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(12) United States Patent (10) Patent No.: US 7,897,788 B2 Fecher Et Al

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(12) United States Patent (10) Patent No.: US 7,897,788 B2 Fecher Et Al US007897788B2 (12) United States Patent (10) Patent No.: US 7,897,788 B2 Fecher et al. (45) Date of Patent: Mar. 1, 2011 (54) INDOL-1-YL-ACETIC ACID DERIVATIVES OTHER PUBLICATIONS Chemical Abstracts Registry No. 347911-97-1, entry date into the (75) Inventors: Anja Fecher, Basel (CH); Heinz Fretz, Registry file on STN is Jul 24, 2001.* Riehen (CH); Kurt Hilpert, Hofstetten Souillac, et al., Characterization of Delivery Systems, Differential (CH); Markus Riederer, Liestal (CH) Scanning Calorimetry in Encyclopedia of Controlled Drug Delivery, 1999, John Wiley & Sons, pp. 212-227.* (73) Assignee: Actelion Pharmaceutical Ltd., Vippagunta et al. (Advanced Drug Delivery Reviews, 48 (2001), pp. Allschwil (CH) 3-26. Doan et al., Journal of Clinical Pharmacology, 2005, 45, pp. 751 (*) Notice: Subject to any disclaimer, the term of this 762.* patent is extended or adjusted under 35 Barnes et al., European Respiratory Journal, 2005, 25, pp. 1084 U.S.C. 154(b) by 1196 days. 1105.* Philip L. Gould. International Journal of Pharmaceutics, vol. 33, pp. (21) Appl. No.: 10/598,781 201-217 (1986). Warawa et al., J. Med. Chem... vol. 44, pp. 372-389 (2001). (22) PCT Filed: Mar. 8, 2005 Gastpar et al., J. Med. Chem... vol. 41, pp. 4965-4972 (1998). Richard C. Larocket al., "Comprehensive Organic Transformations: (86). PCT No.: PCT/EP2OOS/OO2418 A Guide to Functional Group Preparations'. Wiley-VCH publishers, Second Edition (1999). S371 (c)(1), Berge et al., Journal of Pharmaceutical Sciences, vol. 66, pp. 1-19 (2), (4) Date: Sep. 11, 2006 (1977). Sawyer et al., British Journal of Pharmacology, vol. 137, pp. 1163 (87) PCT Pub. No.: WO2005/094816 1172 (2002). Sugimoto et al., The Journal of Pharmacology and Experimental PCT Pub. Date: Oct. 13, 2005 Therapeutics, vol. 305, No. 1, pp. 347-352 (2003). (65) Prior Publication Data Hans Bundgaard, “Design of Prodrugs'. Elsevier, pp. 7-9, 21-24 (1985). US 2007/0208004 A1 Sep. 6, 2007 Moriya et al., Chem. Pharm. Bull., vol. 28, No. 6, pp. 1711-1721 (1980). (30) Foreign Application Priority Data R.B. Silverman. The Organic Chemistry of Drug Design and Drug Action, Academic Press, San Diego, CA, U.S.A., pp. 352-401, Mar. 11, 2004 (WO)................. PCTAEP2004/OO2492 (1992). Hata et al., Molecular Pharmacology, vol. 67, pp. 640-647 (2005). (51) Int. Cl. “The Use of indole-3-acetic acids as CRTH2 receptor antagonists'. A6 IK3I/404 (2006.01) Expert Opin. Ther. Patents, vol. 14, No. 1, pp. 125-128 (2004). C07D 209/20 (2006.01) * cited by examiner (52) U.S. Cl. .......................... 548/495; 548/496; 514/419 (58) Field of Classification Search .................. 548/495, 548/496 Primary Examiner — Laura L. Stockton See application file for complete search history. (74) Attorney, Agent, or Firm — Hunton & Williams LLP (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS The invention relates to indol-1-yl-acetic acid derivatives and their use as active ingredients in the preparation of pharma 2001/0039286 A1* 11/2001 Dinnell et al. ................ 514,320 ceutical compositions. The invention also concerns related 2003. O158153 A1 8, 2003 Menta et al. aspects including processes for the preparation of the com 2005/00 14942 A1* 1/2005 Maruyama et al. ........... 544, 183 pounds, pharmaceutical compositions containing one or FOREIGN PATENT DOCUMENTS more of those compounds and methods of treatment compris WO WO95/07294 3, 1995 ing administration of said compounds. WO WO-03/037862 A1 * 5, 2003 WO WO 03.10.1981 A1 12/2003 WO WO 2005/O54232 A1 6, 2005 13 Claims, No Drawings US 7,897,788 B2 1. 2 INDOL-1-YL-ACETIC ACID DERVATIVES its ability to inhibit prostaglandin D2-induced eosinophil migration in vitro has been reported). Further, (2-tert-butoxy FIELD OF THE INVENTION carbonyl-1,2,3,4-tetrahydro-pyrido4.3-bindol-5-yl)-acetic acid and (2-ethoxycarbonyl-1,2,3,4-tetrahydro-pyrido4.3-b The present invention relates to indol-1-yl-acetic acid indol-5-yl)-acetic acid are disclosed by Kyle F. et al in two derivatives and their use as potent “chemoattractant receptor patent specifications i.e. in U.S. Pat. No. 5,817,756 and WO homologous molecule expressed on Th2 cells’ (hereinafter 95/07294, respectively. called CRTH2) antagonists in the treatment of prostaglandin More recently, certain 1-carboxymethyl-indole derivatives mediated diseases, to pharmaceutical compositions contain of the formula ing these derivatives and to processes for their preparation. In 10 particular, at least one of Such derivatives of the general formula I may be used in pharmaceutical compositions for the (A1) treatment of both chronic and acute allergic/immune disor R R3 ders comprising allergic asthma, rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel 15 X^n disease, rheumatoid arthritis, allergic nephritis, conjunctivi Y-R tis, atopic dermatitis, bronchial asthma, food allergy, sys 2NN temic mast cell disorders, anaphylactic shock, urticaria, eczema, itching, inflammation, ischemia-reperfusion injury, No. cerebrovascular disorders, pleuritis, ulcerative colitis, eosi nophil-related diseases, such as Churg-Strauss syndrome and sinusitis, basophil-related diseases, such as basophilic leuke wherein R' can notably be hydrogen, halogen or C, alkyl, mia and basophilic leukocytosis in humans and other mam R can notably be hydrogen and R is optionally substituted mals. aryl or heteroaryl, have been disclosed. These compounds are The invention also relates to novel compounds of Formula 25 presented as being active on the CRTH2 receptor and there II which may also be used in pharmaceutical compositions as fore potentially useful for the treatment of various respiratory outlined above. diseases. BACKGROUND OF THE INVENTION DESCRIPTION OF THE INVENTION 30 Prostaglandin D2 is a known agonist of the thromboxane The present invention firstly relates to the compounds of A2 (TxA2) receptor, the PGD2 (DP) receptor and the recently general formula I identified G-protein-coupled “chemoattractant receptor-ho mologous molecule expressed on Th2 cells' (CRTH2). The response to allergen exposure in a previously sensi 35 tized host results in a cascade effect involving numerous cell types and release of a number of cytokines, chemokines, and multiple mediators. Among these critical initiators are the cytokines interleukin (IL)-4, IL-13, and IL-5, which play critical roles in Th2 cell differentiation, immunoglobulin 40 (Ig)E synthesis, mast cell growth and differentiation, upregu lation of CD23 expression, and the differentiation, recruit ment, and activation of eosinophils. The stimulated release of the array of mediators, causes end-organ damage, including constriction and hyperresponsiveness, vascular permeability, 45 edema, mucous secretion, and further inflammation. Because of the number of responses targeted, corticoster oids have proven to be the most effective therapy. Rather than wherein antagonizing these specific responses in a directed way, A represents hydrogen; alkyl, halogen or cyano; another approach is to alter the immune response, that is, to 50 B represents hydrogen; alkyl or halogen; change the nature of the immunological response to allergen. R", R, R and R' independently represent hydrogen; alkyl: CRTH2 is preferentially expressed on Th2 cells and is a halogen; nitro; cyano or formyl (and preferably indepen chemoattractant receptor for PGD2 that mediates PGD2-de dently represent hydrogen, alkyl, halogen or nitro); pendent migration of blood Th2 cells. Chemoattractants are R and R independently represent hydrogen; alkyl; responsible for the recruitment of both Th2 cells and other 55 cycloalkyl cycloalkyl-alkyl; heteroaryl; heteroaryl-alkyl: effector cells of allergic inflammation and may provide the alkenyl; carboxyalkyl, cyanoalkyl, diphenylalkyl, arylaryl conceptual basis for the development of new therapeutic alkoxy-aryl, aryl-alkyl, aryl-alkyl-aryl, arylcarbonyl-aryl or strategies, especially in allergic conditions. aryloxy-aryl, or RandR, together with the nitrogenatom to So far, few compounds having CRTH2 antagonistic activ which they are attached, form a heterocyclic ring system; ity have been reported in the patent literature. Bayer AG 60 for use as medicaments. claims in GB Patent Specification No. 2388 540 the use of Any reference to a compound of general formula I for use Ramatroban ((3R)-3-(4-fluorobenzene-sulfonamido)-1.2.3, as a medicament is to be understood as referring also to 4-tetrahydrocarbazole-9-propionic acid) for the prophylaxis optically pure enantiomers, mixtures of enantiomers, race and treatment of allergic diseases, such as asthma, allergic mates, optically pure diastereoisomers, mixtures of diastere rhinitis or allergic conjuvatitis (see also Journal of Pharma 65 oisomers, diastereoisomeric racemates, mixture of diastere cology and Experimental Therapeutics (2003), 305(1), 347 oisomeric racemates, meso forms, geometric isomers, as well 352, wherein a certain oral bioavailability of Ramatrobanand as Solvates and morphological forms and pharmaceutically US 7,897,788 B2 3 4 acceptable salts thereof. The same will apply mutatis mutan atom to which they are attached, form a dihydro dis to the compounds of formula I, I, I., I, II, III, or IV, phenanthiridine, dihydroacridine, dihydrodibenzoazo (in which case the reference to the compounds is in addition cine, dihydrodibenzoazepine, dihydroindole, dihydro to be understood as referring also to salts other than pharma quinoline, dibenzoazepine, phenothiazine, oxa-aza ceutically acceptable salts), to the same as medicaments, to
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