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WO 2013/167906 Al 14 November 2013 (14.11.2013) P O P C T

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WO 2013/167906 Al 14 November 2013 (14.11.2013) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2013/167906 Al 14 November 2013 (14.11.2013) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/554 (2006.01) A61K 31/485 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 45/06 (2006.01) A61P 11/00 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (21) International Application Number: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, PCT/GB2013/051213 NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, (22) International Filing Date: RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, 10 May 2013 (10.05.2013) TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 1208315.0 11 May 2012 ( 11.05.2012) GB UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (71) Applicant: NUMEDICUS LIMITED [GB/GB]; 5 Ten- EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, ison Avenue, Cambridge, Cambridgeshire CB1 2DX (GB). MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (72) Inventor; and ML, MR, NE, SN, TD, TG). (71) Applicant (for US only): CAVALLA, David [GB/GB]; 5 Tenison Avenue, Cambridge, Cambridgeshire CB1 2DX Published: (GB). — with international search report (Art. 21(3)) (74) Agent: FRITH, Richard; Alchemie IP, 6 Lombard Street, — before the expiration of the time limit for amending the Abingdon, Oxfordshire OX14 5BJ (GB). claims and to be republished in the event of receipt of (81) Designated States (unless otherwise indicated, for every amendments (Rule 48.2(h)) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (54) Title: TREATMENT OF RESPIRATORY DEPRESSION (57) Abstract: Tricyclic dibenzothiazepine compounds for use in the treatment of respiratory depression. TREATMENT OF RESPIRATORY DEPRESSION The present invention relates to tricyclic dibenzothiazepine type compounds for use in the treatment of respiratory depression in a subject (i.e. a mammal such as an animal or human, especially a human) as a result of a medical condition or pharmacological agents such as opiates, opioids or barbiturates. In particular, although not exclusively, the present invention relates to a alleviating respiratory depression with l- yl)amino]heptanoic acid S,S-dioxide (tianeptine) and or its MC5 metabolite (7-[(3-chloro-6,l'-dihydro-6- methyl-dibenzo[c,fJfl,2]thiazepin-l l-yl)amino]pentanoic acid S,S-dioxide) in a subject as a result of a medical condition or pharmacological agents such as opiates, opioids or barbiturates. Additionally, the present invention relates to pharmaceutical compositions including tricyclic dibenzothiazepine type compounds and the use of such compositions as a medicament, particularly a human medicament. Tianeptine, as depicted below, is originally described in French patent 2,104,728 and has been reported that it may be used in the treatment of neurodegenerative pathologies, neuropathic pain, fibromyalgia, chronic fatigue syndrome and irritable bowel syndrome. Opiates are known to reduce respiratory rate and inspirational volume, as well as reduce sensitivity to C0 ; µ- and δ-opioid receptors as well as their endogenous ligands are present in essentially all respiratory regions of the pons and medulla. Exogenous application of opioids has also been shown both in vivo and in vitro to depress inspiratory and expiratory neuronal activity. Because opiates depress breathing, their use is contraindicated in many instances, especially in patients with compromised cardiovascular and pulmonary function. Respiratory depression, otherwise known as respiratory insufficiency or hypoventilation, is often a limiting factor in the degree of analgesia that a patient may receive. Thus, there is an outstanding need to produce the analgesia of the opiates and opioids, without depressing the respiratory function of the patient. In addition to the disturbance of respiratory rhythm as a result of drugs, abnormalities as a consequence of a medical condition, such as hypoventilation in association with obesity or irregular breathing during sleep, are also increasingly recognized clinically as potentially having serious health consequences. One of the most common physiological conditions involving disturbance of respiratory rhythm is sleep apnea, which may be of an obstructive, central or mixed pathophysiology. Obstructive sleep apnea (OSA) primarily involves the loss of tone in the genioglossus muscle of the tongue, which is innervated by the hypoglossal nerve, causing sufferers to stop breathing (apnea), often hundreds of times per night and sometimes for a minute or longer. As many as 20% of adults have at least mild OSA, and at least 2% of women and 4% of men have moderate to severe OSA. OSA is associated with a variety of health risks, such as central hypoxia, which leads to activation of the sympathetic nervous system, resulting in acute hypertension and tachycardia; it can also lead to sleep arousal and poor sleep quality, resulting in daytime fatigue, potentially with serious consequences, such as falling asleep while driving. Chronically, repeated hypoxia and spiking blood pressure cause increased propensity for neurocognitive impairment, hypertension, myocardial infarction and stroke. Chronic snoring is another sleep disorder which often predicts the development of OSA. In central sleep apnea, the brain's respiratory control centers are unbalanced during sleep, and commonly patients with this condition repeatedly stop breathing during sleep. A form of central sleep apnea commonly occurs in people with congestive heart failure. Obesity hypoventilation syndrome (OHS), also known as Pickwickian syndrome, is an under-recognised condition related to, but also potentially occurring separately from, OSA. Its origin has been hypothesised to involve problems in mobilizing the chest wall and diaphragm, leading to ineffective gas exchange, and consequent low levels of blood oxygen saturation, with concomitant high levels of blood C0 2. Patients with sleep apnea or snoring may be provided with machines providing continuous positive airway pressure (CPAP), intrusive dental appliances, or reconstructive surgery to reshape the patient's upper airway to reduce obstructions. However, CPAP and appliances typically have a low level of patient compliance, and surgery is often ineffective in the long term. Treatment for OHS also involves mechanical ventilation (e.g. BiPAP), but this is also not entirely satisfactory and is associated with low levels of patient compliance. It is also important to recognise that patients using opioids are at risk for disorders of breathing during sleep including central and obstructive apneas, hypopneas, ataxic breathing and non- apneic hypoxemia. Accordingly, there is a need to reduce, inhibit or prevent respiratory depression in a subject which may result as a result of drug administration or due to abnormalities as a consequence of a medical condition. According to a first aspect, the present invention provides a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity or a pharmaceutical or veterinary composition containing any of the foregoing for use in the treatment of respiratory depression in a subject (i.e. mammal such as an animal or human, e rmula (I) comprises: (I) wherein: R and R each independently represent, at each occurrence when used herein, H or C to C alkyl; R and R each independently represent, at each occurrence when used herein, H or halo; R4 represents H or C to C alk l and, is an integer of 2 to 1 inclusive. By the term "treatment" or "treating" as used herein, we include both therapeutic (curative), palliative and prophylactic treatment. Suitably, the treatment of respiratory depression is accomplished by administration of a therapeutically effective amount of a compound of formula (I), or a pharmacologically active metabolite thereof, or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity or a pharmaceutical or veterinary composition containing any of the foregoing to the subject. The term "effective amount" or "therapeutically effective amount" as used herein refers to the amount or dosage of an agent sufficient to effectuate a desired therapeutic effect. Such amount may vary depending on the effect to be achieved, the agent used and the body weight of the subject. Typically, a therapeutically effective amount of a compound of formula (I), or a pharmacologically active metabolite thereof, or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity to be administered is 2 to about 600 mg/day, preferably from about 5 to about 400 g day, and more preferably about 10 to 300 mg day. Preferably, R in a compound of formula (I) represents C to C alkyl, more preferably, R represents C \ to C alkyl, even more preferably linear Cj to C alkyl. Most preferably, R represents a methyl group. Preferably, R2 in a compound of formula (I) is H, fluoro or chloro, more preferably H or chloro. Most preferably, R2 is chloro. Preferably, R n a compound of formula (I) represents H or Ci to C alkyl. More preferably, R represents H or linear Ci to C alkyl.
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