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(12) Patent Application Publication (10) Pub. No.: US 2006/0120972 A1 Engels Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2006/0120972 A1 Engels Et Al US 2006O120972A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0120972 A1 Engels et al. (43) Pub. Date: Jun. 8, 2006 (54) 9-(N-METHYL-PIPERIDYLIDEN-4)- Related U.S. Application Data THOXANTHENE FOR TREATMENT OF PULMONARY HYPERTENSION (60) Provisional application No. 60/626.249, filed on Nov. 9, 2004. (76) Inventors: Peter Engels, Gladbach (DE); Beate Publication Classification Schmitz, Koln (DE) (51) Int. Cl Correspondence Address: 3. if: 308: KNOBBE MARTENS OLSON & BEAR LLP A 6LX 9/70 (2006.015 2O4O MAN STREET A6IL 9/04 (2006.01) FOURTEENTH FLOOR (52) U.S. Cl. ............................. 424/46; 514/320: 424/449 IRVINE, CA 92614 (US) 57 ABSTRACT (21) Appl. No.: 11/255,567 (57) Pimethixene is used as a medicament for the treatment of (22) Filed: Oct. 21, 2005 pulmonary hypertension. US 2006/0120972 A1 Jun. 8, 2006 9-(N-METHYL-PIPERIDYLIDEN-4)- Additionally, current evidence strongly Supports a therapeu THOXANTHENE FOR TREATMENT OF tic role for selective 5-HT, receptor antagonists that will PULMONARY HYPERTENSION offer distinct therapeutic advantages collectively in efficacy, rapidity of onset and absence of side effects. Such agents are CROSS-REFERENCE TO RELATED expected to be useful in the treatment of hypertension, APPLICATION disorders of the gastrointestinal track (e.g., irritable bowel 0001. This application claims priority under 35 U.S.C. S syndrome, hypertonic lower esophageal sphincter, and 119(e) to U.S. Provisional Application No. 60/626.249, filed motility disorders), restenosis, asthma and obstructive air Nov. 9, 2004, which is entirely incorporated herein by way disease, and prostatic hyperplasia (e.g., benign prostatic reference. hyperplasia). 0008 EP 1270.568 and WO 03/35646 describe selective BACKGROUND OF THE INVENTION 5HT2B receptor antagonists which are derivatives of 4-(thio or selenoxanthene-9-ylidene)-piperidine or acridine having 0002) 1. Field of the Invention in any case several side groups in the aromatic ring system. 0003. The present invention relates to the use of 9-(N- 0009. The involvement of 5-HT receptor activation in the methyl-piperidyliden-4)-thioxanthene as a medicament for development of pulmonary hypertension has been described the treatment of diseases aggravated by increased levels of by M. MacLean in TiPS, vol. 20, pg. 490-495 (1999). 5-HT and mediated by 5HT receptors. However, in this review article, the disorder state is referred 0004 2. Description of the Related Art to activation of 5HT and 5HT2A receptors. 0005 Serotonin, a neurotransmitter with mixed and com 0010 J.-M. Launay et al. describe in Nature Medicine plex pharmacological characteristics, was first discovered in Vol. 8, No. 10 (2002), p. 1129-1135 that serotonin as well as 1948, and subsequently has been the subject of substantial other agonists of the 5-HT2B receptor Support the develop ment of pulmonary hypertension. Further, the study showed research. Serotonin, also referred to as 5-hydroxytryptamine that 5HT2B receptor expression is upregulated in pulmonary (5-HT), acts both centrally and peripherally on discrete hypertension. 5-HT receptors. Currently, fourteen subtypes of serotonin receptor are recognized and delineated into seven families, 0011 Pimethixene is the common name of 9-(N-methyl 5-HT, to 5-HT7. Within the 5-HT, family, 5-HT, A, 5-HT piperidyliden-4)-thioxanthene. Pimethixene was developed and 5-HT. Subtypes are known to exist. These subtypes in the 1960s and has been used for the treatment of sleep share sequence homology and display similarities in their disorders, hyperactivity, anxiety, allergy, as bronchodilator, specificity for a wide range of ligands. Nomenclature and and for anesthesia. classification of 5-HT receptors have been reviewed (see Martin and Humphrey, Neuropharm. 1994, 33, 261-273 and SUMMARY OF THE INVENTION Hoyer et al., Pharm. Rev. 1994, 46, 157-203). 0012 Preferred embodiments provide for a method of treating a disease aggravated by increased levels of 5-HT 0006 The 5-HT, receptor, initially termed 5-HT, or comprising administering to a Subject a compound accord serotonin receptor like (SRL), was first characterized in rat ing to the formula: isolated stomach fundus (see Clineschmidt et al., J. Phar macol. Exp. Ther. 1985, 235, 696–708; Cohen and Wit tenauer, J. Cardiovasc. Pharmacol. 1987, 10, 176-181) and initially cloned from rat (see Foguet et al., EMBO 1992, 11, 3481-3487) followed by the cloning of the human 5-HT, receptor (see Schmucket al., FEBS Lett. 1994, 342, 85-90; Kursar et al., Mol. Pharmacol. 1994, 46, 227-234). The closely related 5-HT, receptor, widely distributed in the human brain, was first characterized as a 5-HT Subtype (see Pazos et al., Eur. J. Pharmacol. 1984, 106,539-546) and was Subsequently recognized as belonging to the 5-HT receptor family (see Pritchett et al., EMBO J. 1988, 7. CH3 4135-4140). 0007 Because of the similarities in the pharmacology of or a pharmaceutically acceptable salt thereof. ligand interactions at 5-HTP and 5-HT2 receptors, many of the therapeutic targets that have been proposed for 5-HT DETAILED DESCRIPTION OF THE receptor antagonists are also targets for 5-HT, receptor PREFERRED EMBODIMENT antagonists. Current evidence strongly supports a therapeu tic role for 5-HT2 receptor antagonists in treating anxi 0013 The preferred embodiments provide a new medi ety (e.g., generalized anxiety disorder, panic disorder and cament comprising a compound effective for treatment of obsessive compulsive disorder), alcoholism and addiction to disease aggravated by increased levels of 5-HT in blood or other drugs of abuse, depression, migraine, steep disorders, blood vessels, such as, but not limited to, pulmonary hyper feeding disorders (e.g., anorexia nervosa) and priapism. tension. US 2006/0120972 A1 Jun. 8, 2006 0014. The preferred embodiments provide the use of a right side of the heart, which pumps blood into the lungs, has compound according to formula: to pump against a higher resistance to blood flow. This makes it more difficult to pump the blood through the lungs, particularly when increased flow is needed, as when a Subject exercises. 0020. The compound of the preferred embodiments has been found to be a human 5-HT, receptor antagonist. Affin ity for the 5-HT, receptors was demonstrated using an in vitro binding assay utilizing cloned human 5-HT2B receptors radiolabelled with H-5HT, as well as luciferase reporter gene assays as shown in the examples. Antagonist properties for the human 5-HT, receptor were shown by counter N screening at human 5-HT, and 5-HT, receptors. Affinity CH3 for the human H receptor was determined using an in vitro binding assay utilizing cloned human H receptors radiola belled with H-mepyramine and antagonistic properties also called pimethixene, or a pharmaceutically acceptable were determined by a luciferase reporter gene assay, as salt thereof for the development of a medicament for the shown in the examples. treatment of disease aggravated by increased levels of 5-HT, 0021 Accordingly, the compound of the preferred Such as, but not limited to, pulmonary hypertension. embodiments is useful for treating diseases which can be 0015 The preferred embodiments further relate to a ameliorated by blockade of 5-HT, and in particular 5HT pharmaceutical composition comprising Such a compound receptors. Because of the similarities in the pharmacology of or a pharmaceutically acceptable salt thereof, in admixture ligand interactions at 5-HT2 and 5-HT2B receptors, many of with one or more pharmaceutically acceptable carriers. the therapeutic targets that have been proposed for 5-HT receptor antagonists are also targets for 5-HT2B receptor 0016 “Pharmaceutically acceptable salt” refers to those antagonists. salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise 0022 Experimental evidence supports a therapeutic role undesirable, formed with inorganic acids such as, but not for 5-HT, receptor antagonists in treating pulmonary limited to, hydrochloric acid, hydrobromic acid, sulfuric hypertension. In pulmonary hypertension, one of the most acid, nitric acid, phosphoric acid and the like, and organic profound increases in vascular responsiveness is observed acids such as, but not limited to, acetic acid, propionic acid, for serotonin. Two lines of evidence imply that this results glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic from a Switch in the receptor mediating vasoconstriction acid, Succinic acid, maleic acid, fumaric acid, tartaric acid, from predominantly 5-HT, to predominantly 5-HT. citric acid, benzoic acid, cinnamic acid, mandelic acid, First, serotonin induced contractions of isolated blood ves methanesulfonic acid, ethanesulfonic acid, p-toluene sels from hypertensive animals become resistant to block by Sulfonic acid, salicylic acid, ascorbic acid and the like. selective 5-HT2A receptor antagonists, but remain sensitive to non-selective 5-HT2B receptor antagonists. Second, there 0017. The term “treatment” as used herein covers any is an increase in 5-HT, receptor mRNA in vessels from treatment of a disease in a mammal, particularly a human, hypertensive animals (see Watts et al., J. Pharmacol. Exp. and includes: Ther. 1996, 277, 1103-13 and Watts et al., Hypertension (i) preventing the disease from occurring in a Subject which 1995, 26, 1056-1059). This hypertension-induced shift in may be predisposed to the disease but has not yet been the population of receptor Subtype mediating constrictor
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