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(12) Patent Application Publication (10) Pub. No.: US 2004/0024038A1 Ebert Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2004/0024038A1 Ebert Et Al US 2004.0024.038A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0024038A1 Ebert et al. (43) Pub. Date: Feb. 5, 2004 (54) GABA ENHANCERS IN THE TREATMENT (30) Foreign Application Priority Data OF DISEASES RELATING TO REDUCED NEUROSTEROID ACTIVITY Nov. 20, 2000 (DK)................................ PA 2000 O1743 (75) Inventors: Bjarke Ebert, Farum (DK); Peter Hongaard Andersen, Vaerlose (DK) Publication Classification Correspondence Address: DARBY & DARBY PC. (51) Int. Cl." .................. A61K 31/4164; A61K 31/198; Post Office BOX 5257 A61K 31/195 New York, NY 10150-5257 (US) (73) Assignee: H. Lundbeck A/S, Valby-Copenhagen (52) U.S. Cl. ............................................ 514/396; 514/561 (DK) (21) Appl. No.: 10/430,704 (57) ABSTRACT (22) Filed: May 1, 2003 The invention provides the use of a non-Steroid compound Related U.S. Application Data which acts on the GABA receptor for the treatment of disorders relating to reduced neurosteroid activity. The non (63) Continuation of application No. PCT/DK01/00773, Steroid compounds may be GABA agonists, GABA uptake filed on Nov. 20, 2001. inhibitors or enhancers of GABAergic activity. US 2004/0024038A1 Feb. 5, 2004 GABA ENHANCERS IN THE TREATMENT OF modulators exhibit considerable side-effects. In relation to DISEASES RELATING TO REDUCED disorderS Such as anxiety and pre-menstrual dysphoric dis NEUROSTEROID ACTIVITY order modulation of the thalamic areas may play a key role. In these areas a high abundance of C. Bö/y containing 0001. This application is a continuation of International receptors are found, making interaction with these receptors Application No. PCT/DKO1/00773, filed Nov. 20, 2001. The particularly interesting. With the large density of C. con prior application is hereby incorporated by reference herein, taining receptors located extrasynaptically (Sur et al. Mol. in its entirety. Pharmacol. 1999, 56, 110-115; Sassoe-Pognetto et al. J 0002 The invention provides the use of non-steroid com Comp Neurol 2000, 15,420: 481-98; Mody, 2000, Presen pounds which are GABA agonists, GABA uptake inhibitors tation at GABA2000 meeting July 23 to July 29) only a or enhancers of GABAergic activity in the treatment of relatively low level of activation at the individual extrasyn disorders relating to reduced neurosteroid activity. aptic receptors will Sum up to a significant inhibition of the neurone, raising the possibility that highly functional Selec BACKGROUND OF THE INVENTION tive compounds can be developed for these receptors. 0.003 Receptors for the major inhibitory neurotransmit 0009. The ovarian hormone progesterone and its metabo ter, gammaaminobutyric acid (GABA), are divided into two lites have been demonstrated to have profound effects on main classes: GABAA receptors which are members of the brain excitability. The levels of progesterone and its metabo ligand gated ion channel Superfamily; and the GABA lites vary with the phases of the menstrual cycle. It has been receptors which are G-protein coupled receptorS. documented that progesterone and its metabolites decrease prior to the onset of menses. The monthly recurrence of 0004 GABAA receptors are formed as a pentameric certain physical Symptoms prior to the onset of menses has assembly of different families of receptor subunits. The also been well documented. These symptoms which have assembly, which in most receptors includes 2 C. Subunits, 2 been associated with premenstrual syndrome (PMS) or B Subunits and a Y or ö Subunit, determines the pharmacol premenstrual dysphoric disorder (PMDD) include stress, ogy of the functional receptor. The binding site for benzo anxiety, and migraine headaches. Patients Suffering from diazepines is located at the interface between the C. and Y PMS have a monthly recurrence of symptoms that are subunit, whereas the binding site for GABA and other present in premenses and absent in postmenses. In a similar GABA agonists is located at the interface between the C. and fashion, a reduction in progesterone has also been tempo B subunit. rally correlated with an increase in Seizure frequency in 0005 GABA receptor assemblies which do exist female epileptics. A more direct correlation has been include, amongst many others, C. BY2, C. Bay, CB23, observed with a reduction in progesterone metabolites. In Os?i-Y22, CfBY2 CfBö, CfBö and C.f32y2. Subtypes contain addition, for patients with primarily generalized petit mal ing the C. Subunit are present in most brain regions and may epilepsy, the temporal incidences of Seizures have been contribute to the functional action of a number of benzodi correlated with the incidence of the symptoms of PMS. aZepines. 0010) A syndrome also related to low progesterone levels 0006. In a number of clinical conditions, hypoactivity of is postnatal depression (PND). Immediately after delivery, the inhibitory GABA system has been hypothesised as the progesterone levels decrease dramatically leading to the underlying mechanism of the pathology in question. These onset of PND. The symptoms of PND range from mild conditions include epilepsy, anxiety, StreSS, Sleep disorders depression to psychosis requiring hospitalization. PND is and pain. However, although positive modulators of the also associated with severe anxiety and irritability. PND GABA receptor complex, such as benzodiazepines, in a asSociated depression is amenable to treatment by classical number of circumstances are very effective, there is a antidepressants and women experiencing PND Show an general consensus that unselective benzodiazepines produce increased incidence of PMS. So many Side effects that compounds Substituting for pres 0.011 Premenstrual dysphoric disorder (PMDD) is ently used drugs are needed (Costa and Guidotto Trends thought to be a consequence of the rapid drop in progest Pharmacol. Sci. 1996, 17, 192-200). erone levels, and especially progesterone metabolites, which 0007 The C. containing receptors exist predominantly in act as positive modulators of the GABAergic activity (Gallo the thalamic area (Sur et al. 1999). Recent studies (Sassoe and Smith, 1993 Pharmacol. Biochem. Behav. 46, 897-904). Pognetto et al. J Comp Neurol 2000, 15,420: 481-98; Mody, 2000, Presentation at GABA2000 meeting July 23 to July 0012. The effect of the neuroactive steroids with direct 29.) have indicated that some of these receptors may be effect at the GABAA receptor has been investigated. located extrasynaptically, making them a potentially very Although neurosteroids like alfaxalone and 3C-5C.-dihy interesting drug target. droxyprogesterone are interacting with all types of GABA receptors, data with CBö containing receptors indicate that 0008. There are differences between benzodiazepines and the potency and efficacy at the receptors are higher than at GABA agonists. One is that benzodiazepines are inactive at other types of GABAA receptors. Neurosteroids have been C. and ö containing receptors, whereas GABAA agonists developed for the treatment of PMDD and other indications, will act irrespective of the Subunit composition (e.g. Ebert et however side effects have resulted in discontinuation of al. Mol. Pharmacol. 1997, 52, 1150-1156). Another, that the most of these compounds. Further, a Series of Studies have benzodiazepines react at a specific Site at the GABA com shown that prolonged application of neurosteroids as hyp plex, thereby causing the GABA receptor to undergo an notics results in compensatory mechanisms which ulti allosteric change which influences the efficacy of GABA in mately lead to dependence (Lancel et al. J. Pharmacol. Exp. promoting chloride channel opening. The GABA receptor Ther: 1997, 282, 1213-1218). US 2004/0024038A1 Feb. 5, 2004 0013 The present invention provides non-steroid com 0025. In a preferred embodiment of the invention, the pounds interacting directly with the recognition Site at the disease or disorder results from a decline in the neurosteroid GABA receptor as agonists or GABA uptake inhibitors or level. as enhancers of GABAergic activity, which all have benefi cial effects in disease States relating to reduced neuroStor 0026. In one specific embodiment of the invention, the oidal activation. disease or disorder results from recurrent periodical decline in the neurosteroid level. 0.014. The diseases, including premenstrual syndrome, postnatal depression and post menopausal related dysphoric 0027. In another specific embodiment of the invention, disorders, are significantly better treated with GABAA ago the disease or disorder results from extraordinary decline in nists and GABA uptake inhibitors or enchancers of the neurosteroid level. GABAergic activity than with benzodiazepines and neuro 0028. In a further specific embodiment of the invention, Steroids which produce tolerance after short term treatment. the disease or disorder results from age-related decline in the 0.015 The present invention also provides specific non neurosteroid level. allosteric GABA agonistic compounds useful for the treat 0029. In a preferred embodiment of the invention, the ment of the disorders relating to reduced neurosteroid acti neurosteroid is progesterone. Vation. The compounds are known as useful in the treatment of other diseases and disorders. 0030. In a more preferred embodiment of the invention, the neurosteroid is a metabolite of progesterone. DETAILED DESCRIPTION OF THE 0031. In a preferred embodiment of the invention, the INVENTION disease or disorder is premenstrual disorder, postnatal 0016. The invention is directed to treatment
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