USOO8268878B2 (12) United States Patent (10) Patent No.: US 8,268,878 B2 Armer et al. (45) Date of Patent: Sep. 18, 2012 (54) COMPOUNDS HAVING CRTH2 ANTAGONIST 2009, OO23788 A1 1/2009 Middlemiss et al. ACTIVITY 2009,0192195 A1 7/2009 Armer et al. 2010.0022613 A1 1/2010 Armer et al. 2010.0041699 A1 2/2010 Boyd et al. (75) Inventors: Richard Edward Armer, Cambridge 2010/0330.077 A1 12/2010 Armer et al. (GB); Graham Michael Wynne, 2011/O123547 A1 5, 2011 Armer et al. Bicester (GB); Colin Richard Dorgan, 2011/O124683 A1 5, 2011 Hunter et al. Abingdon (GB); Peter David Johnson, 2011/O142855 A1 6/2011 Armer et al. Oxford (GB) FOREIGN PATENT DOCUMENTS EP 1505061 A1 2, 2005 (73) Assignee: Oxagen Limited, Abingdon (GB) WO WO 2005/044260 A1 5, 2005 WO WO 2009,077728 A1 6, 2009 (*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 Hata et al. (Pharmacology & Therapeutics 103 (2004) 147-166).* U.S.C. 154(b) by 0 days. Kubinyi (3D QSAR in Drug Design: Ligand-Protein Interactions and Molecular Similarity, vol. 2-3, Springer, 1998, 800 pages), TOC and (21) Appl. No.: 13/180,157 pp. 243-244 provided.* Wermuth, The Practice of Medicinal Chemsitry, 2d ed. (2003), 768 (22) Filed: Jul. 11, 2011 pages. Chapters 9-10 provided.* Parket al. (Toxicology Lett., 120 (2001), 281-91).* (65) Prior Publication Data * cited by examiner US 2011 FO268.693 A1 Nov. 3, 2011 Primary Examiner — Robert Havlin Related U.S. Application Data (74) Attorney, Agent, or Firm — Sterne, Kessler, (62) Division of application No. 12/374,702, filed as Goldstein & Fox PLLC application No. PCT/GB2007/002761 on Jul. 20, (57) ABSTRACT 2007, now Pat. No. 7,999,119. Compounds of general formula (I) wherein R is phenyl optionally substituted with one or more halo substituents; and (30) Foreign Application Priority Data their pharmaceutically acceptable salts, hydrates, Solvates, complexes or prodrugs are useful in orally administrable Jul. 22, 2006 (GB) ................................... O6146088 compositions for the treatment of allergic diseases Such as Dec. 4, 2006 (GB) ................................... O624 1764 asthma, allergic rhinitis and atopic dermatitis. (51) Int. Cl. A6 IK3I/40 (2006.01) (I) CO7D 209/04 (2006.01) (52) U.S. Cl. ........................................ 514/416: 548/510 (58) Field of Classification Search .................. 514/416; 548/510 See application file for complete search history. (56) References Cited U.S. PATENT DOCUMENTS 5,641,800 A 6, 1997 Bach et al. 6,214,991 B1 4/2001 Jones et al. 7,582,672 B2 9, 2009 Middlemiss et al. 7,750,027 B2 7, 2010 Armer et al. 7.919,512 B2 4/2011 Armer et al. 7.999,119 B2 8/2011 Armer et al. OH 2009 OO18138 A1 1/2009 Middlemiss et al. 2009 OO18139 A1 1/2009 Middlemiss et al. 2009 OO18338 A1 1/2009 Middlemiss et al. 5 Claims, 5 Drawing Sheets U.S. Patent Sep. 18, 2012 Sheet 1 of 5 US 8,268,878 B2 Figure 1 22O5 OO OO 5 OO aaaa-ra-a-a-a-a-a---a-M.------SSS ----sex O 2 4 6 8 a & 8 & 28 22 2s inst his 5 OO 1 OO O 500 O U.S. Patent Sep. 18, 2012 Sheet 2 of 5 US 8,268,878 B2 Figure 3 4500 2500 is: 2 OO O 15 O O 1000 500 24 Figure 4 1500 1250 - OOO . 75O O re-rearrasrar------------...rssser --- sea-----exis O 2 4 6 8 O 2 14 16 18 20 22 24 Time (hr) U.S. Patent Sep. 18, 2012 Sheet 3 of 5 US 8,268,878 B2 Figure 5 1OOO 750. 50 O 250 O is areasserrrrrrror-rewro--ess sessessex 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (hr) certgei K-82 (.x: (...it T {{ {tisti i kg ... -- *-*s U.S. Patent Sep. 18, 2012 Sheet 4 of 5 US 8,268,878 B2 Control K-GO (.00 . Corport 2 gig g.o.) - 8-G control okret. ooo oo 0.1 1 Compound 3 (ug/kg p.o.) + DK-PGD2 U.S. Patent Sep. 18, 2012 Sheet 5 of 5 US 8,268,878 B2 Contre DK-PGD2 0.01 0.1 1.0 Compound A (mg/kg p.o.) + DK-PGD2 Sigis rei control Dkiped, ooof ool of 10 Compound 8 (ngikg, p.o.) --K-G2 US 8,268,878 B2 1. 2 COMPOUNDS HAVING CRTH2 ANTAGONST asthma, chronic obstructive pulmonary disease (COPD) and a ACTIVITY number of other diseases including various conditions of bones and joints, skin and eyes, GI tract, central and periph The present invention relates to compounds which are use eral nervous system and other tissues as well as allograft ful as pharmaceuticals, to methods for preparing these com rejection. These compounds are all indole derivatives with an pounds, compositions containing them and their use in the acetic acid Substituent at the 3-position of the indole ring. treatment and prevention of allergic diseases such as asthma, PL 65781 and JP 43-244.18 also relate to indole-3 acetic allergic rhinitis and atopic dermatitis and other inflammatory acid derivatives which are similar in structure to indometha diseases mediated by prostaglandin D. (PGD) or other ago cinand, like indomethacin, are said to have anti-inflammatory nists acting at the CRTH2 receptor on cells including eosino 10 and antipyretic activity. Thus, although this may not have phils, basophils and Th2 lymphocytes. been appreciated at the time when these documents were PGD is an eicosanoid, a class of chemical mediator Syn published, the compounds they describe are COX inhibitors, thesised by cells in response to local tissue damage, normal an activity which is quite different from that of the com stimuli or hormonal stimuli or via cellular activation path pounds of the present invention. Indeed, COX inhibitors are ways. Eicosanoids bind to specific cell Surface receptors on a 15 contraindicated in the treatment of many of the diseases and wide variety of tissues throughout the body and mediate conditions, for example asthma and inflammatory bowel dis various effects in these tissues. PGD is known to be produced by mast cells, macrophages and Th2 lymphocytes and has ease for which the compounds of the present invention are been detected in high concentrations in the airways of asth useful, although they may sometimes be used to treat arthritic matic patients challenged with antigen (Murray et al. (1986), conditions. N. Engl. J. Med. 315: 800-804). Instillation of PGD, into There is further prior art which relates to indole-1-acetic airways can provoke many features of the asthmatic response acid compounds, although these are not described as CRTH2 including bronchoconstriction (Hardy et al. (1984) N. Engl.J. antagonists. For example WO-A-9950268, WO-A-0032180, Med. 311: 209-213; Sampson et al. (1997) Thorax 52: 513 WO-A-0151849 and WO-A-01 64205 all relate to com 518) and eosinophil accumulation (Emery et al. (1989) J. pounds which are indole-1-acetic acid derivatives but these Appl. Physiol. 67: 959-962). 25 compounds are said to be aldose reductase inhibitors useful, The potential of exogenously applied PGD, to induce in the treatment of diabetes mellitus (WO-A-9950268, WO inflammatory responses has been confirmed by the use of A-0032180 and WO-A-0164205) or hypouricemic agents transgenic mice overexpressing human PGD synthase which (WO-A-0151849). There is no suggestion in any of these exhibit exaggerated eosinophilic lung inflammation and Th2 documents that the compounds would be useful for the treat cytokine production in response to antigen (Fujitani et al. 30 ment of diseases and conditions mediated by PGD, or other (2002).J. Immunol. 168: 443-449). CRTH2 receptoragonists. The first receptor specific for PGD, to be discovered was U.S. Pat. No. 4,363,912 relates to indole-1-acetic acid the DP receptor which is linked to elevation of the intracel derivatives which are said to be inhibitors of thromboxane lular levels of cAMP. However, PGD is thought to mediate synthetase and to be useful in the treatment of conditions such much of its proinflammatory activity through interaction with 35 as thrombosis, ischaemic heart disease and stroke. a G protein-coupled receptor termed CRTH2 (chemoattrac WO-A-9603376 relates to compounds which are said to be tant receptor-homologous molecule expressed on Th2 cells) sPLA inhibitors which are useful in the treatment of bron which is expressed by Th2 lymphocytes, eosinophils and chial asthma and allergic rhinitis. These compounds all have basophils (Hirai et al. (2001).J. Exp. Med. 193:255-261, and amide or hydrazide substituents in place of the carboxylic EP0851030 and EP-A-1211513 and Bauer et al, EP-A- acid derivative of the compounds of the present invention. 1170594). It seems clear that the effect of PGD, on the acti 40 JP 2001 247570 relates to a method of producing a 3-ben vation of Th2 lymphocytes and eosinophils is mediated Zothiazolylmethyl indole acetic acid, which is said to be an through CRTH2 since the selective CRTH2 agonists 13,14 aldose reductase inhibitor. dihydro-15-keto-PGD, (DK-PGD) and 15R-methyl-PGD, U.S. Pat. No. 4,859,692 relates to compounds which are can elicit this response and the effects of PGD are blocked by said to be leukotriene antagonists useful in the treatment of an anti-CRTH2 antibody (Hirai et al., 2001; Monneret et al. 45 conditions such as asthma, hay fever and allergic rhinitis as (2003).J. Pharmacol. Exp. Ther: 304: 349-355).