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(12) Patent Application Publication (10) Pub. No.: US 2005/0096395A1 Rao Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2005/0096395A1 Rao Et Al US 20050096395A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0096395A1 Rao et al. (43) Pub. Date: May 5, 2005 (54) METHODS OF TREATING ATTENTION Publication Classification DEFICIT/HYPERACTIVITY DISORDER (ADHD) (51) Int. Cl." ............................................ A61K 31/137 (76) Inventors: Srinivas G Rao, Encinitas, CA (US); Jay D. Kranzler, La Jolla, CA (US) (52) U.S. Cl. .............................................................. 514/649 Correspondence Address: DARBY & DARBY PC. P. O. BOX 5257 (57) ABSTRACT NEW YORK, NY 10150-5257 (US) The present invention provides a method of treating atten (21) Appl. No.: 10/504,435 tion deficit/hyperactivity disorder (AD/HD) and associated tic disorders in an animal Subject comprising administering (22) PCT Filed: Feb. 12, 2003 an effective amount of an anti-AD/HD compound or a (86) PCT No.: PCT/US03/04095 pharmaceutically acceptable salt thereof. The anti-AD/HD compound useful in the present invention is characterized by Related U.S. Application Data ant-AD/HD and anti-tic properties and exhibits at least two distinct pharmacological activities. In particular, the use of (60) Provisional application No. 60/356,688, filed on Feb. milnacipran to treat AD/HD and comorbid tic and psychi 12, 2002. atric disorders is disclosed. US 2005/0096395 A1 May 5, 2005 METHODS OF TREATING ATTENTION positive effect on attention and hyperactivity Symptoms. DEFICIT/HYPERACTIVITY DISORDER (ADHD) However, the increased dopamine is also known to contrib ute to the pathophysiology of tics. Thus, the increased FIELD OF THE INVENTION dopamine can exacerbate an existing tic disorder or cause 0001. The present invention relates to methods for the the onset of tics in patients who previously did not exhibit treatment of attention deficit/hyperactivity disorder (AD/ any Symptoms of tic disorders. HD). In particular, AD/HD patients, with comorbid tic 0009. Although the drugs that act on the noradrenergic disorders, are treated with compounds that exhibit both System have a better Side effect profile compared to dopam anti-AD/HD and anti-tic properties. The compounds used in ine Stimulating drugs and are effective against tic disorders, the present invention exhibit these two properties in the this class of drugs is not particularly effective in improving Same molecule and are characterized by at least two distinct pharmacological activities. attention and/or hyperactivity Symptoms in AD/HD patients. 0010 Another drawback of the current treatments for BACKGROUND OF THE INVENTION AD/HD is that they are not particularly effective in treating 0002 Attention deficit/hyperactivity disorder (AD/HD) psychiatric disorders. Very often, AD/HD patients are diag is among the most common pSychiatric disorder in children, nosed with comorbid psychiatric disorders. In these patients, with prevalence estimated to be as high as 3-7% in School the current therapy is often Supplemented with anti-depres age children. The disorder is more common in boys than in Sants to treat the comorbid psychiatric disorders. The addi girls, and often improves over time. However, a significant tion of another therapeutic agent into the patient's treatment number of adults are affected as well. regimen increases the risk of development of Side effects and decreaseS patient compliance. 0003. It is widely believed that AD/HD is caused by defects in dopamine transmission, particularly in the 0011. Due to the reasons presented above, there is a meSolimbic and cortical areas that are involved in attention, demand for more effective agents to treat AD/HD patients, persistence, and control. Neuroimaging Studies also Suggest and in particular those who Suffer from associated psychi that Structural and functional changes in the cortical or atric and tic disorders. The ideal agent would treat the limbic regions contribute to the pathophysiology of AD/HD. underlying disorder and/or reduce the Symptoms associated 0004 Hence, strategies for treating AD/HD are directed with AD/HD and comorbid psychiatric and tic disorders, act primarily at increasing the amount of dopamine within the Satisfactorily whether given orally or parenterally, and pro brain. The most widely used drugs include methylphenidate duce minimal or no side effects. (Ritalin, Concerta), dextroamphetamine and amphetamine Salts (Dexedrine, Adderall, Attendaid), and pemoline SUMMARY OF THE INVENTION (Cylert). All these drugs act by increasing dopamine within the Synapse by blocking the dopamine transporter and/or by 0012. In one aspect, the invention provides a method of causing the release of dopamine from the presynaptic ter treating attention deficit/hyperactivity disorder (AD/HD) and optionally tic disorders associated with AD/HD in an minal. animal Subject including a human. The method generally 0005. A second treatment strategy utilizes drugs that act involves administering to an animal Subject Suffering from on the noradrenergic System. Two Such drugs, clonidine AD/HD and comorbid tic disorders an effective amount of (Catapres) and guanfacine (Tenex) are agonists of the C2 an anti-AD/HD compound or a pharmaceutically acceptable adrenergic receptors, the receptor thought to be involved in salt thereof. The anti-AD/HD compounds that are useful in the cognitive effects of norepinephrine (NE). the present invention are characterized by anti-AD/HD and 0006 Other agents, such as buproprion, which is thought anti-tic properties and exhibit at least two distinct pharma to increase both dopamine and NE mediated neurotransmis cological activities. sion, and venlafaxine (Effexor) which blocks reuptake of 0013 The invention also provides a method of treating Serotonin and norepinephrine, have also been used (Adler et attention deficit/hyperactivity disorder (AD/HD) and option al., 1995, Psychopharmacol Bull, 31: 785-8 and Olevera et ally tic disorders associated with AD/HD involving the al., 1996, J Child Adolesc psychopharmacol, 6: 241-50). administration to an animal subject suffering from AD/HD 0007. The positive effects on attention produced by and optionally comorbid tic disorders an effective amount of dopamine Stimulating drugs are not observed in all patients. an anti-AD/HD (zDA, NE) compound or a pharmaceutically In addition, these drugs produce Serious Side effects in Some acceptable salt thereof. The anti-AD/HD (zDA, NE) com patients. For example, these drugs can cause insomnia and pounds that are useful in the present invention are charac appetite reduction, and hence are contraindicated in patients terized by anti-AD/HD and anti-tic properties, at least two with a history of eating disorders. Patients taking these drugs distinct pharmacological activities, and the lack of both can also experience a withdrawal or rebound reaction at the dopamine and norepinephrine Stimulating activities in the end of the day, when blood levels drop. Moreover, since Same molecule. these drugs can be abused, they are not typically used in 0014) Another aspect of the invention provides a method patients with an history of illicit drug use. of treating AD/HD and optionally tic disorders associated 0008. The use of dopamine stimulating drugs is highly with AD/HD involving the administration to an animal controversial in AD/HD patients with concomitant tic dis subject suffering from AD/HD and optionally comorbid tic orders or in patients at a risk of developing tic disorders. The disorders an effective amount of milnacipran or a pharma increase in dopamine caused by these drugs produces the ceutically acceptable Salt thereof. US 2005/0096395 A1 May 5, 2005 0.015. In yet another aspect, the invention provides a kit 0027. The term “alkyl refers to a monoradical branched comprising a compound useful in the present invention or unbranched Saturated hydrocarbon chain preferably hav packaged in association with instructions teaching a method ing from 1 to 40 carbon atoms, more preferably 1 to 10 of using the compound according to one or more of the carbon atoms, and even more preferably 1 to 6 carbon atoms. above-described methods. The kit can contain the compound This term is exemplified by groupS Such as methyl, ethyl, packaged in unit dosage form. In one embodiment, mil n-propyl, iso-propyl, n-butyl, iso-butyl, Sec-butyl, n-hexyl, nacipran or a pharmaceutically acceptable Salt thereof is n-decyl, tetradecyl, and the like. included in the kit. 0028. The alkyl can optionally be substituted with one or more alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, DETAILED DESCRIPTION OF THE heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbo PREFERRED EMBODIMENTS nyl, amino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alky 0016. Abbreviations lthio, alkylsulfinyl, alkylsulfonyl and cyano. 0017 AD/HD attention deficit/hyperactivity disorder 0029. The term “alkylene" refers to a diradical branched or unbranched Saturated hydrocarbon chain preferably hav 0018) AMPA alpha-amino-3-hydroxy-5-methylisox ing from 1 to 40 carbon atoms, more preferably 1 to 10 aZole-4-proprionic acid carbon atoms, and even more preferably 1 to 6 carbon atoms. This term is exemplified by groupS Such as methylene, 0019 GABA Y-aminobutyric acid ethylene, n-propylene, iso-propylene, n-butylene, iso-buty 0020 5-HT serotonin lene, Sec-butylene, n-hexylene, n-decylene, tetradecylene, and the like. 0021 NE norepinephrine 0030 The alkylene can optionally be substituted with one 0022 NMDA N-methyl D-aspartate or more alkoxy, halo, haloalkyl, hydroxy,
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