for a patent, wherein the orpine adrenaline reuptake inhibitor is dexipapar sun and moon. 49. The product of any one of the 44th to 46th patent applications, wherein the orpinephrine reuptake inhibitor is 1- [1_ (3-chlorophenyl) _2_ (4_methyl-hexakidone ratio Trapyl) ethyl] cyclohexanol or a pharmaceutically acceptable salt thereof. 50. The product according to any one of claims 44 to 46 in the scope of patent application, wherein the orpinephrine reuptake inhibitor is 1-[1-(3-chlorophenyl) -2- (4-methyl-1 -Hexamidine, ethyl) ethyl] cyclohexanol, the pure mirror isomer. 5 1 · The product according to any one of claims 44 to 46 in the scope of patent application, wherein the dual adrenaline reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI) is venlafaxine, 0-go Methyl-venlafaxine (DVS-233 or CDV), Minapril, Duloxetine or a mixture thereof or a pharmaceutically acceptable salt. 52. The product of any one of claims 44 to 51 in the scope of patent application, wherein the vasomotor symptoms are flushing during menopause. 53. The product of claim 52 in which the patient is a human. 54. The article of claim 53 in the scope of patent application, wherein the human is a female. 55. If the product of the scope of patent application No. 54 is applied, the woman is in the menopause period. 56. The product of claim 54 in which the woman is in the period of menopause. 57. The product of claim 54 in which the woman is after menopause. 58. The article of claim 54 in which the human is a male. -48- 200526227 59. The product of claim 54 in which the male is naturally, chemically or surgically menopausal. 60. A use of an active ingredient for preparing a medicine for treating vasomotor symptoms in a patient, the active ingredient consisting of at least one selective adrenal α2B receptor antagonist or a pharmaceutically acceptable salt thereof. 61. —Use of the following ingredients for preparing medicine for treating vasomotor symptoms in a patient, the ingredients being at least one selective adrenal α2B receptor antagonist or a pharmaceutically acceptable salt thereof, and at least one ortho-adrenal NRI or NAD / SRI or a pharmaceutically acceptable salt thereof. 62. —The use of the following ingredients for the preparation of a medicine for treating vasomotor symptoms in a patient, this ingredient is at least one selective adrenal α2B receptor antagonist or a pharmaceutically acceptable salt thereof; the medicine also contains at least An ortho-adrenergic reuptake inhibitor (NRI), or at least one ortho-adrenergic reuptake inhibitor / serotonin reuptake inhibitor (NRI / SRI), or a pharmaceutically acceptable salt thereof. 63. —The use of the following ingredients for the preparation of medicine for treating vasomotor symptoms in a patient, this ingredient is at least one norepinephrine reuptake inhibitor (NRI), or at least one norepinephrine reuptake inhibitor / serum NRI / SRI, or a pharmaceutically acceptable salt thereof; the medicine also contains at least one * selective adrenal α2B receptor antagonist or a pharmaceutically acceptable salt thereof. -49-