US008148546B2 (12) United States Patent (10) Patent No.: US 8,148,546 B2 Schuster et al. (45) Date of Patent: Apr. 3, 2012 (54) TETRAHYDROCARBAZOLE DERIVATIVES (58) Field of Classification Search .................. 548/448: ASLGANDS OF G-PROTEIN COUPLED 51474 11 RECEPTORS See application file for complete search history. (75) Inventors: Tilmann Schuster, Grossostheim (DE); Klaus Paulini, Maintal (DE); Peter (56) References Cited Schmidt, Schoeneck (DE); Silke Baasner, Schoeneck (DE); Emmanuel FOREIGN PATENT DOCUMENTS Polymeropoulos, Frankfurt (DE); WO WO O3051837 * 6, 2003 Eckhard Guenther, Maintal (DE); WO WO 2006005484 * 1, 2006 Michael Teifel, Weiterstadt (DE) OTHER PUBLICATIONS (73) Assignee: AEterna Zentaris GmbH, Frankfurt Kubinyi (3D QSAR in Drug Design: Ligand-Protein Interactions and (DE) Molecular Similarity, vol. 2-3, Springer, 1998, 800 pages), TOC, pp. 243-244 provided.* *) NotOt1Ce: Subjubject to anyy d1Sclaimer,disclai theh term off thisthi Tatsuta et al. (Bioorg. Med. Chem. Lett. 15 (2005) 2265-2269).* patent is extended or adjusted under 35 Wermuth, The Practice of Medicinal Chemsitry, 2d ed. (2003), 768 U.S.C. 154(b) by 852 days. pages, chs. 9-10 provided.* CAPLUS Abstract of WO O3051837.* (21) Appl. No.: 12/109,479 * cited by examiner (22) Filed: Apr. 25, 2008 (65) Prior Publication Data Primary Examiner — Robert Havlin (74) Attorney, Agent, or Firm — Oblon, Spivak, US 2009/O 170783 A1 Jul. 2, 2009 McClelland, Maier & Neustadt, L.L.P. Related U.S. Application Data (60) Provisional application No. 60/914,424, filed on Apr. (57) ABSTRACT 27, 2007. The present invention provides novel tetrahydrocarbazole compounds according to formula (I) as ligands of G-protein (30) Foreign Application Priority Data coupled receptors (GPCR) which are useful in the treatment and/or prophylaxis of physiological and/or pathological con Apr. 27, 2007 (EP) ..................................... O7107094 ditions in mammals mediated by GPCR or of physiological and/or pathological conditions which can be treated by modu (51) Int. Cl. lation of these receptors. C07D 209/82 (2006.01) A6 IK3I/403 (2006.01) (52) U.S. Cl. ........................................ 548/448: 514/411 14 Claims, 2 Drawing Sheets U.S. Patent Apr. 3, 2012 Sheet 1 of 2 US 8,148,546 B2 Figure 1 4 5 4 O - 33O5 2 5 20 15 - 10 - 5 - O O 1 2 4 6 8 12 24 Time Post Dose (h) -- compound 52 - - - - WO 2006/005484 - substance 76 U.S. Patent Apr. 3, 2012 Sheet 2 of 2 US 8,148,546 B2 Figure 2 4.5 23. O O 5 O. 5 20 25 US 8,148,546 B2 1. 2 TETRAHYDROCARBAZOLE DERVATIVES gonadotropins FSH and LH. The two hormones are trans ASLGANDS OF G-PROTEIN COUPLED ported via the circulation to the target organs the testes and RECEPTORS ovaries respectively. There they stimulate the production and release of the appropriate sex hormones. In the opposite DESCRIPTION OF THE INVENTION direction there is a complex feedback mechanism by which the concentration of the sex hormones formed in turn regu 1. Field of the Invention lates the release of LH and FSH. The present invention relates to novel tetrahydrocarbazole In the male organism, LH binds to membrane receptors of derivatives as ligands of G-protein coupled receptors the Leydig cells and stimulates testosterone biosynthesis. (GPCRs), in particular as ligands of the luteinizing hormone 10 FSH acts via specific receptors on the Sertolicells and assists releasing hormone (LHRH) receptor, processes of manufac the production of spermatozoa. In the female organism, LH turing thereofand uses for the treatment and/or prophylaxis of binds to the LH receptors of the theca cells and activates the physiological and/or pathophysiological conditions in mam formation of androgen-synthesizing enzymes. FSH stimu mals, in particular in humans. lates proliferation of granulosa cells of certain follicle stages 2. Description of Related Art 15 via the FSH receptors thereof. The androgens which are G-protein coupled receptors representa Superfamily of cell formed are converted in the adjacent granulosa cells to the membrane-associated receptors which play an important part estrogens estrone and estradiol. in numerous biochemical and pathobiochemical processes in A number of disorders distinguished by benign or malig mammals and especially in humans. All GPCRs consist of nant tissue proliferations depend on stimulation by sex hor seven hydrophobic, transmembrane alpha-helical domains mones such as testosterone or estradiol. Typical disorders of which are connected together by three intracellular and three this type are prostate cancer and benign prostate hyperplasia extracellular loops and have an extracellular amino terminus (BPH) in men, and endometriosis, uterine fibroids or uterine and an intracellular carboxy terminus. One or more heterot myomas, pubertas praecox, hirsutism and polycystic ovary rimeric G proteins are involved in their cellular signal trans syndrome, and breast cancer, uterine cancer, endometrial can duction. Diverse physiological stimuli such as photosensitiv 25 cer, cervical cancer and ovarian cancer in women. ity, taste and odor, but also fundamental processes Such as Since its discovery in 1971 by Schally et al. (Schally A et metabolism, reproduction and development are mediated and al., Science 1971, 173: 1036-1038) more than 3000 synthetic controlled by them. GPCRs exist for exogenous and endog analogues of natural LHRH have been synthesized and tested. enous ligands. Peptide hormones, biogenic amines, amino Peptide agonists such as triptorelin and leuprolide have been acids, nucleotides, lipids, Ca", but also photons, have inter 30 established for many years successfully in the therapy of alia been identified as ligands; moreover one ligand may gynecological disorders and cancers. However, the disadvan activate different receptors. tage of agonists is generally that they stimulate LHRH recep According to a recent investigation, 367 sequences have tors in the initial phase of use and thus lead to side effects via been identified in the human genome for G-protein coupled an initial increase in the sex hormone levels. Only after down receptors (GPCRs) with endogenous ligands (Vassilatis DK 35 regulation of the LHRH receptor as a result of this overstimu et al., PNAS 2003, 100(8): 4903-4908). Of these, 284 belong lation can the Superagonists display their effect. This leads to to class A, 50 to class B, 17 to class C and 11 to class F/S. a complete reduction in the sex hormone levels and thus to Examples belonging to class A are the bombesin, the dopam pharmacological castration with all the signs and symptoms. ine and the LHRH receptors, and to class B are the VIP and the This disadvantage is associated with the impossibility of tar calcitonin receptors. The natural ligands for numerous 40 geted adjustment of the level of sex hormones via the dosage. GPCRs are as yet unknown. Thus, therapy of diseases which do not require a total reduc Owing to their function, GPCRs are suitable as targets for tion of the sex hormone levels to the castration level. Such as, medicaments for the therapy and prevention of a large number for example, benign tissue proliferations, with an agonist is of pathological conditions. It is speculated that about 50% of not optimal for the patient. currently known targets for active ingredients are GPCRs 45 This has led to the development of peptide LHRH receptor (Fang Yet al., DDT 2003, 8(16): 755-761). Thus, GPCRs antagonists, of which, for example, cetrorelix (CetrotideeR) play an important part in pathological processes such as, for has been successfully introduced for controlled ovarian example, pain (opioid receptor), asthma (beta2-adrenocep stimulation in the context of the treatment of female infertil tor), migraine (serotonin 5-HT1B/1D receptor), cancer ity. The antagonists inhibit the LHRH receptor immediately (LHRH receptor), cardiovascular disorders (angiotensin 50 and dose-dependently, and thus lead to an immediate reduc receptor), metabolic disorders (GHS receptor) or depression tion in the plasma levels of testosterone or estradiol and (serotonin 5-HT, receptor) (Pierce KL et al., Nat. Rev. Mol. progesterone. The peptide antagonists are, however, some Cell. Biol. 2002, 3: 639-650). General information about what less potent than the agonists, and thus higher doses must GPCRs is to be found under http://www.gpcrorg. be given. The natural ligand of this receptor, the peptide hormone 55 Reviews of the clinical applications and the potential of LHRH, is synthesized in cells of the hypothalamus and LHRHagonists and antagonists are given by Millar R Petal. released in pulsatile fashion from the hypothalamic neurons (Millar R P et al., British Med. Bull. 2000, 56: 761-772), into the capillary plexus of the ementia mediana. In the ante Felberbaum R E et al. (Felberbaum R E et al., Mol. Cell. rior lobe of the pituitary, LHRH binds to the LHRH receptors Endocrinology 2000, 166:9-14) and Haviv Fetal. (Haviv F of the gonadotropic cells and stimulates certain trimeric 60 et al., Integration of Pharmaceutical Discovery and Develop G-proteins, which initiate a branched signal transduction cas ment: Case Studies, Chapter 7, ed. Borchardt et al., Plenum cade. The initial event is activation of phospholipase C. A Press, New York 1998). and/or D. This leads to an increased provision of the second Besides the treatment of malignant and benign neoplastic messengers diacylglycerol and IPs, followed by Ca" mobi diseases, further possible applications are controlled ovarian lization from intracellular pools, and activation of various 65 stimulation in the context of in vitro fertilization, fertility subordinate protein kinases. Finally, there is stimulation of control (contraception), and protection from unwanted side the production and temporally defined pulsatile release of the effects of radio- or chemotherapy, the treatment of HIV infec US 8,148,546 B2 3 4 tions (AIDS) and of neurological or neurodegenerative dis Patent EP 0679 642 B 1 describes fused heterocyclic com orders such as Alzheimer's disease.