US 2006O183905A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0183905 A1 Lubbert et al. (43) Pub. Date: Aug. 17, 2006 (54) DERIVATIVES OF 4-(THIO-OR Related U.S. Application Data SELENOXANTHENE-9-YLIDENE)-PIPERIDINE OR ACRIDINE AND ITS USE ASA (63) Continuation of application No. 10/281,415, filed on SELECTIVE 5-HT2B RECEPTOR Oct. 25, 2002, now Pat. No. 7,060,711. ANTAGONST (60) Provisional application No. 60/343,817, filed on Oct. (75) Inventors: Hermann Lubbert, Leverkusen (DE): 25, 2001. Christoph Ullmer, Bergisch Gladbach (DE); Emile Bellott, Beverly, MA (US); Publication Classification Mark Froimowitz, Newton Centre, MA (US); Douglas Gordon, Burlington, (51) Int. Cl. MA (US) C07D 219/08 (2006.01) A6II 3/545 (2006.01) Correspondence Address: (52) U.S. Cl. ......................... 54.6/104: 514/297: 514/324; KNOBBE MARTENS OLSON & BEAR LLP 514/2O2 2O4O MAN STREET FOURTEENTH FLOOR (57) ABSTRACT IRVINE, CA 92614 (US) (73) Assignee: BIOFRONTERA BOSCIENCE The present invention relates to derivatives of 4-(Thio- or GmbH, Leverkusen (DE) Selenoxanthene-9-ylidene)-piperidine or acridine and phar maceutically acceptable salts thereof, use of these com (21) Appl. No.: 11/379,353 pounds as a medicament and for the manufacture of a medicament for treatment of a disease state which can be (22) Filed: Apr. 19, 2006 alleviated by treatment with a 5-HT2B antagonist. US 2006/0183905 A1 Aug. 17, 2006 DERIVATIVES OF 4-(THIO-OR disorders of the gastrointestinal track (e.g., irritable bowel SELENOXANTHENE-9-YLIDENE)-PIPERIDINE OR syndrome, hypertonic lower esophageal sphincter, motility ACRIDINE AND ITS USE AS A SELECTIVE disorders), restenosis, asthma and obstructive airway dis 5-HT2B RECEPTOR ANTAGONST ease, and prostatic hyperplasia (e.g., benign prostatic hyper 0001. This application is a continuation of application plasia). Ser. No. 10/281,415, filed Oct. 25, 2002, which claims 0006 U.S. Pat. No. 3,275,640 describes generically sub priority to Provisional Appl. No. 60/343,817, filed Oct. 25, stituted 1-hydrocarbyl-4-(9H-thioxanthene-9-ylidene)-pip 2001. eridines and their preparation. It is also disclosed that the compounds may be used as therapeutic agents because of FIELD OF THE INVENTION their antihistaminic and/or antiserotonin properties. 0002 The present invention relates to derivatives of 0007 U.S. Pat. No. 3,557,287 relates to a combination 4-(Thio- or Selenoxanthene-9-ylidene)-piperidine and acri preparation for use in the treatment of headaches of vascular dine and pharmaceutically acceptable salts thereof, which origin containing as active constituents (a) a vasotonic exhibit useful pharmacological properties, including utility lysergic acid selected from ergostine, ergotamine, dihydro as selective 5-HTB receptor antagonists for treatment of a ergostine, dihydroergotamine, ergovaline, 5'-methylergoala disease state which can be alleviated by treatment with a nine; (b) caffeine; and (c) 9-(1-methyl-4-perperidylidene)th 5-HT2B receptor antagonist. ioxanthene (=1-methyl-4-(9H-thioxanthene-9-ylidene)- piperidine. DESCRIPTION OF THE RELATED ART 0008 German patent DE 22 56 392 discloses 4-(9H 0003 Serotonin, a neurotransmitter with mixed and com thioxanthene-9-ylidene)-piperidine derivatives wherein the plex pharmacological characteristics, was first discovered in nitrogen atom of the piperidine ring is bonded to an alkyl 1948, and subsequently has been the subject of substantial radical substituted with cyano. —COR or —COOR. Sleep research. Serotonin, also referred to as 5-hydroxytryptamine inducing properties are attributed to these derivatives. (5-HT), acts both centrally and peripherally on discrete 0009 Japanese patent JP 61106573 refers to the use of 5-HT receptors. Currently, fourteen subtypes of serotonin substituted 4-(9H-thioxanthene-9-ylidene)-piperidines as receptor are recognized and delineated into seven families, pesticides. 5-HT, to 5-HT7. Within the 5-HT family, 5-HTA, 5-HT and 5-HT subtypes are known to exist. These subtypes share sequence homology and display similarities in their SUMMARY OF THE INVENTION specificity for a wide range of ligands. Nomenclature and 0010. Accordingly, there is a need for a compound acting classification of 5-HT receptors have been reviewed in as selective 5-HT2B receptor antagonist. Martin & Humphrey 1994 Neuropharm 33:261-273; and Hoyer et al. 1994 Pharm Rev 46:157-203). 0011. In accordance with preferred embodiments, there is provided a compound according to the formula below: 0004) The 5-HT2B receptor, initially termed 5-HT, or serotonin receptor like (SRL), was first characterized in rat isolated stomach fundus (Clineschmidt et al. 1985J Phar macol Exp. Ther 235:696–708; Cohen & Wittenauer 1987J Cardiovasc Pharmacol 10:176-181) and initially cloned from rat (Foguet et al. 1992 EMBO 11:3481-3487) followed by the cloning of the human 5-HT, receptor (Schmucket al. 1994 FEBS Lett 342:85-90; Kursar et al. 1994 Mol Pharmacol 46:227-234). The closely related 5-HT, recep tor, widely distributed in the human-brain, was first charac terized as a 5-HT subtype (Pazos et al. 1984 Eur J Pharmacol 106:539-546) and was subsequently recognized as belonging to the 5-HT, receptor family (Pritchett et al. 1988 EMBOJ 7:4135-4.140). 0005 Because of the similarities in the pharmacology of ligand interactions at 5-HT, and 5-HT, receptors, many of the therapeutic targets that have been proposed for 5-HT or a pharmaceutically acceptable salt thereof, wherein R' is receptor antagonists are also targets for 5-HT, receptor methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl antagonists. Current evidence strongly supports a therapeu (straight or branched), hexyl (Straight or branched), meth tic role for 5-HT2 receptor antagonists in treating anxi oxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, phe ety (e.g., generalized anxiety disorder, panic disorder and noxy, trifluoromethyl, trifluoromethoxy, amino, dimethy obsessive compulsive disorder), alcoholism and addiction to lamino, fluorine, chlorine, bromine. —CONCCH) or other drugs of abuse, depression, migraine, sleep disorders, CONCCHs); R is methyl, ethyl, propyl, isopropyl, butyl, feeding disorders (e.g., anorexia nervosa) and priapism. isobutyl, pentyl, hexyl, hydroxy or hydrogen, or R1 and R2 Additionally, current evidence strongly supports a therapeu are forming a heterocycle; R is methyl, ethyl, propyl. tic role for selective 5-HT2B receptor antagonists that will isopropyl, butyl isobutyl, pentyl, hexyl, hydroxy or hydro offer distinct therapeutic advantages collectively in efficacy, gen; R is hydroxy, methoxy, ethoxy, propoxy, isopropoxy, rapidity of onset and absence of side effects. Such agents are butoxy, isobutoxy, trifluormethyl, amino, dimethylamino, expected to be useful in the treatment of hypertension, diethylamino, fluorine, chlorine or bromine, methyl, ethyl, US 2006/0183905 A1 Aug. 17, 2006 propyl, isopropyl, butyl or hydrogen; R is methyl or hydro pain (e.g. acute, chronic, neuropathic, inflammatory and gen; R is methyl or ethyl; and X is S. N or Se, with the cancer pain) hypertension, disorders of the gastrointestinal proviso that if R is ethoxy and X is S at least one of R. R. tract (e.g., irritable bowel syndrome, hypertonic lower R" and R is not hydrogen. esophageal sphincter, motility disorders), restenosis, asthma 0012) The residues R' and Rare of particular interest in and obstructive airway disease, prostatic hyperplasia (e.g., the present invention. R' is involved in mediating the benign prostatic hyperplasia), and priapism. selectivity of the compound for the 5-HT, receptor. R', 0022. In a preferred embodiment of the present invention however, is involved in mediating the affinity for the H the residues in the general formula shown above are as receptor. Preferably R' is a lower alkyl or alkoxy group, or follows: R' is an isopropyl, dimethylamino, methoxy or halogenated alkyl or alkoxy group, Sterically promoting, but ethoxy group, R is methyl, ethyl or hydrogen, or R' and R' not hindering the receptor binding. R is preferably a polar are forming a heterocycle, R is ethyl or hydrogen, R is group, particularly a small polar group, however, each group methoxy, hydroxy, ethyl, methyl or hydrogen, R is methyl lowering the H1 affinity is suitable for the according use. R*, or hydrogen, R is methyl and X is S, N or Se, or a RandR independently can be any residue, as long as the pharmaceutically acceptable salt thereof, with the proviso binding to the 5-HT, receptor is not hindered. that if R is ethoxy and X is S at least one of R. R. R. and 0013 The present invention is also directed to methods of R is not hydrogen. using the compound shown above, or a pharmaceutical 0023. In a particularly preferred embodiment of the composition comprising said compound, for treatment of a present invention the compound is selected of the group disease state which can be alleviated by treatment with a consisting of 4-(6-Isopropyl-1-methoxy-thioxanthen-9- 5-HT, receptor antagonist. yliden)-1-methyl-piperidine, 4-(6-Isopropyl-1-hydroxy 0014. The present invention further relates to a pharma thioxanthen-9-yliden)-1-methyl-piperidine, 4-(6-Ethoxy-1- ceutical composition comprising Such a compound or a ethyl-thioxanthen-9-yliden)-1-methyl-piperidine, 4-(6- pharmaceutically acceptable salt thereof, in admixture with Ethoxy-1-methoxy-thiox-9-yliden)-1-methyl-piperidine, one or more pharmaceutically acceptable carriers. 4-(6-Ethoxy-1-hydroxy-thioxanthen-9-yliden)-1-methyl-pi peridine, 4-(6-Methoxy-1-methoxy-thioxanthen-9-yliden)-