TW200526197A - Combination of serotonin reuptake inhibitors and norepinephrine reuptake inhibitors - Google Patents

Abstract

This invention is directed in one embodiment to pharmaceutical compositions and methods for treating depression in a mammal. To a mammal in need of such treatment are administered: (i) at least one serotonin reuptake inhibitor or pharmaceutically acceptable salt thereof; and (ii) at least one norepinephrine reuptake inhibitor or pharmaceutically acceptable salt thereof, wherein the norepinephrine reuptake inhibitor is selected from the group consisting of structure II, structure III, and structure IV as defined herein.

Description

200526197 IX. Description of the invention: [Technical power to which the invention belongs] The present invention is directed to a species containing a serotonin reuptake inhibitor or a pharmaceutically acceptable salt thereof, and // aderepinephrine re-shoot ## 齐 丨 & amp # 1 $ A pharmaceutical composition of a scientifically acceptable salt, and is directed to a method of treatment by the composition. The present invention is also directed to a pharmaceutical composition comprising a serotonin reuptake inhibitor or a pharmaceutically acceptable salt thereof, and optionally a norepinephrine reuptake inhibitor or a pharmaceutically acceptable salt thereof ' And it is directed to the treatment method by the composition, wherein the serotonin reuptake inhibitor is present in an amount sufficient for dopamine reuptake inhibition. [Prior art] Serotonin is used in a number of mental disorders (including anxiety, Alzheimer's disease, and depression). Nausea and vomiting, eating disorders and migraines (see Rasmussen et al. Annual Reports in Medicinal ChemigLrY Part I, 30, pp. 1-9, `` Chapter 1 · Recent Progress in Serotonin (5HT) 1A Receptor Modulators (Chapter 1 Recent Advances in Serotonin (5HT) 1A Receptor Modulators) ", 1995, Academic Press, Inc .; Artigas et al., Trends Neurosci. '19 (9), 1996, p. 378-383 pages; and Wolf et al., Dru_Cen

Development Research, 40, 1997, pp. 17-34). Serotonin also plays a role in the positive and negative symptoms of schizophrenia, as described by Sharma et al. In Psychiatric Annals ·, 26 (2), February 1996, pages 88-92. Serotonin reuptake inhibitors have been used to treat conditions or diseases such as depression, 95429.doc 200526197, as described in WO 94/00047. The antidepressant effect of a norepinephrine reuptake inhibitor has been disclosed, for example, in U.S. Patent No. 6,403,645. The effect of combining selective serotonin reuptake inhibitors (SSRIs) with norpinephrine reuptake inhibitors desipramine has been disclosed in JC Nelson et al., Arch. Gen. Psychiatry, 39 : 1419-1422, 1982; JC Nelson et al., Arch. Gen. Psychiatry, 48: 303-307, 1991; JC Nelson and LH Price, Am. J.

Psychiatry, 1 52: 1 538-1 539, 1 995; and M. Fava et al., Am. J. Psychiatry, 152: 1539, 1995. The combination of sertraline and reboxetine has been included in Eur J Pharmacol. 1999, 364 (2-3): 123-32 and J. Neural Transm. 2000, 107: 1213-1227 Be described. A comparison of the stimulating properties of reboxetine with those of a serotonin reuptake inhibitor has been disclosed in Pychopharmacology. 2001, 1 54: 21 3-21 8. The combination of citalopram and reboxetine has been disclosed in WO 02/076461 ° According to Brunswick et al. Am. J. Psychiatry, 2003, Vol. 160: 10, pages 1836-1841 The dopamine transporter affinity in the basal ganglia of depression patients may be higher than normal. Racemic reboxetine (a norepinephrine reuptake inhibitor) has been shown to affect the dopaminergic system during the incubation period, increasing dopamine in the prefrontal cortex. See Sacchetti et al., Br. J. Pharmacol. 1999, Vol. 128, pp. 1332-1338; Page et al., Neuropsychopharmacology, 2002, 95429.doc 200526197 Vol. 27, pp. 237-247; and Invernizzi et al. , British J. of Pharmacology, 200 1, vol. 32, pp. 1 83-1 88. However, 疋 'cetabram, a serotonin reuptake inhibitor, did not show reuptake inhibition by yuba women. Kugaya et al., NeuroSychopharmacology, 2003 'Vol. 28, pp. 413-420. Similarly, serotonin and the adrenaline reuptake inhibitor venlafaxine did not show dopamine reuptake inhibition (Marek et al., Society for Neuroscience

Meeting 'New Orleans (November 2003). None of the previous studies on the gross surface revealed or proposed a combination of serotonin reuptake inhibition, orthopinephrine reuptake inhibition, and dopamine reuptake inhibition in dual-component therapies. A composition, or a method of treatment by such a composition. [Summary of the Invention] The present invention is directed to a pharmaceutical composition for treating a disorder or disorder of a mammal selected from the group consisting of the following disorders: anxiety, phobia, avoidant personality Disorders, eating disorders, chemical dependence, Parkinson's disease, obsessive-compulsive disorder, schizophrenia: Symptom 2: Cognitive function related to schizophrenia, Premenstrual symptoms: Dust suppression incontinence, headache, nerves Sexual pain, chronic pain, urinary loss ... meat fiber pain, insomnia with muscle fiber pain, obesity, migraine, neuropathic pain associated with diabetes = feeling μ and combinations thereof, the composition includes: (1) at least _ = reuptake inhibitor or a pharmaceutically acceptable salt thereof; ⑼ at least a 2 epinephrine reuptake inhibitor or a pharmaceutically acceptable salt thereof, its center 95429.doc 200526197 less- Adrenaline reuptake inhibition is selected from the group consisting of: (A) a compound having formula II

Where n and η are independently 1, 2 or 3; each R and R1 group may be the same or different, and they are hydrogen, dentin, dentate_Cl_C6 alkyl, meridian, Moxy, and optionally Cl_c6 Nostril or dentition-substituted nostril, optionally substituted with arsenyl or dentin-substituted aryl «6 noradyl, optionally substituted with alkyl or dentin-substituted aryl sulfonyloxy, __N〇2 , R5 and R6 are independently hydrogen or Ci_C6, or two adjacent r groups or two adjacent R groups circle together to form a _〇-CH2-10 group); A is hydrogen or OR2; R2 is hydrogen; optionally substituted with a ClM group or a halo group, or an aryl-cvc6 alkyl group; the groups may be the same or different; they are hydrogen, optionally substituted with a sulfanyl group or a halo group. , C2_C4 alkenyl, C2_c4 block group, aryl group substituted by CVC group or functional group as appropriate, as appropriate 95429.doc 200526197 C! -C6 alkyl or halogen substituted CrC7 cycloalkyl group, or R3 & R4 and the nitrogen atom to which it is bonded form a five-membered or six-membered, saturated or unsaturated, optionally substituted by C! -C6 alkyl or halogen heterocyclic ring group, the group optionally contains other selected from 0 , S Hetero atom group consisting of N; or R2 and R4 - together form a - CH2-CH2- group; (B) a compound having the formula III

Where D is N or CR9, where R9 is hydrogen, optionally substituted with CVC6 alkyl, CVC4 alkenyl, alkynyl, optionally substituted with q-C6 alkyl or halogen, aryl / C ^ alkyl, or C ^ C7 cycloalkyl substituted with alkyl or i-substances as appropriate; (^ is; ^^, where each ... and R8 are independently hydrogen, optionally Ci_C6 alkyl or halogen Substituted 6 < 6 alkyl, CrC4 alkenyl, CrC4 alkynyl, aryl-CrC4 alkyl optionally substituted with Ci_C6 alkyl or halogen, or ^ -C7 cycloalkyl optionally substituted with Ci_c6 alkyl or halogen Or ... and ... together with the nitrogen atom to which it is bonded, form a five- or five-shell, saturated or unsaturated heterosaponyl ring group optionally substituted by a C6c6 alkyl or halogen, the group may optionally include One or more additional heteroatoms selected from the group consisting of 8 and N;]) and the ring carbon bonded to G is a single fluorene or double bond; and J is 0 or L, where ^ is 95429 .doc 200526197 Μ C \ Μ NR3R4 where the bond between the ring carbon of L and the carbon of L bonded to M is a single or double bond; Μ is (^ alkylene chain, where n is between 1 and 3 And each R] 3 and R〗 4 are independent Is hydrogen, Ci alkyl substituted with Ci-C6 alkyl or halogen, C4 alkenyl, C2-C4 alkynyl, optionally substituted with C〗 -C6 alkyl or halo-c ^ c: 4 alkyl, optionally substituted by Ci-(^ alkyl or halogen.-^^ ring: group 'or R and R14 together with the nitrogen atom to which it is bonded to form a five member or six ^: saturated or unsaturated, depending on In the case of Ci_C6 alkyl or oxine-substituted heteromonocoating groups, hydrazones optionally contain-or more heteroatoms additionally selected from the group consisting of 0, S and N; and (c) compounds having formula IV:

N R Bismuth

Formula IV "is a cn-carbon-based chain 'wherein n is between 丄 and); and each of C23 and anti-Cd6 are hydrogen, optionally substituted with Ci-C6 or halogen-substituted CVC6 :) 95429.doc 200526197 Group, CrC4 alkenyl, CrC4 alkynyl, aryl-Ci-C: 4 alkyl optionally substituted with ei_C6 alkyl or halogen; CrC7 cycloalkyl optionally substituted with Ci_C6 alkyl or halogen; or Han 24 forms a five- or six-membered, saturated or unsaturated, monocyclic group substituted with Ci_c6 alkyl or halogen, together with the nitrogen atom to which it is bonded, which optionally contains one or more additional options A heteroatom of the group consisting of 0, S and N; and (iii) a pharmaceutically acceptable carrier.

The present invention is also directed to:-a method for treating a disorder or condition in a mammal described in the previous paragraph ^, 4 the method comprising administering a therapeutic ingredient described in the previous paragraph of a mammal in need of such treatment; and ( ii); means the ingredients described in the previous paragraph; and (ii) a pharmaceutical composition for the treatment of a disorder or condition in a mammal described in the preceding paragraph By boosting mammalian blood

Neurotransmission, mammalian orthrenergic neurotransmission, or a combination thereof, the composition comprising the tillers, (ii) and (iii) described in the previous paragraph; Method of increasing serotonin neurotransmission in mammals, or adrenergic neurotransmission in animals, or a combination thereof for the treatment of disorders or disorders, ancient, and native—4 administration to a mammal in need of this treatment previously Described ingredients ⑴ and (ii); a pharmaceutical composition for treating mammalian depression, the combination 95429.doc -12- 200526197 contains the ingredients ⑴, (π) and (in) described in the previous paragraph; A method for treating depression in a mammal, the method comprising administering ingredients ⑴ and (ii) described in the previous paragraph to a mammal in need of such treatment; and ingredients ⑴ and (ii) used in the previous paragraph to Use of a medicament for treating depression in a mammal. The invention is also directed to a composition for treating a mammalian disorder or condition described in the previous paragraph, which composition consists essentially of ingredients VII, (Π) and (iii) described in the previous paragraph. The present invention is also directed to:

— Υ Θ ... Wang Xiyi blood> Poor Jingran uptake inhibitor or drug can be added to the salt of X ', where the at least-serotonin reuptake inhibition is selected from sertraline, flucy>, (FluGxet㈣ and ambush

a group consisting of (uVoxamine); and 一 at least one readrenaline: a preparation or a pharmaceutically acceptable salt thereof, wherein the at least one adrenal): a reuptake inhibitor. It is selected from the group consisting of racemic reposoxyl Pak-M㈣ 匕 -Riboziye ebGxetlne), amosapine ⑽. Qing Yi and ^ 2-I-formed group. The composition can be used for treatment of muscle fibrous complexes; urinary incontinence, muscle fiber pain, companionship;

Ears, depression, obesity, migraine, and diabetes I: No: two! Pain, schizophrenia, emotional symptoms, and combinations thereof, a group of mammalian disorders or conditions; and a composition, which is basically composed of a reuptake inhibitor or a medical treatment / and. ⑴ at least-serum y, the salt of the fork, wherein the at least one 95429.doc -13- 200526197 serotonin reuptake inhibitor is selected from the group consisting of sertraline (se valence eh, fluoxehne) and fluorine A group consisting of fluoxamine and ⑴) at least one ortho-adrenergic reuptake inhibitor or a pharmaceutically acceptable salt thereof, wherein the at least one ortho-adrenergic reuptake inhibitor is selected from the group consisting of A group consisting of eboxetine, [S, S] -reboxetine (reboxetjne), amoxapine and maprotihne. The composition can be used for treating a disease selected from the group consisting of neuropathic pain, chronic pain, urinary incontinence, muscle fiber pain, pain with muscle fiber pain, obesity, migraine, neuropathic pain associated with diabetes, mental illness A combination of the emotional symptoms of schizophrenia and mammalian disorders or conditions of which M is a group. The present invention is also directed to: A method for treating a mammalian disorder or condition described in the previous paragraph, the method comprising administering to a mammal in need of the treatment ... at least one serotonin reuptake inhibitor or a medicament thereof A scientifically acceptable salt, wherein the at least one serotonin reuptake inhibitor is selected from the group consisting of satMine, fluoxetine, and fluvoxamine; and (ii ) At least one ortho-adrenaline reuptake inhibitor or a pharmaceutically acceptable salt thereof, wherein the at least one ortho-adrenaline reuptake inhibitor is selected from the group consisting of racemic reboxetine, [S, S] _ A group consisting of reboxetine ([s, s] _reboxetine), amoxapine and maprotiline; and the ingredients ⑴ and (ii) described in the previous paragraph are used to prepare Use of a medicament for treating a mammalian disorder or condition described in the previous paragraph. 95429.doc -14- 200526197 This preparation month is also aimed at a kind containing sertraHne or its pharmaceutically acceptable salt of X and [s, s] -Reposi, Reboxetine or its Composition of a pharmaceutically acceptable salt. The present invention is also directed to a composition for treating, for example, a disorder or condition that can be treated by enhancing mammalian serotonin neurotransmission, mammalian dopaminergic transmission, mammalian adrenaline neurotransmission, or a combination thereof, The composition contains the ingredients described in the previous paragraph and optionally the knife (11), wherein the ingredient is present in an amount sufficient for dopamine reuptake inhibition. Ingredient (1) is preferably sertraline or a pharmaceutically acceptable salt thereof. The present invention is also directed to a method for treating a disorder or condition that can be treated by enhancing mammalian serotonin neurotransmission, mammalian dopaminergic transmission, mammalian adrenaline neurotransmission, or a combination thereof, the method comprising administering Mammals in need of such treatment include ingredient ⑴ and, optionally, ingredient (ii) as described in the previous paragraph, where ingredient ⑴ is present in an amount sufficient for dopamine reuptake inhibition. Ingredient ⑴ is preferably senraline or a pharmaceutically acceptable salt thereof. The present invention is also directed to a composition comprising sertraline or a pharmaceutically acceptable salt thereof and optionally selected from the group consisting of racemic reboxetine, [S, S] -Ribo A group of orpine adrenaline reuptake inhibitors or their pharmaceutically acceptable salts consisting of reboxetine, amoxapine, and maprotihne Sertraline or a pharmaceutically acceptable salt thereof is present in an amount sufficient to inhibit dopamine reuptake. 95429.doc -15- 200526197 The present invention is also directed to a composition comprising sertraline or a pharmaceutically acceptable salt thereof and optionally [s, s] _reboxetine Or a pharmaceutically acceptable salt thereof, in which sertraline is present in an amount sufficient to inhibit dopamine reuptake. Used in the treatment selected from the group consisting of anxiety, phobia, avoidant personality disorder, eating disorders, chemical dependence, Parkinson's disease, obsessive-compulsive disorder, negative symptoms of schizophrenia, premenstrual syndrome, depressive incontinence, headache, nerves Pain, chronic pain, urinary incontinence, post-traumatic stress disorder, chronic depression, acute depression, post-traumatic stress disorder, depression with muscle fiber pain, obesity, mammal disorders, or disorders In the method, the serotonin reuptake inhibitor may be sertraHne, which is present in an amount sufficient to inhibit dopamine reuptake. Similarly, in a composition for treating a disorder or condition described in this paragraph, the serotonin reuptake inhibitor may be sertraline, which is present in an amount sufficient to inhibit dopamine reuptake. Similarly, in the treatment of selected from the group consisting of neuropathic pain, chronic pain, incontinence, post-traumatic dysfunction, chronic dysfunction, acute history, post-traumatic recurrent disease, muscle fiber pain, depression with muscle fiber pain In the method of the disorder or condition of the formed group, serotonin reuptake = agent; is sertraline, which is present in an amount sufficient for dopamine reuptake to inhibit sertratness, and the serotonin reuptake inhibitor may be Inhibition of dopamine reuptake. In —shi # is present in an amount sufficient for doxtretraline or its medicine II = 'Serotonin reuptake inhibitors are formulated as Qing Rui Bo Xi :: Er Shang Qi 丁 Ding Ci with a celecologically acceptable salt, where She 95429.doc 200526197 koji, which is present in an amount sufficient for dopamine reuptake inhibition, wherein the content of sertraline is from about 150 mg to about 200 mg. The serotonin reuptake inhibitor in the composition for treating depression can be sertraline, which is present in an amount of serotonin for use in dopamine reuptake inhibition. In the examples, the serotonin reuptake inhibitor is Sertraline or a pharmaceutically acceptable salt thereof, and the adrenaline reuptake inhibitor is [s, s] _ Ribozepam, a pharmaceutically acceptable salt thereof, and the content of sertraline in Λ is sufficient for Dopamine reuptake inhibition, with sertraline content ranging from about 150 mg to about 200 mg. Including at least one serotonin reuptake inhibitor or a pharmaceutically acceptable salt thereof, wherein the at least one serotonin reuptake inhibitor is selected from the group consisting of sertraline, fluoxetine and fluvoxamine A group consisting of (fluvoxamine), and (ii) to J / a lunar adrenaline reuptake inhibitor or an acceptable salt thereof, wherein the at least one adrenaline reuptake inhibitor is selected from the group consisting of Composition of a group consisting of racemic reboxetine, reboxetine, [S, S] -reboxetine, amoxapine, and maprotiline The serotonin reuptake inhibitor may be sertraline, which is present in an amount sufficient to inhibit dopamine reuptake. Similarly 'in at least one serotonin reuptake inhibitor or a pharmaceutically acceptable salt thereof, wherein the at least one serotonin reuptake inhibitor is selected from the group consisting of sertraline, fluoxetine, and A group consisting of fluvoxamine (fiuv0Xamin0); and (ii) at least one ortho-adrenergic reuptake inhibitor or a pharmaceutically acceptable salt thereof, wherein the at least one ortho-adrenergic reuptake inhibitor is selected from the group consisting of A group of racemic reboxetine, Ding (reboxetine), [S, S] -Reboxetine, Ding 95429.doc 200526197 (reboxetine), amoxapine and maprotiline In the composition, the serotonin reuptake inhibitor may be sertraline, which is present in an amount sufficient to inhibit dopamine reuptake. The pharmaceutical composition and method of the present invention can also be used to administer the composition to a mammal in need of prevention And (ii) to prevent the recurrence of the disorder or condition described in the previous paragraph. The pharmaceutical compositions and methods of the present invention can be further used to treat the disorders or conditions described in the previous paragraph. Symptoms, wherein the symptoms are selected from the group consisting of cognitive dysfunction and physical diseases. As used herein, "enhancing serotonin neurotransmission" means increasing or improving the neuronal process by which monoamine serotonin is used by Pre-synaptic cells are released when stimulated and cross the synapse to stimulate or inhibit post-synaptic cells. As used herein, "enhancing dopaminergic neurotransmission" means increasing or improving neuronal processes, whereby monoamine dopamine is used by presynaptic Cells are released when stimulated and can stimulate or inhibit post-synaptic cells across the canine. As used herein, "enhancing orthopinephrine neurotransmission" means increasing or improving neuronal processes, whereby monoamine adrenaline is passed through presynapses Cells are released when stimulated and stimulate or inhibit post-synaptic cells across the synapse. The term "drug-dependent drug dependence" as used herein means an abnormal desire or need for or desire for a drug. Usually by including These drugs are administered to affected individuals by any of the various intestinal, nasal, or inhalation methods. Used herein , Household, mochi μ wind — 1 ^ used by ten people / oral treatment of chemical drug dependence, meaning to reduce or alleviate this dependence. Bit dose of serotonin reuptake The "unit dosage form" used herein contains a single 95429 .doc 200526197 Inhibitors or pharmaceutically acceptable salts, reuptake inhibitors or pharmacologically active diadrenaline reuptake inhibitors or pharmacologically acceptable di == serum uptake inhibitory system or „ Accessible in school = adrenaline, let's say that the unit Nan 刮 scrapes any of the dosage forms of the & dish. For example, it is a fixed dose or capsule. The dosage form I can also be κ ^, such as a solution or suspension. In liquid form, "serotonin reuptake inhibitors, inhibitors, as used herein. For example, △ 生 本本 过 女 血 / 月 素 再 取 生 音 ϋ "Vegetarian reuptake inhibition is -selective blood ^ ^ J1 H j, vegetative reuptake inhibitors can have amounts ^, D5-HTl 5eHT2A / c receptor antagonistic or part of the adrenaline transporter (briber). As described further herein, at a certain amount or more than a certain dose, the serotonin reuptake inhibitors exhibit poly-Z-amine reuptake Included! Is sufficient for dopamine reuptake inhibition, meaning an amount sufficient to transfer at least about 15% rit from the dopamine transporter, which can be analyzed by spect imaging. Exemplary selective serotonin reusable according to the present invention Uptake inhibitors (SSRI) include selective serotonin reuptake inhibitors having the structure shown below:

Structure I 95429.doc 19- 200526197

Or a pharmaceutically acceptable salt thereof, wherein Rn is selected from the group consisting of hydrogen and a conventional alkyl group of 1-3 carbon atoms, R32 is a conventional alkyl group of 1-3 carbon atoms, and 2 is

X γ X and Υ are each selected from the group consisting of hydrogen ′ I, chlorine, bromine, trifluoromethyl, alkoxy groups of 1-3 carbon atoms, and cyano, and at least one of χ & γ is not hydrogen, * Digas methyl, 1-3 carbon atoms W is selected from the group consisting of hydrogen, fluorine, chlorine, and bromooxy groups, and NR ^ R32 and Z have a cis relationship. structure! Z-Exemplary compound is Sezanne, (is_cis) _ 4- (3,4-difluorophenylsulfonium from tetrahydrophosphonium + naphthalene, which can be as described in US Patent No. 4,536,518 SSRIs that can be used in accordance with the present invention also include (but are not limited to): preparations described in No. 3,912,743; preparations described in No. 4,314,081), famoxetine (which can be used as described in US Patent No., Fluoxetine It can be prepared as described in U.S. Pat. No. 9,529.doc -20-200526197 4,085,225, indinapine (which can be prepared as described in U.S. Pat. No. 4,064,255), Indenochlorine (11 (161〇 乂 32 丨 1 ^) (which can be found in the United States, ..., π., ..., v one heart), take one, use y • Deng Xiaoping (milnacipran) (which can be Prepared as described in U.S. Patent No. 4,478,836), paroxetine (which can be prepared as described in U.S. Patent No. 3,912,743 or U.S. Patent No. 4,007,196), sibutramine (which can be prepared Prepared as described in U.S. Patent No. 4,929,629), zimeldine (which can be used as described in U.S. Patent No. 3,928,369) To prepare), citalopram, esciUlopram, fenfluramine, venlafaxine, and duloxetine. This article The epinephrine reuptake inhibitor used is a monoamine norepinephrine reuptake inhibitor. For example, the epinephrine reuptake inhibitors are selective selective epinephrine reuptake inhibitors. As another example, positive Kidney == inhibitors may have additional pharmacological properties, such as body resistance. As another lupus can be affected by-of _; renylamine: epinephrine reuptake and anti-radiation capacity As an example, the branch of the population according to the standard prostaglandin reuptake inhibitors include the positive kidney or pharmaceutically acceptable salt thereof that can be used above. Epinephrine reuptake inhibition Qi Er: 'Compounds which can be constructed in accordance with the present invention III or its medicines ㈣ have the knots defined above can be made according to the present invention. As another example, epinephrine reuptake __Includes 95429.doc 200526197 A compound of the defined structure ιν or a pharmaceutically acceptable salt thereof. In an exemplary embodiment of the present invention, the orpinephrine reuptake inhibitor is the [S, S] -enantiomer of structure II , As shown in the following structure IΓ: where A = OR2 and R, R2, R3, R4, ηΑη1 is as defined in structure π:

Structure II, for example, an adrenaline reuptake inhibitor of structure Γ can be [8,8> reboxetine, which is disclosed in British Patent GB 2,167,407, US Patent Application No. 2002006 1910, and US Patent 6,465,458. No. described. In another exemplary embodiment of the present invention, the norepinephrine reuptake inhibitor of the structure π is atomoxetine hydrochloride or racemic reboxetine. In another exemplary embodiment of the present invention, the norepinephrine reuptake inhibitor of structure m is amoxapine, nortriptyline, or protriptyline. In another exemplary embodiment of the present invention, the norepinephrine reuptake inhibitor of structure IV is maprotiline. 95429.doc -22- 200526197 In one exemplary embodiment of the composition of the present invention, the composition comprises a norepinephrine reuptake inhibitor with 'Structure II', and a home as a serotonin reuptake inhibitor Qu Lin (sertraline). In another exemplary embodiment of the composition of the present invention, the composition includes sertraline (^ hraline) as a hemagglutinin reuptake inhibitor and [s, s] · as a norepinephrine reuptake inhibitor. Riboxitin. xetine). In another exemplary embodiment of the Benxinming composition, the composition is substantially equal to sertraline as a serotonin reuptake inhibitor and [3bie_reboxetine ( reb〇xetin Lu Cheng. The combination of a major adrenaline reuptake inhibitor or a pharmaceutically acceptable salt thereof and a serotonin reuptake inhibitor or a pharmaceutically acceptable salt thereof is also referred to herein as sex A The combination " term " active combination " can also be used to mean a combination of a norepinephrine reuptake inhibitor or a pharmaceutically acceptable salt thereof and a serotonin reuptake inhibitor or a pharmaceutically acceptable salt thereof, Among them, serotonin uptake inhibition 剤 or a pharmaceutically acceptable salt thereof can also inhibit dopamine recurrence

Ingest. The active combination is a useful psychotherapy and can be used in the treatment of the " periodism or condition " Examples of disorders or conditions that can be treated by the methods and compositions of the present invention are as follows: Depression & Depression, including depression in cancer patients, depression in Parkinson's patients, post-myocardial infarction suppression, human immunodeficiency disease # ( (hiv) Patients with depression, sub-syndromes #, infertile women with depression, children with depression, severe snoring, single episode of depression, relapsed depression, depression caused by child abuse, postpartum Depression, severe depression, difficult to treat 95429.doc -23-200526197 treatment of major depression, major depression, psychotic depression, post-stroke depression, neuropathic pain, bipolar disorder (including Mixed episodes of bipolar disorder and depression are described as depression), seasonal mental disorders, bipolar depression Bp I, bipolar: depression BP II, depression, or severe depression with mental depression; anxiety, including Examples include generalized anxiety, panic disorder, PTSD, and father-in-law anxiety; phobias, including, for example, plaza phobia, social phobia, or simple phobia; eating disorders, such as anorexia nervosa or binge eating disorder Chemical drug dependence, including for example, amphetamine and other psychostimulants to alcohol, cocaine, amphetamine, right. Non-, heroin and other sedative agonists 爿 丨 Sedative hypnotics and other barbiturates, nicotine, diazepam, benzodiazepine and other psychotropic substances; Parkinson's disease, including for example Parkinson's Dementia, Parkinson's disease or tardive dyskinesia caused by tranquilizers, and headaches, including, for example, headaches associated with vascular disease. Disorders or disorders that can be treated by the compositions and methods of the present invention also include withdrawal syndromes; adaptation disorders, including depression, mixed anxiety and depression, disorder of conduct, and conduct and depression Mixed | disorders; age-related learning and mental disorders, including Alzheimer's disease; emotional apathy; attention deficit disorder, ... other cognitive disorders of the condition; attention deficit hyperactivity disorder ^ HD) 'double Extremely upset; Chronic fatigue syndrome; Chronic or acute stress disorder; Cyclic affective disorder; Arrangement disorders such as somatization syndrome, pain, suspected disorder, physical deformity, undifferentiated Somatoform disorder, and somatoform Nos syndrome; mania; anti-reverse "... 7 'and entry barrier; poisoning resistance, peripheral neuropathy; posttraumatic stress 95429.doc -24- 200526197 f, late x Physical anxiety; psychiatric disorders, including schizoaffective disorder; sleep ^ including narcolepsy and enuresis; special developmental disorders; SSRI " fatigue " Maintain a good response to ssRW therapy; and tic disorders (including Lata's disease (Weue, s)). As an example, mammals in need of treatment or prevention can be humans. As another example, 'in need of treatment or prevention The mammal may be a mammal other than a human. The orprenaline reuptake inhibitor and the serotonin reuptake inhibitor each used to formulate the pharmaceutical composition of the present invention are referred to herein as " active compounds " Basic active compounds can form various salts with various inorganic and organic acids. The test compounds are treated by a substantially equal amount of the selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol ' It is easy to prepare acid addition salts. The solvent is carefully evaporated to obtain the desired solid salt. It is pharmaceutically acceptable for preparing the active compound (which is essentially alkaline) used in the pharmaceutical composition of the present invention Acids of acid salts are acids which form non-toxic acid addition salts (meaning salts containing pharmacologically acceptable anions). Non-limiting examples of such salts include Acetate, benzoate, hydrazone-hydroxybutyrate, bisulfate, bisulfite, bromide, butyne-+ diacid, carpoate, gaseous, chlorobenzoate Acid salt, citrate salt, acid dihydrogen salt, distone succinyl benzoate, trans-butenedioate, glycolate, acetate, hexanoate Salts, broken compounds 'lactate, maleate, malonate, mandelate, metalinate L «' methoxybenzoate, methylbenzoate, acid filler 95429.doc -25 · 200526197 salt, naphthalene-1-sulfonate, naphthalene-2-sulfonate phenylpropionate, phosphate, phylacetate, propanesulfonate, salt, pyrosulfate, sebacic acid Salt, sulfite, dibasic acid, phosphate, acid citrate, oxalate, phenylbutyrate, diformate, phenylacetate propionate, propionate, caprylic acid Diacids, succinates, tartrate sulfates, xylene sulfonates, acid sulphates, succinates, gluconates, nitrates, mesylate and parabens

(PateH 1,1-methylene-bis- (2-Cyclo-3 · naphthoate) ;; Epiadrenaline reuptake inhibitors, such as reboxetine ⑽OXetine) j [s, s ]-Riboxi Jiangxi oxetine), advantageous examples include transbutyl disulfide, succinate, citrate and tartrate. [Embodiment] Orthopinephrine reuptake inhibitor 1 ' monthin reuptake inhibitor (which also displays dopamine resuppression as described herein) for use in shoulder-fitting the pharmaceutical composition of the present invention

Uptake inhibition) is preferably administered together in a pharmaceutical composition. For example, a composition containing a norepinephrine reuptake inhibition d and a serotonin reuptake inhibitor may be administered in a solution in an amount of liter / kg. The vehicle used will vary depending on the solubility of the adrenaline reuptake inhibitor used and the solubility of the serotonin reuptake inhibitor. Adding adrenergic reuptake inhibition d and serotonin reuptake inhibitors (which also show dopamine reprocessing as described herein) for regulating the pharmaceutical composition of the present invention can be conveniently used with and without significant obstruction Serotonin reuptake or other therapeutics of monoamine oxidase (such as miazapine, mienserin, amphetamine (dark mouth) 〇〇〇, salt, such as 95429.doc -26- 200526197

caramazepine, sodium 2-propylvalerate, lamotrigine, topiramate, gabapentin, pregabalin antiepileptic drugs) in combination, and / or It is preferably used in combination with an anti-Parkinson's disease agent such as a dopaminergic anti-Parkinson's disease agent (such as levodopa) with a peripheral decarboxylase inhibitor (such as besenzide or carbodopa). ) Combination. As another example, the adrenaline reuptake inhibitors and serotonin reuptake inhibitors (which also demonstrate dopamine reuptake inhibition as described herein) used to formulate the pharmaceutical composition of the present invention can be advantageously combined with 5-111 " 3 antagonists are used in combination. One example is elzasonan or a pharmaceutically acceptable salt thereof. For example, elzasonan can be, for example, about 0.01 to about 2 mg, such as scoop 0.1. 1 to 50 milligrams is present, as another example is about ^ to about gram grams, as another example is about 0.1 to about 10 mg, and as another example, about 0.1 to about 5 ^: G. The treatment method of the present invention may also include the treatment of a disorder or condition by means of an orbital reuptake inhibitor, a serotonin reuptake inhibitor, and a 5-HT1B antagonist such as elzasonan. It should be understood The present invention encompasses the use of a combination of a serotonin reuptake inhibitor or a pharmaceutically acceptable salt thereof, and an adrenaline reuptake inhibitor or a pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents. Active combination of depression The activity and related pharmacological properties can be measured by the following ⑴ ·) method, which is described in K () e, B, et al., Ding herapeutics. 226 (3), 686 (1 983). Specifically, Activity can be measured by the following g: ⑴ by Pors0l "t, behavi〇r desp ^" thirst

95429.doc -27- 200526197, to study its ability to affect mice's efforts to escape from the swimming pool, and (2) to study their ability to promote behavioral symptoms caused by 5-hydroxytryptophan in mice, and (3) The ability of synaptosomal mouse brain cells in vivo to block the reuptake of serotonin, norepinephrine, dopamine, or a combination thereof was investigated. The ability of the active combination to resist reserpine hypothermia in vivo in mice can be determined according to the method described in U.S. Patent No. 4,029,731. The activity and related pharmacological properties of the active combination as an antidepressant can also be determined by the following methods (4) to (8). Specifically, the activity can be measured by the following methods: (4) Investigating its ability to reverse the reduction of sucrose reuptake caused by repression in rodents, Shikou Papp, M. et al., European Journal of Pharmacology, 261, 141-147 (1994), (5) study learning paradigms, as described in Martin P et al., Life Sciences. 48, 2505-2511 (1991), (6) study reversing behavioral defects in mice with olfactory resection, such as Broekkamp CL et al., Pharmacology. Biochemistry pm Η Behavior, 1 3, 643-646 (1980), (7) Study to increase the down-regulation or desensitization of the adrenoceptor, such as Mishra R. et al., As described in Neuropharmacology, 19, 983-987 (1980), and (g) studies to increase the extracellular content of serotonin, norepinephrine, and / or dopamine in freely moving rodents' prefrontal cortex by living dialysis, such as Millan MJ, etc. Human, as described in European Journal of Neuroscience, 12, IO79.1095 (2000). The activity of the active combination in the treatment of anxiety can be measured from panic-like reactions caused by lactate in panic-prone mice, such as shekhar, A · and Keim SR ·, J. Neurosci, 1997, 17: 9726-9735 and Shekhar , A and 95429.doc -28- 200526197

Keim, S.R., NeuropharmacoK, 2000, 39 · 1 1 39-1 146. The activity of the active combination in the treatment of anxiety can also be measured from the masked anxiety of rodents (such as various derivatives including conflict mode or punishment mode) such as JL Howard and GT Pollard ^ PsYchoDharmacoloev of ~ __ ^ ώΛ_Antidepressants (ED ) SE File (1991), Pergamon press Inc. (New York), page U1_153.

The pharmaceutical composition described herein may be a prescription pharmaceutical composition or an over-the-counter certain composition. As used herein, the term "prescription signed pharmaceutical composition" refers to a composition in which the active compound can be legally delivered to a person only after a physician has issued a prescription. "Over the counter signed pharmaceutical composition" means that the The active compound is a composition legally delivered to a person for administration to that person.

The pharmaceutical compositions described herein can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Therefore, the active combination of the present invention can be adjusted-into a suit, oral, intranasal, parenteral (such as intravenous, intramuscular or sublingual or rectal drug), or in the form of a patch or suitable for inhalation or: In the form of administration, and can be administered orally, orally, intranasally, parenterally (such as intravenously, intramuscularly, or subcutaneously) rectally or by inhalation or insufflation. X Oral medicine, but the pharmaceutical composition can take, for example, tablets In the form of an agent or capsule, it is prepared by a known method with a pharmaceutically acceptable excipient, and excipients such as β are, for example, a binder, including pre-gelatinized corn flour, polyethylene, etc. Methylcellulose; filling in, including lactose, microcrystalline cellulose, or calcium phosphate; lubricants, including magnesium stearate, talc, or silicon knife, including potato starch or sodium starch glycolate; or moisturizing, Includes sodium lauryl sulfate. Lozenges can be applied by methods well known in the art 95429.doc • 29- 200526197. For oral administration in the form of a syrup or suspension, or a suitable vehicle The combination of dry production σ. One person other daggers Body preparations can be supplemented by pharmacologically acceptable supplements by the law of Fangnan County, Fang County, and other additives are, for example, sorbitol syrup, methyl cellulose, or hydrogen = dagger, Including tincture or gum arabic; non-aqueous agents: packages:, :: divine vinegar or ordinary alcohol; and preservatives, including methyl or propyl to basic formate or sorbic acid. Say 'composition can be taken to the conventional

Or in the form of lozenges. The active compound of the pharmaceutical composition of the present invention can be formulated for parenteral administration by injection, including the use of conventional catheterization techniques or infusion. Formulations for injection can be connected to a single-dose unit in a ampoule or multi-dose container with a preservative added. : The active compound-containing composition may take the form of, for example, an oily or aqueous vehicle, solution, or emulsion, and may contain a formulation such as a suspending, stabilizing or dispersing agent. Alternatively, the active ingredient can be in powder form: the active compound can be formulated with water or other suitable vehicle (such as sterile pyrogen-free) before use. In the rectal composition, the rectal composition (e.g., cocoa butter or other glycerin S is a conventional test agent. It is administered intranasally or by inhalation for the preparation of the medicine of the present invention, and is administered orally. The active compounds of the substance can be delivered as a solution or suspension in a suction jet container (which is squeezed by the patient 95429.doc -30 · 200526197 or Γ and), or as a dust container or

^ Server: The gas-solvent spraying form, which uses a suitable propellant, such as gas one, gas one, three-portion gas, other suitable gas two: gas, four gas, two, carbon dioxide, or a valve to deliver the measured In this case, a solution or suspension may be provided by providing a sprayer which can contain a living container or an ancient compound. Use: Capsules and cartridges made of, for example, gels can be formulated to contain =: Ming compound mixed with a suitable powder base agent (such as lactose or starch) powder and = = invented medicine, the adrenal gland Reuptake Inhibitors Reuptake Inhibitors

Early alone or better and medically available in both A-single or multi-dose :: of :: ^ ιν. ^^ ^ Dingengte 疋 & of the active combination can be administered in a variety of different pharmaceutical forms, This means active combinations: ,, tablets, hard candies, powders, sprays, aqueous suspensions, can.:! Liquids: various pharmaceutically acceptable carrier combinations in the form of wine, sugar polysaccharides and the like. These carriers include

Two no: water-based: quality and various non-toxic organic solvents. Various types of medicaments of J-Jin at this temple 'can appropriately sweeten and / or flavor the oral formulation containing the active ingredient. Guangqingsu reuptake inhibitors or their pharmaceutically acceptable adrenaline reuptake inhibitors or their adamantine, and the amount of the salt that is administered to J. Fork combination is an amount effective to treat a disorder or condition. The amount of serum axin reuptake inhibitor or a pharmaceutically acceptable salt thereof is preferably an amount effective for 95429.doc -31-200526197 diserotonin neurotransmission. The amount of norepinephrine reuptake inhibiting medically acceptable salt is preferably an amount effective to enhance breastfeeding ^ norepinephrine neurotransmission. In -preferred, the content of serum ^ uptake inhibitor is sufficient to inhibit the dopamine uptake. The affinity to the Semallne transporter (CaT) and the DAT transporter can be determined from the amount of ⑽T transferred. The degree of inhibition of dopamine reuptake was measured by combining the extracellular dopamine stimulating metabolism = / 5 CIT transmission and transfer to the degree of female placebo. Single: t Guangzhi? The le composition achieves the serotonin transporter occupancy rate and positive by combining the serotonin reuptake inhibitor or its medicinal-acceptable salt with orprenaline reuptake ㈣ = the accepted salt :: gland ^ transporter Share. In one exemplary embodiment of the present invention, 'two ::: uptake inhibitor or a pharmaceutically acceptable salt thereof may be sufficient to transport / metastasis from the second: about 45% of palpitations (for example by SpEC Ding Chenglizi. Orthopinephrine reuptake inhibitor or its medical treatment =: 二: 存 = ”上 _ 运…: As a general example, it has a share of at least 75%, and as another example, it is between 75% and 90% The occupancy rate is, as another example, at least the predominant rate, and as another example, 90% and 10% (including 100% occupancy). In an exemplary embodiment, the dimension ^: Epinephrine transporter 5 φ 7 < 〇 / T ^ continuous unit dose type II Γ :: rate up to the drug's occupant's occupancy rate, the sound is therefore / used in this article "adrenaline to abundance is all positive Occupation rate of epinephrine transporters. Similarly, for example, at least 75% of the adrenaline transporters are being glanced at, which means 95429.doc -32- 200526197. All adrenaline transporters have A share of at least 75%. Similarly, 'as another example, the adrenaline transporter knows that the share of at least 9G%' means All norepinephrine transporters have a share of at least 90%. Similarly, as used herein, "an amount sufficient to transfer at least about 45% / 3-CIT from a serotonin transporter" is sufficient to remove from all serotonin transporters. In at least about 45% / 5-CIT. In another embodiment of the present invention, the serotonin reuptake inhibitor is present in an amount sufficient to inhibit dopamine reuptake. The content sufficient to inhibit dopamine reuptake is sufficient. Content of at least about 15% citrate is transferred from dopamine transporters, where " is sufficient to transfer at least about 15% of citrate from dopamine transporters. '' Means sufficient to transfer at least about 15% from all dopamine transporters Cardiac CIT content. For example, the hydrazones sufficient for dopamine reuptake inhibition may be sufficient to transfer about 15%, 16%, 17%, 18%, 19%, 20%, 21% from the dopamine transporter. %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, and 40% / 3-CIT content. When sertraline is used as a serotonin reuptake inhibitor, it is sufficient to remove sertraline from dopamine transporters. The content of CIT shifted by at least 15% is about 150 mg. Adhesion data are shown in Tables 1-3 herein. In cycles 1, 2, and 3, the treatment groups for each brain site shown in the table are statistically statistically significant There were significant differences (ρ < 0 · 040). For the midbrain and mesobrain, the average [⑴ 丨] & CIT adhesion of sertraline 25 mg and semaline 50 mg was significantly lower than placebo The average [123l] / 5-CIT combination. For the striatum, sertraline 25 ^: g and sertraline 50 mg average [1231] 95429.doc -33- 200526197 / 3-CIT adhesion is significantly higher than the placebo average [123l ] / 3-CIT bonding. There were no statistically significant periodic or carryover effects (p > 0.052). A comparison of treatments in consecutive random cycles 1, 2 and 3 is summarized in Table 1 below. Table 1: Overview of [123l] iS-CIT Adhesion Analysis for Cycles 1, 2, and 3 Site Treatment Test Reference Mean (LS Mean) Test Reference Difference 90% Confidence Limit, Lower Limit Upper Cerebral Sertraline 25 Mg placebo 0.91 1.49 -0.58 -1.03 -0.13 sertraline 50 mg placebo 0.60 1.49 -0.89 -1.34 -0.45 sertraline 25 mg placebo 1.91 3.42 -1.51 -2.23 -0.80 sheraline Sertraline 50 mg placebo 1.58 3.42 -1.84 -2.56 -1.13 Striatum sertraline 25 mg placebo 10.06 9.44 0.62 0.26 0.98 sertraline 50 mg placebo 9.83 9.44 0.39 0.03 0.75 For the comparison of cycles 1, 2, 3, and 4, there were statistically significant differences in the treatment groups at each site (p ^ O.007). For the midbrain and midbrain, the average [1231] / 3-CIT adhesion of sertraline 25 mg, sertraline 50 mg, and sertraline 150 mg was significantly lower than the placebo average [ml] Z3-CIT adhesion. For the striatum, the average [ml] / 5-CIT adhesion of sertraline 150 mg was significantly lower than the average [1231] / 5-CIT adhesion of placebo 95429.doc -34- 200526197. The minimum mean square of sertraline 25 mg and sertraline 50 mg was greater than the mean of placebo, but these differences were not statistically significant. A comparison of treatments in consecutive random cycles 1, 2, 3 and 4 is summarized in Table 2 below. Table 2: Summary of [ml] / 3-CIT Adhesion Analysis for Cycles 1, 2, 3, and 4 90% Treatment Mean LS Mean Confidence Boundary Site Test Reference Test Reference Lower Difference Upper Limit Midbrain Sertraline Comfort Agent 0.93 1.45 -0.52 -0.84 -0.20 25 mg sertraline placebo 0.63 1.45 -0.82 -1.14 -0.50 50 mg sertraline placebo 0.77 1.45 -0.68 -0.99 -0.36 150 mg mesobrain Sertraline placebo 1.88 3.23 -1.35 -1.97 -0.72 25 mg sertraline placebo 1.80 3.23 -1.43 -2.05 -0.80 50 mg sertraline placebo 1.62 3.23 -1.60 -2.23- 0.98 150 mg striatum sertraline placebo 10.04 9.32 0.72 -0.16 1.60 25 mg sertraline placebo 9.97 9.32 0.64 -0.23 1.52 50 mg sertraline placebo 8.17 9.32 -1.15 -2.03 -0.28 150 mg 95429.doc -35- 200526197 Table 3 shows the average adhesion and metastasis in the midbrain, mesencephalon, and striatum based on the images collected by Prism-XP camera [1231] / 5-CIT Minute . These data indicate that sertraline binds to the dopamine transporter at 150 mg. Table 3: Median, mesencephalic, and striatum based on images collected by Px * ism-XP cameras [1231] iS-CIT Mean Adhesion and Metastasis Average Percent Object Number = 6 Sertraline Baseline Placebo 25 mg 50 mg 150 mg Midbrain mean soil standard 1.65 soil 0.39 standard deviation 1.45 ± 0.38 0.93 soil 0.64 0.63 ± 0.36 0.77 ± 0.31 transfer mean percentage-percent soil standard deviation -46.06 soil 26.72 -61.17 soil 24.78 -53.69 ± 10.89 Average number of soil standard 3.28 ± 0.96 standard deviation 3.23 ± 1 +1 1.88 ± 1.4 1.8 ± 0.45 1.62 ± 0.71 transfer average percentage-percentage of soil SD-46.29 ± 23.97-44.12 ± 9.23-49.41 ± 16.02 ± average of striatum 9.79 ± 3.48 standard deviation 9.32 ± 3.48 10.04 ± 3.85 9.97 ± 3.3 8.17 ± 2.66 shifted average percent-percent standard deviation 2.4 ± 6.81 2.66 ± 7.4 -15.27 ± 14.5 Baseline = value at day 0. Percent transfer is based on baseline values. In order to treat the above-mentioned conditions, a typical daily dose of blood in a pharmaceutical composition of the present invention for oral administration, parenteral, rectal or oral administration of 95429.doc -36- 200526197 in the present invention is an inhibitor per unit dose. Re-ingestion of piroxine 1-3 times the unit dose of mg to about 300 mg of the mother's early dose of 25 about 200 mg of shequ enchanting 夂 @ 仏 is 50 grams to "position two .: Early dose Each day can be administered, such as 13-earth stagnation agent ^, or, for example, per unit to 3-person Guxi, Ding m. W, for 5 spoons to about 80 mg of fluoxetin / Ding (fl Etlne), preferably the unit dose of York, can be administered per day such as 4 ^, scoop of 40 grams of ranoxetine each time, for example, 1 to 3 times the unit dose · The unit dose is about 50 Kui * $ ^ For example, mother pen grams to about 300 milligrams * fluvoxamine, preferably] 〇 古 * 々 明 叫叫 — is 1 (^ grams to fan milligrams of fluvoxamine per unit dose ϊ, can be administered on mother's day For example, 丨 3 times the unit dose;: The dose is about 5 mg to about 30 gugu alfalfa s 1. The mother unit brother, Li 30 gram of escitalopram, preferably gram to 20 mg exazep oxalate ^, ^ sunlan, can be administered as a tincture on the mother's day; or, for example, about 10 mg to about 60 mg of citalopram per unit dose, Jiajia mg to about 40 mg of citalopram, each It can be administered, for example, a human, early-dose dose, or, for example, about 10 mg to about 50 mg of paroxetine per unit dose, preferably about 10 mg to about 40 mg of paroxetine. The unit dose is 1 to 3 times. For the treatment of the above-mentioned conditions, a demonstration day for a general adult taking orally, parenterally, rectum, or the medicine composition of the present invention once a month is a demonstration day ^ The dose (where the dose is sufficient for dopamine reuptake inhibition) is $ 150 mg per unit dose or more than 150 mg of serotonin reuptake inhibition ^ Sertraline is used as a serotonin reuptake inhibitor per right The exemplary amount of reuptake inhibition of the foot, prescription, and Xiba edition is about 95429.doc -37- 200526197 150 per unit dose per day, 160, 170, 180, 190, 200, 210, 220, 230, 240,

250, 260, 270, 280, 290, 300, 310, 320, 330, 340 & 350 mg. As another example, the amount of sertraline sufficient to inhibit reuptake with dopamine is about 150 mg to about 350 mg, about 150 mg to about 200 mg, about 170 mg to about 340 mg, and about 190 mg to about 3 30 mg, about 200 mg to about 310 mg, about 210 mg to about 300 mg, about 220 mg to about 290 mg, about 230 mg to about 280 mg, about 240 mg to about 270 mg, about 240 mg to about 250 Mg, about 250 mg to about 260 mg, about 260 mg to about 270 mg, about 270 mg to about 280 mg, about 280 mg to about 290 mg, and about 290 mg to about 300 mg.

In order to treat the above-mentioned conditions, an exemplary adrenaline reuptake inhibitor in an oral, parenteral, rectal, orally administered pharmaceutical composition of the present invention for an average adult is about 1 to 300 mg of adrenaline per unit dose # Uptake inhibitors, for example, per unit dose is about! Mg to 30 mg of reboxetine 'is preferably about 4 mg to 16 mg of racemic reboxetine per unit dose' of Poxetine can be administered, for example, 1 to 3 times per unit dose. Another adrenergic reuptake inhibitor— * The daily dose is from about milligrams to about 15 milligrams [s, s] _reboxetine per unit. xetme), preferably ^ 2 mg to about 8 mg [Noriposacil unit dose, can be administered to China ^ 3 times a day. Another-no adrenaline reuptake inhibitor-the dosage is about ^ ^ ^ ^ level per unit dose, preferably fine milligrams to 275 milligrams: 3 grams of amosa

See Nezak Amosapine per unit dose, every B can be cast for example 1 to 3 times the unit dose. Epinephrine reuptake inhibitor 95429.doc -38- 200526197 II: Indicate that the dose is about 25 mg to about 2 per unit dose. . Mg of horse: "-50 mg to 150 mg of Mapotee can be administered on the mother's day, for example, to 3 times the unit dose. To treat the above-mentioned conditions, a combination of oral, parenteral, and oral administration for ordinary adults Demonstration agent for serum octagonin reuptake inhibitors in formulations * Weight photo: = 20% with Zhengxian upper gland, preferably from about 0.25 to about 2,5. · 005005 to about 8% In the illustrated exemplary embodiment, the amount of serum re-dose in the composition of the present invention is about 5% by weight of the total composition. _ 2 t about 5% to about 80% by weight of the total composition; and Invention: The amount of the norepinephrine reuptake inhibitor in the compound is based on the total composition weight Γ〇〇 / ^ 90 ％ 5 # ^ 1, 1 ^ ^ ^ .. 5〇 / 〇 ^ Inhibition The replacement of the agent and the adrenaline reuptake inhibitor is preferably 20: 1 to 1.20, and more preferably 10: 1 to 1: 1. Aerosol-knee combination formulations that are preferably configured for the treatment of conditions in mammals (eg, adults) such that each metered dose or "puff" aerosol contains: about 100 micrograms to About 30 micrograms of normal kidney ^ adenine reuptake, preferably from about 10 micrograms to about 丨 micrograms; and from about 1,000 micrograms to about 30, micrograms of serotonin again The uptake inhibition is preferably from about 5, _microgram to about 20, _microgram. It can be administered daily, such as 3, 4, or 8 times, and each administration such as 2 or 3 doses. One should understand that the present invention is not limited to the embodiments described herein. Those who have benefited from this article can make a lot of changes. These modifications should be included in the scope of the invention as set forth in the appended patent claims 95429.doc -39-

Claims (1)

200526197 10. Scope of patent application: κ-a method for treating disorders or conditions, which can be called 仏 仏 μ 失 δ cycle disease or condition can be transmitted by animal serotonin neurotransmission, mammalian adrenergic neurotransmission Or a combination thereof for treatment, Fu Yue adrenaline God called it to include the administration of mammals in need of this treatment. (1) at least one serotonin re ', ^ ^, uptake inhibitor or its pharmacologically acceptable, use Inhibition of dopamine reuptake; and n-adrepinephrine reuptake inhibitors or pharmaceutically acceptable salts thereof, wherein the n-adrenaline reuptake inhibitors are selected from the group consisting of the following compounds: (A) a Compounds of Formula II Formula II wherein η and 11! Are independently 1, 2 or 3; each R and Ri group may be the same or different ′ which are nitrogen, hydrogen, halogen-Ci-Cg alkyl, mesogen, Ci-C6 alkyl Oxy, optionally substituted alkyl or halogen-substituted alkyl, optionally substituted CrQ alkyl or halogen-substituted aryl-c] -c6 alkyl, optionally substituted with Cl-C6 alkyl or _ Oxy, -N〇2, -NR5R6, wherein R5 and R6 are independently hydrogen or CVC6 alkyl, or two adjacent 95429.doc 200526197 R groups or two adjacent R1 groups together form a -CH2-0- group Groups; A is hydrogen or OR2; R2 is hydrogen; optionally CVC12 ^ group substituted by CVC6 alkyl or oxine, or aryl-C ^ -Cg alkyl; each R3 and R4 groups may be the same or different, which Is fluorene, optionally substituted with Cl_c6 alkyl or halogen, "C6 alkyl, c2-C4 alkenyl, C2-C4 alkynyl, optionally aromatic substituted with CrC6 alkyl or halogen * _Ci-C4 alkyl, In the case of CyC7 cycloalkyl substituted with CrC6 alkyl or halogen, or R3 and R4 form a five-membered or six-membered, saturated or unsaturated, optionally substituted with 6-alkyl or halogen Heteromonocyclic group Other conditions selected from the group comprising a square, a heteroatom of the group consisting of S and N; R and R, or - together form a -CH2-CH2- group; (B) - in the compound having the formula Where D is _CR9, where R9 is nitrogen, optionally substituted by a radical or halide, c: -c6 alkyl, c2_C4 fluorenyl, c alkyl, optionally substituted by an alkyl group or a halogenated aryl_ Ci-C4 alkyl, or optionally CrC7 cycloalkyl substituted with [ΙΑ alkyl or halogen; 0] is 1 ^ 117118, wherein each of R7 and R8 is independently hydrogen, and optionally substituted with CrC6 alkyl or halide Ci-C6 95429.doc 200526197 alkyl, CrC4 alkenyl, eve: 4 alkynyl, optionally aryl-C ^ C: 4 alkyl substituted with Cl-C6 alkyl or halogen, or optionally alkyl Or halogen-substituted CrC7 cycloalkyl; or R7 & R8 together with the nitrogen atom to which it is bonded form a five-membered or six-membered, saturated or unsaturated, optionally substituted by c〗 -c6 alkyl or halogen heterocyclic ring A group, which optionally contains one or more additional heteroatoms selected from the group consisting of 0, s, and N; the bond between D and the ring slave bonded to G is a single or double bond And J is 0 or L, where L is C Ir3r4, wherein the bond between the ring carbon of L and the carbon atom bonded to LtM is a single or double bond, and M is a Cn extended alkyl chain, where n intervenes Between 1 and 3; and each R13 And R14 is independently hydrogen, optionally substituted by Ci_c ^ alkyl or halogen (^ (: substituted by carbyl, C2-C4 alkenyl, c2-C4 alkynyl, optionally substituted by c, c6 alkyl or halogen Aryl-Cl-C4 alkyl, optionally CrC7 cycloalkyl substituted with Ci_c6 alkyl or carbon; 4Ri3 & Ru together with the nitrogen atom to which it is bonded form a five or six member, saturated or unsaturated, Optionally a heteromonocyclic group substituted with a Crq alkyl group or a functional element, the group optionally containing one or more additional heteroatoms selected from the group consisting of 0, s, and N; and (c) —having the formula Compound of IV: 95429.doc 200526197 Η24 Formula IV where M is a Cn alkynyl bond, where η is between 1 and 3; and each of r2 3 and R is independently hydrogen, optionally substituted by C1-C6 alkynyl or halogen ^ 1 _ pinane Group, CrC4 alkenyl group, CrC4 alkynyl group, aryl-CrC4 alkyl group optionally substituted with € 1 _ (: 6 alkyl or halogen, C3_C7 cycloalkyl group optionally substituted with c] _c0 alkyl or halogen; or R23 And R24 together with the nitrogen atom to which it is bonded form a five-membered or six-membered, saturated or unsaturated, optionally substituted by alkyl or halogen heterocyclic ring group, the group optionally contains one or more additional options A heteroatom of the group consisting of 0, S and N. 2. A method for treating depression in a mammal, which comprises administering to a mammal in need of the treatment ... at least one serotonin reuptake inhibitor or A pharmaceutically acceptable salt thereof is present in an amount sufficient to inhibit dopamine reuptake and (ii) at least one ortho-adrenaline reuptake inhibitor or a medically acceptable salt thereof, wherein the ortho-adrenaline re-uptake inhibitor The uptake inhibitor is selected from the group consisting of the following compounds (A)-a compound having formula II 95429.doc 200526197 (R) n Ιβ3 1 R4 Formula II wherein n and ni are independently 1, 2 or 3; each R and R1 group may be the same or different, and they are hydrogen, halogen, halo-Ci-C6 alkyl, meridian, CVC6 ^ Oxy, CrC6 alkyl optionally substituted with CrG alkyl or halogen, aryl-C! -C6 alkyl optionally substituted with alkyl or halogen, aryl optionally substituted with CVC6 alkyl or halogen- CVC6 alkoxy, · NO2, -NR5R6, where R5 and R6 are independently hydrogen or CVC6 alkyl, or two adjacent R groups or two adjacent R1 groups together form the one 0-CH2-0- group ; A is hydrogen or OR2; R2 is hydrogen; optionally C1-C6 alkyl or halogen-substituted C! -C12 alkyl, or arylalkyl; each R3 and R4 groups may be the same or different氲, CrC6 alkyl, C2_C4 fluorenyl, C2-C4 alkynyl, optionally substituted with c] -C6 alkyl or halogen-substituted aryl-Cl_C4 alkyl, optionally substituted with Cl_c6 alkyl or halogen, optionally CpC: C6 alkyl or halogen substituted CpC: 7 cycloalkyl, or R3 and R4 and the nitrogen atom to which they are bonded form a five-membered or six-membered, saturated or unsaturated, optionally C] -C6 alkyl Heterocyclic ring This group optionally contains heteroatoms case 95429.doc 200526197 group consisting of selected from the group consisting of the other square, S and N; or R2 and R4- from _CH2-CH2- group form; (B) - a compound having the formula ΙΠ Where D is N or CR9, where R9 is hydrogen, optionally substituted with (^ _ (: 6 alkyl or peptin-substituted d-alkyl), cvc: 4 alkenyl, C2_C4 alkynyl, or optionally CVCW group or Aryl_Ci_C4 alkyl substituted with a functional element, or ere? Cycloalkyl substituted with alkyl or halogen as appropriate; (} is] ^ 7118, where each of R7 and R8 is independently hydrogen, and optionally Ci_C6 alkyl Alkyl or sulfan-substituted alkyl, c2-c4 alkenyl, c2_c4 block, aryl-c, -C4 alkyl substituted with Ci_C6 ^ group or dentin, or Ci_C6 alkyl or octyl group as appropriate Substituted C3-C7 ring alkyl groups; together with the nitrogen atom to which they are bonded-a five-membered or six-membered, saturated or unsaturated, optionally a heterocyclic ring group substituted with a radical or a halo, the group optionally Contains—or multiple members selected externally from 0, S, and N and 4; ^ 6: heteroatoms formed by js 7; the bond between D and the ring carbon bonded to G is single Bond or double bond; 0 or [, where [is 95429.doc 200526197 c \ Μ NR3R4 where the bond between the ring carbon in L and the carbon atom bonded to M in L is a single or double bond , M is a cn-expansion group, where η Between 1 and 3; and each of R13 and R14 is independently hydrogen, optionally substituted by Ci-C ^ alkyl or _C, 1 C6 ^, c2_c4 alkenyl, CrC4 alkynyl, and optionally CrQ Alkyl or halogen-substituted aryl_Ci_C4 alkyl, optionally 4 < 7 cycloalkyl substituted with alkyl or halogen; or R13 and R14 together with the nitrogen atom to which they are bonded form a five or six member, A saturated or unsaturated heteromonocyclic group optionally substituted with an alkyl group or a hydrogen atom, the group optionally containing one or more heteroatoms additionally selected from the group consisting of 0, S, and N; and (c ) A compound having formula IV: In M, M is a Cj alkyl group, where n is between; and each of R23 and R24 is independently hydrogen, and optionally Ci_C6 95429.doc -7- 200526197 alkyl, (VC4 alkenyl, CrC4 alkynyl, optionally substituted by (3) -0: 6 alkyl or halogen-CrCU alkyl, CyC: 7 cycloalkyl optionally substituted by Cj-Cs alkyl or halogen Or R23 and R24 together with the nitrogen atom to which they are bonded form a five-membered or six-membered, saturated or unsaturated, optionally substituted by Cl-c6 alkyl or halogen heterocyclic ring group, the group optionally contains One or more additional heteroatoms selected from the group consisting of 0, S, and N. 3. The method of claim 2, wherein the disorder or condition is depression, which is selected from the group consisting of depression in patients with Parkinson's disease, Depression after myocardial infarction, depression in human immunodeficiency virus (HIV) patients, sub-syndrome depression, depression in infertile women, child depression, major depression, single episode depression, recurrent depression, child abuse Depression caused, postpartum depression, DSM-IV major depression, difficult to treat severe depression Depression, major depression, psychotic depression, post-stroke depression, neuropathic pain, bipolar depression, mixed episode bipolar disorder, depressive episode bipolar depression BP I, bipolar depression Βρπ, depression and severe Depression consisting of mental depression. 4. The method of claim 2, wherein the serotonin reuptake inhibitor is sertrahne, which is present in an amount sufficient for dopamine re-production. 5. If requested, The method of 2, wherein the orthrenin reuptake inhibitor ^ is pharmaceutically acceptable and contains 1 such that all ortho kidneys are M transporters with at least 50. 乂 > t Dou Gan ο occupancy rate And the inhibition of serotonin reuptake Qi or its western pharmacologically acceptable _ in the presence of the phoenix contains SPECT imaging split "is sufficient to replace at least about 45% of the serotonin transporter 3_cit. 95429.doc 200526197 6 · = The method of item 2, wherein the oradrenaline reuptake inhibitor or tincture or a pharmaceutically acceptable salt is present in an amount such that all orthoadrenaline transporters have a prevalence of at least 75%. Yueyue East 2 A method, wherein the serotonin reuptake inhibitor and the orangrel adrenaline reuptake inhibitor are administered together in a pharmaceutical composition. 8: Qiu: Method of member 2, wherein the orrepinephrine reuptake inhibitor is, ] ， 波西 ，; 丁 ⑽〇xetlne), which is about 1. to about 15 milligrams [S, S] -Ribobozhi—or multiple unit doses per unit 2. 9. As requested item 2 Xi Shi "+4+", "The adrenaline reuptake inhibitor is Luzhiboxijiang, which contains about-per unit dose! Up to about 15 grams of racemic reboxetine—or multiple unit doses. 10.:!ί The method of item 2, wherein the serotonin reuptake inhibitor is sertraline or a pharmaceutically acceptable salt thereof; the adrenal = tongue flexor is [s, S] -Ribo ... its medicine Academically acceptable salt, heart: t is present in an amount sufficient to inhibit dopamine reuptake, wherein sertraline contains about 150 mg to about 200 mg. η.-A method for treating mammalian disorders or disorders, the disorders are selected from the group consisting of neurological disorders, chronic chronic depression, acute chronic depression, muscle fiber pain, == painful depression, obesity, Migraine, a group consisting of diabetes and diabetes: This method involves administering mammals in need of this treatment: ⑴ At least-a serotonin reuptake inhibitor or a pharmaceutically acceptable salt of $ 95429.doc 200526197, The at least one serotonin reuptake inhibitor is selected from the group consisting of sertraline, fiuoxetine, and fluvoxamine; and (ii) at least one adrenaline reuptake inhibitor Agent or a pharmaceutically acceptable salt thereof, wherein the at least-norepinephrine reuptake inhibition: is selected from the group consisting of racemic ribosporine, duraparic juice, amoxapine (am0xapine), and mapplet ( The group consisting of mapr〇tili_. 12. The method of pursuing immortality, wherein the serotonin reuptake inhibitor is sertraline, which is present in an amount sufficient to inhibit dopamine reuptake. This composition is basically a system , ^-口-w, sister Take 〇) at least-a serotonin reuptake inhibitor or a pharmaceutically acceptable salt thereof, wherein f at least one serotonin reuptake inhibitor is sertraline, the amount ^ is used for dopamine reuptake inhibition; and ⑼ at least _ Positive kidney feeding; ^ inhibitor or a pharmaceutically acceptable salt thereof, wherein the at least _ positive "adenine reuptake inhibitor is [S, S] -reboxetine. 14, Li compound,, including sertraline or its pharmaceutically acceptable trips ^ As appropriate, selected from ^ by [s, s] -h Bosai Juice or its medicinally pleasing-, The adrenaline reuptake of Lin, and, and its pharmacologically acceptable sleep ... Ud reuptake inhibits existence ^ sufficient for dopa use 15. The composition of claim 14 from 150 mg to about 350 mg. The content of sertraline used ranges from about 95429.doc -10- 200526197 7. Designated representative map: (1) The designated representative map in this case is: (none) (II) The component symbols of this representative map are simply explained: When there is a chemical formula, please disclose the chemical formula that best shows the characteristics of the invention: (none) 95429.doc -5-