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 5 dibenzocycloheptene, dihydroisoquinoline ring, which the pharmaceutical compositions containing them and to their may be unsubstituted or substituted with one substituent uses according to the invention. Selected from halogen, methyl, methoxy and trifluorom The present invention also relates to pro-drugs of a com ethyl (and preferably a 5,6-dihydro-phenanthridine, pound of formula I that convert in vivo to the compound of 9,10-dihydro-acridine, 5,6-dihydro-dibenzob.fazo formula I as such. Any reference to a compound of formula I 10 cine, 10,11-dihydro-dibenzob.fazepine, 11,12-dihy is therefore to be understood as referring also to the corre sponding pro-drugs of the compound of formula I, as appro dro-6H-dibenzob.fazocine, 2,3-dihydro-indole, 3,4- priate and expedient. The same will apply mutatis mutandis to dihydro-2H-quinoline, 6,11-dihydro-dibenzob.e. the compounds of formula I, I, I., I, II, III or IV, to the aZepine, dibenzob.fazepine, 2-chlorophenothiazine, same as medicaments, to the pharmaceutical compositions 15 11H-10-Oxa-5-aza-dibenzoa.dcycloheptene, 3,4-di containing them and to their uses according to the invention. hydro-1H-isoquinoline, 7-trifluoromethyl-3,4-dihydro The compounds of the general formula I are CRTH2 recep 2H-quinoline, dibenzob.fazepine, 6,11-dihydro tor antagonists and may be used for the prevention and treat dibenzob.eazepine ring) ment of chronic and acute allergic immune disorders com According to one particularly preferred embodiment, the prising allergic asthma, rhinitis, chronic obstructive compounds of general formula I for use as medicaments will pulmonary disease (COPD), dermatitis, inflammatory bowel be such that A is cyano, B is hydrogen and R. R. Rand R' disease, rheumatoid arthritis, allergic nephritis, conjunctivi are all hydrogen atoms. tis, atopic dermatitis, bronchial asthma, food allergy, sys According to another particularly preferred embodiment, temic mast cell disorders, anaphylactic shock, urticaria, the compounds of general formula I for use as medicaments eczema, itching, inflammation, ischemia-reperfusion injury, 25 will be such that A is cyano, B is hydrogen and one of R', R, cerebrovascular disorders, pleuritis, ulcerative colitis, eosi RandR is halogen (preferably fluorine) while the others are nophil-related diseases comprising Churg-Strauss syndrome all hydrogen. According to an even more particularly pre and sinusitis, basophil-related diseases, comprising baso ferred embodiment, the compounds of general formula I for philic leukemia and basophilic leukocytosis in humans and use as medicaments will be such that A is cyano, B is hydro other mammals. 30 Preferred compounds of general formula I for use as medi gen and one of R and R is halogen (preferably fluorine) caments are those wherein at least one of the following char while the other, R' and Rare hydrogenatoms; a representa acteristics is present: tive example thereof will be the case wherein R is halogen A is cyano; (preferably fluorine) while the other, R', RandR are hydro B is hydrogen or methyl; 35 gen atoms. R", R, R and Rare all hydrogenatoms or one of R', R, Still another preferred embodiment regarding the com R and R is halogen (preferably fluorine) while the pounds of general formula I for use as medicaments is that others are all hydrogen; wherein the groups RandR do not form a heterocyclic ring at least one of RandR is chosen from the group consist system together with the nitrogen atom to which they are ing of heteroaryl, heteroaryl-alkyl, diphenylalkyl, aryl, 40 attached. In Such case, each of the following combinations aryl-alkoxy-aryl, aryl-alkyl, aryl-alkyl-aryl, arylcarbo will constitute a more particularly preferred embodiment: nyl-aryl and aryloxy-aryl; or R and R, together with R being aryl and R being selected from the group con the nitrogen atom to which they are attached, form a sisting of alkyl, cycloalkyl, alkenyl, cyanoalkyl, diphe heterocyclic ring system. nylalkyl, heteroaryl-alkyl, aryl-alkyl and aryl (and pref Even more preferred compounds of general formula I for 45 erably R being phenyl and R being selected from the use as medicaments are those wherein at least one of the group consisting of alkyl, cycloalkyl, alkenyl, following characteristics is present: cyanoalkyl, diphenylalkyl, heteroaryl-alkyl, phenyla A is cyano; lkyl and phenyl); or B is hydrogen; R being aryl-alkyl and R being selected from the group R", R, R and Rare all hydrogenatoms or one of R', R, 50 consisting of alkyl, aryl and aryl-alkyl (and preferably R and R is halogen (preferably fluorine) while the R being phenylalkyl and R being selected from the others are all hydrogen; group consisting of alkyl, phenyl and phenyl-alkyl). R is selected from the group consisting of heteroaryl An alternative preferred embodiment regarding the com alkyl, diphenylalkyl, aryl, aryl-alkoxy-aryl, aryl-alkyl, pounds of general formula I for use as medicaments is that aryl-alkyl-aryl, arylcarbonyl-aryl and aryloxy-aryl 55 wherein the groups RandR form a heterocyclic ring system (aryl, aryl-alkoxy-aryl, aryl-alkyl, aryl-alkyl-aryl, aryl together with the nitrogenatom to which they are attached. In carbonyl-aryl end aryloxy-aryl being preferably Such such case, each of the following NR'R' groups will constitute that their aryl groups are unsubstituted or substituted 1 a more particularly preferred embodiment: or 2 times with substituents independently selected from NRR being an unsubstituted dihydroquinoline ring (for the group consisting of halogen, alkoxy, haloalkoxy and 60 example —NR'R' representing 3,4-dihydro-2H-quino alkylcarbonyl) and R is selected from the group con lin-1-yl); sisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and NR'R' being an unsubstituted dihydroisoquinoline ring cyanoalkyl (aryl and aryl-alkyl being preferably Such (for example —NR'R' representing 3,4-dihydro-1H that their aryl groups are unsubstituted or substituted 1 isoquinolin-2-yl); or 2 times with substituents independently selected from 65 NR'R' being an unsubstituted dibenzoazepine ring (for the group consisting of halogen, alkoxy, haloalkoxy and example —NRR representing dibenzob.fazepin-5- alkylcarbonyl); or RandR, together with the nitrogen yl);

US 7,897,788 B2 15 16 (3-(E)-2-cyano-2-(4-fluoro-phenyl)-methyl-carbamoyl {3-(E)-2-cyano-2-(4-chloro-phenylcarbamoyl)-vinyl-in vinyl-6-methyl-indol-1-yl)-acetic acid; dol-1-yl)-acetic acid; {3-(E)-2-(butyl-phenyl-carbamoyl)-2-cyano-vinyl-6-me {3-(E)-2-cyano-3-(4-methyl-piperidin-1-yl)-3-oxo-prope thyl-indol-1-yl)-acetic acid: nyl-indol-1-yl)-acetic acid; {3-(E)-2-cyano-2-(cyclohexyl-phenyl-carbamoyl)-vinyl 5 {3-(E)-2-(3-chloro-4-methyl-phenylcarbamoyl)-2-cyano 7-methyl-indol-1-yl)-acetic acid; and vinyl-indol-1-yl)-acetic acid; (3-(E)-2-cyano-2-(4-fluoro-phenyl)-methyl-carbamoyl {3-(E)-2-cyano-2-(3-phenyl-propylcarbamoyl)-vinyl-in vinyl-7-methyl-indol-1-yl)-acetic acid. dol-1-yl)-acetic acid; The present invention therefore also relates to compounds {3-(E)-2-cyano-2-(2,3-dichloro-phenylcarbamoyl)-vinyl of general Formula I 10 indol-1-yl)-acetic acid; {3-(E)-2-(5-chloro-2-methyl-phenylcarbamoyl)-2-cyano vinyl-indol-1-yl)-acetic acid; {3-(E)-2-cyano-2-(4-methoxy-benzylcarbamoyl)-vinyl-in dol-1-yl)-acetic acid; 15 {3-(E)-2-cyano-2-(2-fluoro-phenylcarbamoyl)-vinyl-in dol-1-yl)-acetic acid; and {3-(E)-2-cyano-3-oxo-3-(4-phenyl-piperazin-1-yl)-prope nyl-indol-1-yl)-acetic acid. The invention further relates to compounds of general For mula I, wherein

25 wherein A represents hydrogen; alkyl, halogen or cyano; B represents hydrogen; alkyl or halogen; R", R, R and R independently represent hydrogen; alkyl; 30 halogen; nitro; cyano or formyl (and preferably indepen dently represent hydrogen, alkyl, halogen or nitro); R and R independently represent hydrogen; alkyl; cycloalkyl cycloalkyl-alkyl; heteroaryl; heteroaryl-alkyl: alkenyl; carboxyalkyl, cyanoalkyl, diphenylalkyl, aryl, aryl 35 alkoxy-aryl, aryl-alkyl, aryl-alkyl-aryl, arylcarbonyl-aryl or aryloxy-aryl, or RandR, together with the nitrogenatom to which they are attached, form a heterocyclic ring system; wherein with the exception however of the following compounds: A represents hydrogen; alkyl, halogen or cyano; {3-(E)-2-cyano-2-(4-fluoro-phenylcarbamoyl)-vinyl-in 40 B represents hydrogen; alkyl or halogen; dol-1-yl)-acetic acid; R", R, R and R independently represent hydrogen; alkyl; 3-((E)-2-cyano-2-m-tolylcarbamoyl-vinyl)-indol-1-yl)-ace halogen; nitro; cyano or formyl (and preferably indepen tic acid; dently represent hydrogen, alkyl, halogen or nitro); {3-(E)-2-(3-bromo-phenylcarbamoyl)-2-cyano-vinyl-in R and R independently represent hydrogen; alkyl; dol-1-yl)-acetic acid; 45 cycloalkyl cycloalkyl-alkyl; heteroaryl; heteroaryl-alkyl: 3-((E)-2-cyano-2-phenylcarbamoyl-vinyl)-indol-1-yl)-ace alkenyl; carboxyalkyl, cyanoalkyl, diphenylalkyl, aryl, aryl tic acid; alkoxy-aryl, aryl-alkyl, aryl-alkyl-aryl, arylcarbonyl-aryl or 3-((E)-2-benzylcarbamoyl-2-cyano-vinyl)-indol-1-yl)-ace aryloxy-aryl, tic acid; or Rand R, together with the nitrogen atom to which they 3-((E)-2-cyano-2-o-tolylcarbamoyl-vinyl)-indol-1-yl)-ace 50 are attached, form a heterocyclic ring system; tic acid; it being understood however that at least one of the following 3-((E)-2-cyano-2-p-tolylcarbamoyl-vinyl)-indol-1-yl)-ace conditions must be met: tic acid; one of R', R. RandR is different from a hydrogenatom; {3-(E)-2-(4-bromo-phenylcarbamoyl)-2-cyano-vinyl-in O dol-1-yl)-acetic acid; 55 when RandR are such that they do not form a heterocy {3-(E)-2-cyano-2-(4-ethyl-phenylcarbamoyl)-vinyl-indol clic ring system together with the nitrogen atom to 1-yl)-acetic acid: which they are attached, then both Rand Rare differ {3-(E)-2-cyano-2-(4-methoxy-phenylcarbamoyl)-vinyl ent from hydrogenandone of RandR is different from indol-1-yl)-acetic acid; alkyl; or {3-(E)-2-cyano-2-(4-ethoxy-phenylcarbamoyl)-vinyl-in 60 when RandR are such that they form a heterocyclic ring dol-1-yl)-acetic acid; system together with the nitrogenatom to which they are 3-((E)-2-cyano-2-isopropylcarbamoyl-vinyl)-indol-1-yl)- attached, then said heterocyclic ring system is neitheran acetic acid; unsubstituted or Substituted piperidine nor an unsubsti {3-(E)-2-cyano-2-(3-ethoxy-phenylcarbamoyl)-vinyl-in tuted or substituted piperazine. dol-1-yl)-acetic acid; 65 The invention also relates to the compounds of general {3-(E)-2-cyano-3-2-(1H-indol-3-yl)ethylaminol-3-oxo formula I for use as medicaments as well as to the com 1-propenyl-indol-1-yl)-acetic acid; pounds of general formula I as medicaments. US 7,897,788 B2 17 18 A further aspect of the invention relates to pharmaceutical wherein compositions containing, as active principle, at least one A represents hydrogen; alkyl; halogen or cyano; compound of general formula I, and a pharmaceutically B represents hydrogen; alkyl or halogen; acceptable carrier. The invention also encompasses pharma R", R. RandR'independently represent hydrogen; alkyl: ceutical compositions containing, as active principle, at least halogen; nitro; cyano or formyl; one compound of general formula I, and a pharmaceuti R and R' independently represent hydrogen; alkyl; alk cally acceptable carrier as well as pharmaceutical composi enyl; cycloalkyl; heteroaryl; or a member selected from tions containing, as active principle, at least one compound of the group consisting of aryl, alkoxy-aryl, alkoxycarbo general formula I, and a pharmaceutically acceptable car nyl-aryl, alkylcarbonyl-aryl, aryl-alkoxy-aryl, aryl 1. 10 alkyl, aryl-alkyl-aryl, arylcarbonyl-aryl and aryloxy The invention also relates to the use of a compound of aryl, wherein the aryl group is unsubstituted or mono- or general formula I for the preparation of a medicament di-substituted substituted with substituent(s) indepen intended for the prevention and treatment of chromic and dently selected from the group consisting of alkyl, acute allergic immune disorders comprising allergic asthma, alkoxy, halogen, cyano, alkoxycarbonyl, alkylcarbonyl, rhinitis, chronic obstructive pulmonary disease (COPD), der 15 phenyl, benzyl, benzoyl, benzyloxy, benzyloxycarbo matitis, inflammatory bowel disease, rheumatoid arthritis, allergic nephritis, conjunctivitis, atopic dermatitis, bronchial nyl, trifluoromethyl and trifluoromethoxy; asthma, food allergy, systemic mast cell disorders, anaphy or RandR, together with the nitrogenatom to which they lactic shock, urticaria, eczema, itching, inflammation, are attached, form a heterocyclic ring system; ischemia-reperfusion injury, cerebrovascular disorders, pleu and optically pure enantiomers, mixtures of enantiomers, ritis, ulcerative colitis, eosinophil-related diseases compris racemates, optically pure diastereoisomers, mixtures of ing Churg-Strauss syndrome and sinusitis, basophil-related diastereoisomers, diastereoisomeric racemates, mixture diseases, comprising basophilic leukemia and basophilic leu of diastereoisomeric racemates, meso forms, geometric kocytosis. The invention further relates to the use of a com isomers, prodrugs of compounds in which a prodrug pound of general formula I or of a compound of general forming group is present, as well as Solvates and mor formula I for the preparation of a medicament intended for 25 phological forms, pharmaceutically acceptable salts the prevention and treatment of the aforementioned diseases. thereof and usual inert carrier materials or adjuvants; it The medicaments thus prepared can be intended for humans being understood however that in general Formula I. or for other mammals. i) the term “alkyl or “lower alkyl, used alone or in any The invention also relates to methods of preventing and combination, refers to a saturated aliphatic group treating in humans diseases selected from chronic and acute 30 including a straight or branched hydrocarbon chain allergic immune disorders comprising allergic asthma, rhini containing 1-8 carbon atoms (and preferably 1-4 car tis, chronic obstructive pulmonary disease (COPD), derma bon atoms), which saturated aliphatic group can be titis, inflammatory bowel disease, rheumatoid arthritis, aller optionally substituted with one or more substituents, gic nephritis, conjunctivitis, atopic dermatitis, bronchial each independently selected from alkenyl, alkoxy, asthma, food allergy, systemic mast cell disorders, anaphy 35 alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, lactic shock, urticaria, eczema, itching, inflammation, ischemia-reperfusion injury, cerebrovascular disorders, pleu alkylendioxy, alkylsulfinyl, alkylsulfonyl, alkylthio. ritis, ulcerative colitis, eosinophil-related diseases compris alkynyl, amino, aminocarbonyl, aryl, arylalkenyl, ing Churg-Strauss syndrome and sinusitis, basophil-related arylalkyloxy, aryloxy, aryloxycarbonyl, arylsulfinyl, diseases, comprising basophilic leukemia and basophilic leu arylsulfonyl, arylthio, carboxy, cyano, formyl, halo kocytosis, said methods comprising the administration to 40 gen, haloalkoxy, heterocyclyl, hydroxy, mercapto, humans in need thereof of an effective amount of a compound nitro, and the like, appended to any carbonatom of the of general formula I. The invention further relates to methods alkyl moiety; of preventing and treating in humans the same diseases, said ii) the term “alkenyl' or “lower alkenyl', used alone or in methods comprising the administration to humans in need any combination, refers to a straight or branched thereof of an effective amount of a compound of general 45 hydrocarbon chain containing 2-8 carbon atoms with formula I or of a compound of general formula I. at least one carbon-carbon double bond The preferences indicated for the compounds of general (RRC=CRR wherein R. R. refer to substitu formula I are applicable mutatis mutandis the compounds of ents, each individually and independently selected general formula I and to the compounds of general formula from hydrogen and alkyl, alkoxy, alkoxyalkyl and the Ic2. 50 like): Besides, a particular variant of the invention relates, in its iii) the term “alkoxy”, used alone or in any combination, first aspect, to pharmaceutical compositions containing at refers to an alkyl group appended to the parent least one compound of the general Formula I molecular moiety through an oxygen bridge; Ip iv) the term “aryl', used alone or in any combination, 55 refers to an carbocyclic group having at least one aromatic ring, e.g. phenyl or biphenyl, or multiple condensed ring systems, in which at least one ring is aromatic (e.g. 1.2.3,4-tetrahydronaphthyl, naphthyl, anthryl, phenanthryl, fluorenyl, and the like), which 60 aryl group may be optionally substituted with one or more functional groups individually and indepen dently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkyl carbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, 65 alkylendioxy, alkylsulfinyl, alkylsulfinylalkyl, alkyl sulfonyl, alkylsulfonylalkyl, alkylthio, alkylthio alkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, US 7,897,788 B2 19 20 aminocarbonylalkyl, aryl, arylalkenyl, arylalkyloxy, xi) the term "heteroaryl', used alone or in any combina arylalkyl, aryloxy, aryloxycarbonyl, aryloxycarbony tion, is a special case of heterocyclyl and refers to a lalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, mono- or bicyclic or polycyclic aromatic ring system, arylsulfonylalkyl, arylthio, arylthioalkyl, carboxy, in which at least one heterocyclic ring is aromatic. carboxyalkyl, cyano, cyanoalkyl, formyl, formyla 5 Compounds of the above general Formula I are novel, lkyl, halogen, haloalkoxy, haloalkyl, heteroaryl, het with the exception of the following compounds which, how erocyclyl, hydroxy, hydroxyalkyl, mercapto, nitro, ever, are also potent CRTH2 receptor antagonists and were and the like; not previously described in this respect in the literature: v) the term “arylalkoxy”, used alone or in any combina {3-(E)-2-cyano-2-(4-fluoro-phenylcarbamoyl)-vinyl-in tion, refers to an aryl group which may be unsubsti 10 dol-1-yl)-acetic acid; tuted or substituted as previously defined and which is 3-((E)-2-cyano-2-m-tolylcarbamoyl-vinyl)-indol-1-yl)-ace appended to the parent molecular moiety through an tic acid; alkoxy group; {3-(E)-2-(3-bromo-phenylcarbamoyl)-2-cyano-vinyl-in vi) the term “arylalkyl, used alone or in any combina dol-1-yl)-acetic acid; 15 3-((E)-2-cyano-2-phenylcarbamoyl-vinyl)-indol-1-yl)-ace tion, refers to an aryl group which may be unsubsti tic acid; tuted or substituted as previously defined and which is 3-((E)-2-benzylcarbamoyl-2-cyano-vinyl)-indol-1-yl)-ace appended to the parent molecular moiety through an tic acid; alkyl group; 3-((E)-2-cyano-2-o-tolylcarbamoyl-vinyl)-indol-1-yl)-ace vii) the term “aryloxy”, used alone or in any combina tic acid; tion, refers to an aryl group which may be unsubsti 3-((E)-2-cyano-2-p-tolylcarbamoyl-vinyl)-indol-1-yl)-ace tuted or substituted as previously defined and which is tic acid; appended to the parent molecular moiety through an {3-(E)-2-(4-bromo-phenylcarbamoyl)-2-cyano-vinyl-in oxygen bridge; dol-1-yl)-acetic acid; viii) the term “arylcarbonyl or “aroyl', used alone or in {3-(E)-2-cyano-2-(4-ethyl-phenylcarbamoyl)-vinyl-indol any combination, refers to an aryl group appended to 25 1-yl)-acetic acid; the parent molecular moiety through a carbonyl {3-(E)-2-cyano-2-(4-methoxy-phenylcarbamoyl)-vinyl group; indol-1-yl)-acetic acid; ix) the term “cycloalkyl, used alone or in any combi {3-(E)-2-cyano-2-(4-ethoxy-phenylcarbamoyl)-vinyl-in nation, refers to a saturated cyclic hydrocarbon moi dol-1-yl)-acetic acid; ety containing 3-15 carbon atoms, optionally Substi 30 3-((E)-2-cyano-2-isopropylcarbamoyl-vinyl)-indol-1-yl)- tuted with one or more groups, each individually and acetic acid; independently selected from alkenyl, alkoxy, alkoxy {3-(E)-2-cyano-2-(3-ethoxy-phenylcarbamoyl)-vinyl-in alkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, dol-1-yl)-acetic acid; alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, {3-(E)-2-cyano-3-2-(1H-indol-3-yl)ethylaminol-3-oxo alkylendioxy, alkylsulfinyl, alkylsulfinylalkyl, alkyl 35 1-propenyl-indol-1-yl)-acetic acid; sulfonyl, alkylsulfonylalkyl, alkylthio, alkylthio {3-(E)-2-cyano-2-(4-chloro-phenylcarbamoyl)-vinyl-in alkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aryl, arylalkenyl, arylalkyloxy, dol-1-yl)-acetic acid. arylalkyl, aryloxy, aryloxycarbonyl, aryloxycarbony A second aspect of the abovementioned particular variant lalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, of the invention is the use of compounds of the general For arylsulfonylalkyl, arylthio, arylthioalkyl, carboxy, a mula I, as medicaments to treat the aforementioned diseases. carboxyalkyl, cyano, cyanoalkyl, formyl, formyla A third aspect of the abovementioned particular variant of lkyl, halogen, haloalkoxy, haloalkyl, heterocyclyl, the invention relates to the novel compounds of the general hydroxy, hydroxyalkyl, mercapto, nitro, and the like, Formula II it being understood that polycyclic cycloalkyl groups one of the distal rings may be aromatic (e.g., 1-inda 45 IIp nyl, 2-indanyl, tetrahydronaphthalene, and the like); x) the term "heterocyclyl alone or in any combination, refers to a monocyclic, bicyclic or polycyclic ring system containing up to 15 ring atoms, at least one of these being a hetero atom independently selected 50 from nitrogen, oxygen or Sulfur, which ring system may be saturated, partially unsaturated, unsaturated or aromatic and may be optionally Substituted with one or more groups, each individually and indepen dently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkyl 55 carbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylendioxy, alkylsulfinyl, alkylsulfinylalkyl, alkyl sulfonyl, alkylsulfonylalkyl, alkylthio, alkylthio alkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, wherein aminocarbonylalkyl, aryl, arylalkenyl, arylalkyloxy, 60 A represents hydrogen; lower alkyl, halogen or cyano; arylalkyl, aryloxy, aryloxycarbonyl, aryloxycarbony B' represents hydrogen; lower alkyl or halogen; lalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, R'', R', R' and R'' independently represent hydrogen; arylsulfonylalkyl, arylthio, arylthioalkyl, carboxy, lower alkyl, halogen; nitro; cyano or formyl; carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, formyl. R" and R' independently represent hydrogen; lower alkyl: formylalkyl, halogen, haloalkoxy, haloalkyl, hetero 65 lower alkenyl: aryl; lower alkoxy-aryl; lower alkoxycarbo cyclyl, heteroaryl, hydroxy, hydroxyalkyl, mercapto, nyl-aryl; lower alkylcarbonyl-aryl: aryl-lower alkoxy-aryl; nitro, and the like: aryl-lower alkyl: aryl-lower alkyl-aryl: arylcarbonyl-aryl; US 7,897,788 B2 21 22 aryloxy-aryl; whereby the aryl group is unsubstituted or wherein mono- or di-substituted with lower alkyl, lower alkoxy, halo A" represents hydrogen; methyl; trifluoromethyl: chloro; or gen, cyano, lower alkoxycarbonyl, lower alkylcarbonyl, phe cyano; nyl, benzyl, benzoyl, benzyloxy, benzyloxycarbonyl, trifluo B" represents hydrogen; methyl; trifluoromethyl; or chloro; rmethyl or trifluormethoxy; cycloalkyl or heteroaryl; R. R. R* and R represent independently hydrogen: RandR'', together with the nitrogenatom to which they are lower alkyl; halo-lower alkyl, lower alkoxy; halogen; nitro: attached, form a heterocyclic ring system; cyano or formyl; and optically pure enantiomers, mixtures of enantiomers, R° and R represent independently hydrogen, lower alk racemates, optically pure diastereoisomers, mixtures of dias enyl, alkoxy-aryl, alkoxycarbonyl-aryl, lower alkyl, alkylcar tereoisomers, diastereoisomeric racemates, mixture of dias bonyl-aryl, arylalkoxy-aryl, arylalkyl, arylalkyl-aryl, aryl, tereoisomeric racemates, meso forms, geometric isomers, arylcarbonyl-aryl, aryloxy-aryl, cycloalkyl, heteroaryl; prodrugs of compounds in which a prodrug forming group is RandR'', together with the nitrogenatom to which they are present, as well as Solvates and morphological forms and attached, form a heterocyclic ring system with 3 to 15 ring pharmaceutically acceptable salts thereof; atoms; with the proviso that the substituents R'', R', R', R'', R' 15 R represents hydrogen; lower alkyl; or arylalkyl; and and R'' all at the same time do not represent hydrogen or in R’ represents lower alkyl; alkoxy-aryl; alkoxycarbonyl-aryl; addition and in case either one of the substituents R' or R' alkylcarbonyl-aryl; arylalkoxy-aryl; arylalkyl, arylalkyl represents hydrogen and the other aryl then the aryl group is aryl; arylcarbonyl-aryl; aryloxy-aryl or cyclylalkyl, and opti not an unsubstituted indol-3-yl-ethyl, benzyl, or phenyl cally pure enantiomers, mixtures of enantiomers, racemates, group, and also not a C-C alkyl, C-C alkoxy or halogen optically pure diastereoisomers, mixtures of diastereoiso mers, diastereoisomeric racemates, mixture of diastereoiso mono-substituted phenyl group, or RandR' together with meric racemates, meso forms, geometric isomers, prodrugs the nitrogen atom to which they are attached do not form a of compounds in which a prodrug forming group is present, as phenyl Substituted piperazine ring; well as Solvates and morphological forms and pharmaceuti it being understood however that in general Formula II, the 25 cally acceptable salts thereof; same definitions i) to Xi) apply as those given for general with the proviso that the substituents R. R. R', R. R. Formula I. and Rall at the same time do not represent hydrogen or in A fourth aspect of the abovementioned particular variant of addition and in case either one of the substituents R or R the invention thus relates to these novel compounds perse as represents hydrogen and the other aryl then the aryl group is well as to their use as pharmaceutically active ingredients. A 30 not an unsubstituted indol-3-yl-ethyl, benzyl, or phenyl fifth aspect of the abovementioned particular variant of the group, and also not a C-C alkyl, C-C alkoxy or halogen invention relates to pharmaceutical compositions containing mono-substituted phenyl group, or RandR together with one or several of these novel compounds. A sixth aspect of the the nitrogen atom to which they are attached do not form a abovementioned particular variant of the invention relates to phenyl Substituted piperazine ring; the use of these novel compounds as CRTH2 antagonists for 35 it being understood however that in general Formula III, the the prevention and/or treatment of chronic and acute allergic same definitions i) to Xi) apply as those given for general immune disorders comprising allergic asthma, rhinitis, Formula I. chronic obstructive pulmonary disease (COPD), dermatitis, In an eighth aspect of the abovementioned particular vari inflammatory bowel disease, rheumatoid arthritis, allergic 40 ant of the invention, Rand R', together with the nitrogen nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, atom to which they are attached, may form a heterocyclic ring food allergy, systemic mast cell disorders, anaphylactic system with 3 to 15 ring atoms and this preferred aspect shock, urticaria, eczema, itching, inflammation, ischemia encompasses novel compounds of Formula IV, reperfusion injury, cerebrovascular disorders, pleuritis, ulcer ative colitis, eosinophil-related diseases. Such as Churg 45 Strauss syndrome and sinusitis, basophil-related diseases, IVP Such as basophilic leukemia and basophilic leukocytosis in humans and other mammals. A seventh aspect of the abovementioned particular variant of the invention relates to novel compounds of the general 50 Formula III,

IIIp 55

COOH

wherein 60 R. R., R and R represent independently methyl; trif luoromethyl: methoxy; fluoro, chloro; RandR, together with the nitrogenatom to which they are attached, form an acridine, azepine, azocine, carbazole, indole, phenanthiridine or quinoline ring; or R represents 65 hydrogen, R represents 2-ethoxy-phenyl, 2-methoxycarbonyl-phenyl, 2-methyl-5-methoxycarbonyl-phenyl, 3-methoxycarbonyl

US 7,897,788 B2 27 28 Therefore, and unless explicitly stated otherwise, the gen the phenyl group may be unsubstituted or substituted with 1 to eral terms and names used hereinbefore and hereinafter pref 3 Substituents selected independently from the group consist erably have within the context of this disclosure the following ing of halogen, alkyl, alkoxy, trifluoromethyl and trifluo meanings: romethoxy. Representative examples of phenylalkyl include, Firstly, any reference to a compound of general formula I is but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, to be understood as referring also to configurational isomers, and the like. mixtures of enantiomers such as racemates, diastereomers, The term “diphenylalkyl, as used herein, alone or in any mixtures of diastereomers, diastereomeric racemates, and combination, refers to an alkyl group wherein two hydrogen mixtures of diastereomeric racemates, as well as salts, solvent atoms have each been replaced by an unsubstituted phenyl complexes, and morphological forms of such compounds, as 10 group. appropriate and expedient. The term “arylalkoxy’, as used herein, alone or in any The term “alkyl or “lower alkyl, as used herein, alone or combination, refers to an aryl group appended to the parent in any combination, refers to a saturated aliphatic group molecular moiety through an alkoxy group wherein however including a straight or branched hydrocarbon chain contain the aryl group may be unsubstituted or substituted with 1 to 3 ing 1-8 carbon atoms, preferably 1-4 carbon atoms. Repre 15 Substituents selected independently from the group consist sentative examples of alkyl include, but are not limited to, ing of halogen, alkyl, alkoxy, trifluoromethyl and trifluo methyl, ethyl, n-propyl, iso-propyl. n-butyl, sec-butyl, tert romethoxy. Representative examples of arylalkoxy include, butyl, iso-butyl (or 2-methylpropyl), n-pentyl (or n-amyl), but are not limited to, 2-phenylethoxy, 5-phenylpentyloxy, iso-pentyl (or iso-amyl), n-hexyl, n-heptyl, n-octyl and the 3-naphth-2-ylpropoxy, and the like. like. The term “arylalkyl, as used herein, alone or in any com The term “alkenyl' or “lower alkenyl', as used herein, bination, refers to an aryl group appended to the parent alone or in any combination, refers to a straight or branched molecular moiety through an alkyl group wherein however hydrocarbon chain containing 2-8 carbon atoms with at least the aryl group may be unsubstituted or substituted with 1 to 3 one carbon-carbon double bond. Representative examples of Substituents selected independently from the group consist alkenyl include, but are not limited to, ethenyl, 2-propenyl, 25 ing of halogen, alkyl, alkoxy, trifluoromethyl and trifluo 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl and romethoxy. Representative examples of arylalkyl include, but the like. are not limited to, benzyl, 2-phenylethyl 3-phenylpropyl. The term “alkoxy” or “lower alkoxy’, as used herein, alone 2-naphth-2-ylethyl, and the like. or in any combination, refers to an alkyl group appended to The term “aryloxy’, as used herein, alone or in any com the parent molecular moiety through an oxygen bridge. Rep 30 bination, refers to an aryl group appended to the parent resentative examples of alkoxy include, but are not limited to, molecular moiety through an oxygenbridge wherein however methoxy, ethoxy, propoxy. 2-propoxy, butoxy, tert-butoxy, the aryl group can be unsubstituted or substituted with 1 to 3 pentyloxy, hexyloxy, and the like. Substituents selected independently from the group consist The term “aryl', as used herein, alone or in any combina ing of halogen, alkyl, alkoxy, trifluoromethyl and trifluo tion (except for arylalkoxy, arylalkyl, aryloxy and arylcarbo 35 romethoxy. Representative examples of aryloxy include, but nyl which are defined below), refers either to a carbocyclic are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, group having at least one aromatic ring, e.g. phenyl or biphe 4-chlorophenoxy, 4-methylphenoxy, 3,4-dimethoxyphe nyl, or multiple condensed ring systems, in which at least one noxy, and the like. ring is aromatic (e.g. 1.2.3,4-tetrahydronaphthyl, naphthyl, The term “arylcarbonyl' or “aroyl', as used herein, alone anthryl, phenanthryl, fluorenyl, indanyl, and the like) or to a 40 or in any combination, refers to an aryl group appended to the phenyl group having two vicinal Substituents forming parent molecular moiety through a carbonyl group wherein together a methylenedioxy chain or an ethylene dioxy chain however the aryl group can be unsubstituted or substituted (that is to a 2,3-dihydrobenzo 1.4 dioxinyl or a benzo. 1.3 with 1 to 3 substituents selected independently from the dioxolyl group). The aryl group may be optionally Substituted group consisting of halogen, alkyl, alkoxy, trifluoromethyl with one to three functional groups individually and indepen 45 and trifluoromethoxy. Representative examples of alkylcar dently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcar bonyl include, but are not limited to, phenylcarbonyl (or bonyl, arylalkoxy, arylcarbonyl, arylalkyl, aryloxy, cyano, benzoyl), naphthylcarbonyl and the like. halogen, haloalkoxy, haloalkyl, nitro, and the like. Besides, in The term "carbonyl', as used herein, alone or in any com the particular cases wherein the aryl group consists of mul bination, refers to a —C(O)—group. tiple condensed ring systems, in which not all rings are aro 50 The term "carboxy’, as used herein, alone or in any com matic, one of the carbon atoms that is not member of an bination, refers to a —COH group. aromatic ring may be in an oxidised form and the correspond The term “carboxyalkyl, as used herein, alone or in any ing —CH2— ring member will then be replaced by combination, refers to a carboxy group appended to the parent —C(O)—, representative examples of Such aryl groups molecular moiety through an alkyl group. Representative include, but are not limited to. 9-oxo-9H-fluorenyl. 55 examples of carboxyalkyl include, but are not limited to, A particular example of the “aryl group is “phenyl. The carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, and the term "phenyl', as used herein, alone or in any combination like. (except for phenylalkyl and diphenylalkyl which are defined The term "cyano', as used herein, alone or in any combi below), refers to an unsubstituted phenyl group or to a phenyl nation, refers to a —C=N group. group Substituted with one to three functional groups indi 60 The term “cycloalkyl, as used herein, alone or in any vidually and independently selected from alkoxy, alkoxycar combination, refers to a saturated cyclic hydrocarbon moiety bonyl, alkyl, alkylcarbonyl, arylalkoxy, arylcarbonyl, aryla containing 3-15 carbon atoms. Representative examples of lkyl, aryloxy, cyano, halogen, haloalkoxy, haloalkyl, nitro, cycloalkyl include, but are not limited to, cyclopropyl. and the like. cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl The term “phenylalkyl, as used herein, alone or in any 65 and the like. combination, refers to a phenyl group appended to the parent The term “cyclylalkyl or “cycloalkyl-alkyl, as used molecular moiety through an alkyl group wherein however herein, alone or in any combination, refers to an cycloalkyl US 7,897,788 B2 29 30 group appended to the parent molecular moiety through an erably in the (R)- or (S)-configuration. Such isomers can be alkyl group. Representative examples of cyclylalkyl or obtained by methods within the knowledge of one skilled in cycloalkyl-alkyl include, but are not limited to, cyclopropyl the art, e.g. by Stereochemically controlled synthesis using methyl, cyclohexylethyl, and the like. chiral synthons or chiral reagents, or by means of classical The term “formyl', as used herein, alone or in any combi separation techniques, such as chromatographic or crystalli nation, refers to a —C(O)H group. Zation methods, or by other methods known in the art, Such as The term “halo' or “halogen', as used herein, alone or in through formation of diastereomeric salts, for example by salt any combination, refers to fluorine, bromine, chlorine, and formation with an enantiomerically pure chiral acid, or by iodine. means of chromatography, for example by using chromato The term "heterocyclyl or "heterocyclic ring system’, as 10 used herein, alone or in any combination, refers to a mono graphic materials modified with chiral ligands. Furthermore, cyclic, bicyclic or polycyclic ring system containing up to the present invention refers to compounds containing centers ring atoms, at least one of these being a heteroatom indepen of any geometric asymmetry, like, for example, unsymmetri dently selected from the group consisting of nitrogen, oxygen cally substituted olefinic double bond, including E or Z geo and Sulfur. The ring system may be saturated, partially unsat 15 metric isomers and mixtures thereof. Generally, pure isomers urated, unsaturated or aromatic. Representative examples of of compounds of Formula I, I, II or II are preferred over heterocyclyl or heterocyclic ring system include, but are not isomeric mixtures. limited to, furyl, imidazolyl, imidazolinyl, imidazolidinyl, In the present invention, the compounds of formula I, I, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, I, I, II, III or IV may be used in the form of pharma oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl. ceutically acceptable salts. The term “pharmaceutically pyrazinyl, pyrazolyl pyridyl, pyrimidinyl, pyridazinyl, pyr acceptable salts' refers to relatively non-toxic, inorganic or rolyl pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro organic acid and base addition salts, which retain the biologi furanyl, tetrahydrothienyl, thiadiazolyl, thiazolyl, thiazoli cal effectiveness and properties of the parent compound, and nyl, thiazolidinyl, thienyl, thiomorpholinyl, benzimidazolyl, which are not biologically or otherwise undesirable (see, e.g., benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, 25 Berge et al., J. Pharm. Sci. (1977), 66, 1-19 or “Salt selection indolyl, indolinyl, isobenzofuranyl, isobenzothienyl, isoin for basic drugs’, Int. J. Pharm. (1986), 33, 201-217). dolyl, isoindolinyl, isoquinolinyl, dihydroisoquinolinyl, Certain compounds of the present invention can contain quinolinyl, dihydroquinolinyl, carbazolyl, phenothiazinyl, one or more basic functional groups, such as amino, alky phenoxazinyl, dihydrodibenzoazocinyl, dibenzoazepinyl, lamino, or arylamino, and, thus, be capable of forming phar dihydrodibenzoazepinyl, oxa-aza-dibenzocycloheptenyl, 30 maceutically acceptable acid addition salts. These acid addi and the like. Defined heterocyclyl moieties may be optionally tion salts may be prepared by Standard procedures in a substituted with one or more groups, each individually and suitable solvent from the parent compound of Formula I or II, independently selected from the group consisting of alkoxy, with an appropriate amount of an inorganic acid, including, alkyl, alkylcarbonyl, halogen, haloalkoxy and haloalkyl. but not limited to, for example, hydrochloric acid, hydrobro The term "heteroaryl', as used herein, alone or in any 35 mic acid, Sulfuric acid, or phosphoric acid; or of an organic combination, refers to a mono-, bi- or tricyclic aromatic ring acid, including, but not limited to, acetic acid, propionic acid, system containing up to 14 ring atoms wherein at least one of octanoic acid, decanoic acid, glycolic acid, pyruvic acid, the rings contains at least one heteroatom independently oxalic acid, maleic acid, malonic acid, Succinic acid, fumaric selected from the group consisting of nitrogen, oxygen and acid, tartaric acid, citric acid, ascorbic acid, amino acids, Such sulfur. The heteroaryl group can be unsubstituted or substi 40 as glutamic acid or aspartic acid, benzoic acid, cinnamic acid, tuted with 1 to 3 substituents selected independently from the salicylic acid, mandelic acid, methanesulfonic acid, ethane group consisting of halogen, alkyl, alkoxy, trifluoromethyl Sulfonic acid, p-toluenesulfonic acid, or other acidic organic and trifluoromethoxy. Representative examples of heteroaryl compounds. include, but are not limited to, thienyl, furanyl, pyrrolyl, Certain compounds of the present invention may, on the thiazolyl, imidazolyl, oxazolyl, pyridyl, quinolinyl, benzimi 45 other hand, contain one or more acidic functional groups and, dazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzo thus, becapable of forming pharmaceutically acceptable base furanyl, indolyl, carbazolyl, phenothiazin, phenoxazin, and addition salts. These salts can be prepared by addition of an the like. appropriate amount, usually in Stoichiometric ratio, of an The term "nitro', as used herein, alone or in any combina alkaline reagent, such as hydroxide, carbonate or alkoxide, tion, refers to a —NO group. 50 containing the appropriate cation, to the free acid in a Suitable The term “oxo', as used herein, alone or in any combina solvent. Preferred inorganic salts include, but are not limited tion, refers to a =O group. to, ammonium, Sodium, potassium, calcium or magnesium, The term "oxy’, as used herein, alone or in any combina also Zinc salts and the like. Preferred salts derived from tion, refers to a —O— group. organic bases include, but are not limited to, salts of primary, Within the scope of the present invention, unless indicated 55 secondary, and tertiary amines, Substituted amines, cyclic otherwise, compounds of formula I, I, I, I, or the novel amines, and basic ion exchange resins, such as isopropy compounds of the formula II, III or IV and pharmaceuti lamine, trimethylamine, diethylamine, triethylamine, tripro cally acceptable salts thereof are included that may exist in, pylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, and be isolated in, isomeric forms, including cis- or trans piperidine, polyamine resins, and the like. isomers or mixtures thereof, and tautomers. Other com 60 Compounds of the present invention containing both acidic pounds of this invention may contain one or more stereogenic and basic groups can also form internal salts (Zwitter ions). or asymmetric centers, such as one or more asymmetric car For isolation or purification purposes, it is also possible to bon atoms, and thus may give rise to optically pure enanti use pharmaceutically unacceptable salts, for example per omers, mixtures of enantiomers, racemates, enantiomer-pure chlorates, picolinates, picrates, or the like. For therapeutic diastereomers, mixtures of diastereomers, epimers, and other 65 use, only pharmaceutically acceptable salts or free com stereoisomeric forms that may be defined, in terms of abso pounds are employed, where applicable in the form of phar lute stereochemistry, as (R)-, (S)- or (R.S)-configured, pref maceutical preparations, and these are therefore preferred. US 7,897,788 B2 31 32 Certain compounds of formula I, II, I2, I, II, III or Churg-Strauss syndrome and sinusitis, basophil-related dis IV, including their salts, may exist in solvated as well unsol eases, such as basophilic leukemia and basophilic leukocyto vated forms, such as, for example, hydrated forms, or their S1S. crystals may, for example, include the solvent used for crys In another aspect, the compounds of formula I, II or I tallization. Different crystalline forms may be present. The may be used as standard or reference compounds in tests or present invention encompasses all Such Solvated and unsol assays involving the inhibition of the CRTH2 receptor. Such vated forms. compounds could be made commercially available for use as The present invention also relates to prodrug derivatives of a reference, quality standard or control, for example in phar the parent compounds of formula I, I, I., I, II, III, or maceutical research when developing new assays or proto IV. The term “prodrug” refers to pharmacologically inactive 10 cols related to CRTH2 activity. precursors of a drug that may be converted into its therapeu As mentioned earlier, compounds of formula I, I, I or tically active form under physiological conditions in Vivo, for I, or salts, or prodrugs thereof, antagonize the PGD2 activa example, when they undergo solvolysis, or enzymatic degra tion of the CRTH2 receptor. The biological effect of such dation in blood, or in cells, (Bundgard H., “Design of Pro compounds may be tested in a variety of in vitro, ex vivo and drugs’, pp. 7-9, 21-24. Elsevier, Amsterdam (1985); Silver 15 in vivo assays. man R. B., “The Organic Chemistry of Drug Design and Drug The ability of the compounds of formula I, I, I or I to Action’, pp. 352-401, Academic Press, San Diego, Calif. bind to the CRTH2 receptor may be measured by methods (1992); Higuchi T. et al., “Pro-drug as Novel Delivery Sys similar to those described in Sawyer N. et al., Br. J. Pharma tems, A.C.S. Symposium Series, Vol. 14). The term “pro col. (2002), 137, 1163-1172 and by the method described drug also includes any covalently bonded carriers, which below in Example B-1. release the active parent compound in vivo when adminis With this type of assay, ICso values (i.e. the concentrations tered to a mammal. Prodrug modifications of a compound where half-maximal inhibition of the interaction is found) in often offer advantages of solubility, bioavailability, absorp the range of 0.001 to 10 uM, preferably values below 1 uM, in tion, tissue compatibility, tissue distribution, or delayed particular values below 0.05 uM, are found with test com release in the mammalian organism. Prodrugs are variations 25 pounds of formula I, I, I or I (see the paragraph entitled or derivatives of the compounds of formula I, which have “Biological results). groups cleavable under metabolic conditions, for example, A functional assay with cells expressing the human pharmaceutically acceptable esters, or amides. Such groups CRTH2 receptor may be used to detect changes in the levels can be cleaved enzymatically or non-enzymatically, or hydro of intracellular calcium concentration following compound lytically to the free hydroxy, carboxy, or amino group of the 30 treatment. After addition of the compound the cells are chal active parent compound. In another embodiment, the prodrug lenged with PGD. In a Fluorescent Imaging Plate Reader is a reduced form, which is oxidized in vivo to the therapeutic (FLIPRTM, Molecular Devices, Sunnyvale, Calif.) fluores compound, for example, a thiol, which is oxidized to a Sul cence emission is recorded during both additions, emission fonate or Sulfate, an alcohol to a carboxylic acid. peak values above base level after PGD addition were Further included within the scope of the present invention 35 exported, normalized to low controls (no PGD) and high are pharmaceutically acceptable esters of the compounds of controls (no active compound). The relative values of the formula I, I, I, I, II, III or IV. The term “pharmaceu remaining activity were used to determine ICso values by tically acceptable esters’ refers to relatively non-toxic, esteri curve fitting the data to a single site to a four-parameter fied products of the parent compound. These esters can be logistic sigmoid dose response curve of the equation (A+((B- prepared in situ during the final isolation and purification of 40 A)/(1+((C/x) D)))). the compounds, or by separately reacting the purified com The ability of the compounds to antagonize PGD induced pounds in its free acid or hydroxyl form with a suitable change of intracellular calcium levels via CRTH2 activation esterifying agent. Carboxylic acids can be converted into may be measured by methods known of one skilled in the art esters via treatment with an alcohol in the presence of a or by the method described below in Example B-2. catalyst. Hydroxyl containing derivatives can be converted 45 With this assay, ICso values (i.e. the concentration of a into esters via treatment with an esterifying agent Such as compound at which the remaining activity is 50%) in the alkanoyl halides. The term further includes lower hydrocar range of 0.001 and 10 uM, preferably below 0.5 LM, are bon groups capable of being Solvated under physiological obtained with test compounds of formula I, II or I (see conditions, for example, alkyl esters, preferred methyl, ethyl, the paragraph entitled “Biological results'). and propyl ester, methoxymethyl ester, methylthiomethyl 50 The results of these assays clearly demonstrate that the ester, pivaloyloxymethyl ester and the like (see, e.g., Berge et present invention provides functional antagonists of the al., J. Pharm. Sci. (1977), 66, 1-19). PGD receptor. The compounds of the present invention have useful, in On the basis of the biological studies discussed herein particular pharmacologically useful, properties. They are above, a compound of Formula I according to the invention able to specifically antagonize the effect of endogenous 55 may show therapeutic efficacy against chronic and acute PGD, on the CRTH2 receptor. allergic/immune disorders such as allergic asthma, rhinitis, A compound or a pharmaceutical composition of the chronic obstructive pulmonary disease (COPD), dermatitis, invention may be used as a drug (medicine) or therapeutic inflammatory bowel disease, rheumatoid arthritis, allergic agent for prevention and/or treatment of both chronic and nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, acute allergic/immune disorders such as allergic asthma, 60 food allergy, systemic mast cell disorders, anaphylactic rhinitis, chronic obstructive pulmonary disease (COPD), der shock, urticaria, eczema, itching, inflammation, ischemia matitis, inflammatory bowel disease, rheumatoid arthritis, reperfusion injury, cerebrovascular disorders, pleuritis, ulcer allergic nephritis, conjunctivitis, atopic dermatitis, bronchial ative colitis, eosinophil-related diseases, such as Churg asthma, food allergy, systemic mast cell disorders, anaphy Strauss syndrome and sinusitis, basophil-related diseases, lactic shock, urticaria, eczema, itching, inflammation, 65 Such as basophilic leukemia and basophilic leukocytosis. ischemia-reperfusion injury, cerebrovascular disorders, pleu A compound of formula I, II or I, a pharmaceutically ritis, ulcerative colitis, eosinophil-related diseases, such as acceptable salt or a prodrug thereof, can be administered US 7,897,788 B2 33 34 alone in pure form or in combination with one or more other The dose to be administered to warm-blooded animals, for therapeutic agents, possible combination therapy taking the example humans of approximately 70 kg body weight, is form of fixed combinations or the administration of a com preferably from approximately 3 mg to approximately 30 g, pound of the invention and one or more other therapeutic more preferably from approximately 10 mg to approximately agents being staggered or given independently of one another, 1000 mg per person per day, divided preferably into 1 to 3 or the combined administration of fixed combinations and single doses which may, for example, be of the same size. The one or more other therapeutic agents. A compound of For amount of the compound actually administered will typically mula I can besides or in addition be administered especially be determined by a physician, in the light of the relevant for prevention and/or treatment of both chronic and acute circumstances, including the condition to be treated, the cho allergic or immune disorders in combination with other 10 Sen route of administration, the actual compound adminis inflammatory diseases. Long-term therapy is equally possible tered, the age, the weight, and response of the individual as is adjuvant therapy in the context of other treatment strat patient, the severity of the patient's symptoms, and the like, egies, as described above. Other possible treatments are pre for example, children usually receive half of the adults dose. ventive therapies, for example in patients at risk. The pharmaceutical compositions comprise from approxi The invention relates to pharmaceutical compositions 15 mately 1% to approximately 95%, preferably from approxi comprising compounds of formula I, II or I, to their use mately 20% to approximately 90%, active ingredient. Phar in therapeutic, in a broader aspect of the invention also pro maceutical compositions according to the invention may be, phylactic treatment or a method of treatment of the diseases for example, in unit dosage forms such as coated and mentioned above, to the compounds for said use and to the uncoated tablets, pills, ampoules, vials, Suppositories, drag preparation of pharmaceutical formulations (medicines). ées, or capsules. Further dosage forms are, for example, oint The pharmaceutically acceptable compounds of the ments, creams, pastes, emulsions, foams, chewable gums, present invention may be used, for example, for the prepara tinctures, lip-sticks, drops, sprays or aerosols, syrups or elix tion of pharmaceutical compositions that comprise an effec irs, dispersions, transdermal patches or pads, or via an intra tive amount of the active ingredient together or in admixture vitreal device that releases the compound in a Sustained with a significant amount of one or more inorganic, organic, 25 capacity, and the like. Examples are capsules containing from Solid or liquid, pharmaceutically acceptable carriers. about 0.05 g to about 1.0 g active ingredient. The invention relates also to a pharmaceutical composition The pharmaceutical compositions of the present invention that is suitable for administration to a warm-blooded animal, are prepared in a manner known, perse, for example by means especially a human (or to cells or cell lines derived from a of conventional mixing, granulating, coating, dissolving, lyo warm-blooded animal, especially a human, for the treatment 30 philizing or confectioning processes. or, in a broader aspect of the invention, prevention of (i.e. Solutions of the active ingredient, and also suspensions, prophylaxis against) a disease that responds to blockade of and especially isotonic aqueous solutions or Suspensions, are the interaction of the CRTH2 receptor with PGD, compris preferably used, it being possible, for example in the case of ing an amount of a compound of formula I, I, I2 or I or a lyophilized compositions, that comprise the active ingredient pharmaceutically acceptable salt or a prodrug thereof, which 35 alone or together with a carrier, for example mannitol, for is effective for said inhibition, together with at least one Such solutions or Suspensions to be produced prior to use. The pharmaceutically acceptable carrier. pharmaceutical compositions may be sterilized and/or may The pharmaceutical compositions according to the inven comprise excipients, for example preservatives, stabilizers, tion are those for enteral administration, Such as nasal, buccal, wetting agents and/or emulsifiers, solubilizers, salts for regu rectal, dermal or, especially oral administration, and for 40 lating osmotic pressure and/or buffers and are prepared in a parenteral administration, Such as intramuscular, intravenous manner known perse, for example by means of conventional or Subcutaneous, intrasternal, intravitreal, injection or infu dissolving or lyophilizing processes. The said solutions or Sion, to warm-blooded animals, especially humans. Such Suspensions may comprise Viscosity-increasing Substances, compositions comprise an effective dose of the pharmaceu Such as Sodium carboxymethylcellulose, carboxymethylcel tically active ingredient, alone or together with a significant 45 lulose, dextran, polyvinylpyrrolidone or gelatin. amount of a pharmaceutically acceptable carrier. The dosage Suspensions in oil comprise as the oil component the Veg of the active ingredient depends on the species of warm etable, synthetic or semi-synthetic oils customary for injec blooded animal, the body weight, the age and the individual tion purposes. There may be mentioned as such especially conditions, individual pharmacokinetic data, the disease to be liquid fatty acid esters that contain as the acid component a treated and the mode of administration. 50 long-chain fatty acid having from 8 to 22, especially from 12 The invention relates also to a process or a method for the to 22, carbon atoms, for example lauric acid, tridecylic acid, treatment of a pathological condition mentioned hereinabove, myristic acid, pentadecylic acid, palmitic acid, margaric acid, especially a disease, which responds to blockade of the inter Stearic acid, arachidic acid, behenic acid or corresponding action of the CRTH2 receptor with PGD, especially allergic/ unsaturated acids, for example oleic acid, elaidic acid, erucic immune disorders such as allergic asthma, rhinitis, chronic 55 acid, brasidic acid or linoleic acid, if desired with the addition obstructive pulmonary disease (COPD), dermatitis, inflam of antioxidants, for example vitamin E, B-caroteine or 3,5-di matory bowel disease, rheumatoid arthritis, allergic nephritis, tert-butyl-4-hydroxytoluene. The alcohol component of conjunctivitis, atopic dermatitis, bronchial asthma, food those fatty acid esters has a maximum of 6 carbon atoms and allergy, systemic mast cell disorders, anaphylactic shock, is mono- or poly-hydroxy, for example a mono-, di- or trihy urticaria, eczema, itching, inflammation, ischemia-reperfu 60 droxy, alcohol, for example methanol, ethanol, propanol, sion injury, cerebrovascular disorders, pleuritis, ulcerative butanol, or pentanol or the isomers thereof, but especially colitis, eosinophil-related diseases, such as Churg-Strauss glycol and glycerol. The following examples of fatty acid syndrome and sinusitis, basophil-related diseases, such as esters are therefore to be mentioned: ethyl oleate, isopropyl basophilic leukemia and basophilic leukocytosis. The com myristate, isopropyl palmitate, “Labrafil M2375” (polyoxy pounds of formula I, I, I, I or salts or prodrugs thereof 65 ethylene glycerol trioleate, Gattefossé, Paris), “Miglyol 812 can be administered as such or especially in the form of (triglyceride of saturated fatty acids with chain length of Cs to pharmaceutical compositions. C, Hills AG, Germany), but especially vegetable oils, such US 7,897,788 B2 35 36 as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, meant methods used heretofore or described in the literature, Soybean oil and more especially groundnut oil. for example those described by Larock R. C. in “Comprehen The injection or infusion compositions are prepared in sive organic transformations: a guide to functional group customary manner understerile conditions; the same applies preparations”, VCH publishers, 1999. also to introducing the compositions into ampoules or vials In the reactions described hereinafter, it may be necessary and sealing the containers. to protect reactive functional groups, for example hydroxy, Pharmaceutical compositions for oral administration can amino, imino, thio or carboxy groups, where these are desired be obtained by combining the active ingredient with solid in the final product, to avoid their unwanted participation in carriers, if desired granulating a resulting mixture, and pro the reactions. Conventional protecting groups may be used in cessing the mixture, if desired or necessary, after the addition 10 of appropriate excipients, into tablets, dragée cores or cap accordance with standard practice, for example see Greene T. sules. It is also possible for them to be incorporated into W. and Wuts P. G. M. in “Protective groups in organic syn plastics carriers that allow the active ingredients to diffuse or thesis” Wiley-Interscience, 1999. be released in measured amounts. Generally, the synthesis of indolacetic acid derivatives of formula I starts as outlined in Scheme 1 and 2 with indole of Suitable carriers are especially fillers, such as Sugars, for 15 example lactose, Saccharose, mannitol or Sorbitol, cellulose formula 1, which by means of phosphorous oxychloride in preparations and/or calcium phosphates, for example trical dimethylformamide is converted in a Vilsmeyer reaction to cium phosphate or calcium hydrogen phosphate, and binders, the formyl derivative of formula 2 (R. Gastpar et al., J. Med. Such as starch pastes using for example corn, wheat, rice, or Chem. (1998), 41, 4965-4972). Subsequent condensation potato starch, gelatin, tragacanth, methylcellulose, hydrox with a secondary amine, such as pyrrolidine or the like, in a ypropylmethylcellulose, Sodium carboxymethylcellulose Solvent appropriate to azeotropically remove waterformed in a reaction, such as toluene, benzene or the like, leads to Schiff and/or polyvinylpyrrolidone, and/or, if desired, disintegra base of formula 3, that then reacts with a compound of for tors, such as the above-mentioned starches, and/or carboxym mula L-CHCOR, in which R represents an alkyl group. ethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic preferably ethyl or tert-butyl, and L is a leaving group, in the acid or a salt thereof. Such as Sodium alginate. Excipients are 25 presence of a base. Such as caesium carbonate, Sodium especially flow conditioners and lubricants, for example hydride or the like, in a suitable solvent, such as alcohol, silicic acid, talc, Stearic acid or salts thereof. Such as magne preferably ethanol, or acetone, tetrahydrofuran, dioxane, to sium or calcium Stearate, and/or polyethylene glycol. Dragée yield indolium salt of Formula 4. Suitable L is a leaving group cores are provided with Suitable, optionally enteric, coatings, such as halo, in particular bromo or chloro. Preferably, the there being used, inter alia, concentrated Sugar Solutions 30 compound of formula L-CHCOR is ethyl bromoacetate. which may comprise gum Arabic, talc, polyvinylpyrrolidone, Indolium salt of formula 4 is condensed with cyanoacetic polyethylene glycol, and/or titanium dioxide, or coating solu acid ester of formula NC CH-COOR', wherein R' repre tions in Suitable organic solvents, or, for the preparation of sents an alkyl group, preferably ethyl or tert.-butyl, in the enteric coatings, solutions of Suitable cellulose preparations, presence of a base. Such as Sodium ethoxide, to form such as ethylcellulose phthalate or hydroxypropylmethylcel 35 cyanoacrylic ester of formula 5 (T. Moriya et al., Chem. lulose phthalate. Capsules are dry-filled capsules made of Pharm. Bull. 1980, 28, 1711-1721). Cleavage of the ester gelatin and of soft sealed capsules made of gelatine and a group, either under acidic or basic conditions, such as TFA in plasticiser, such as glycerol or Sorbitol. The dry-filled cap dichloromethane or sodium hydroxide in THF, respectively, Sules may comprise the active ingredient in the form of gran gave carboxylic acid of formula 6, which then was converted ules, for example with fillers, such as lactose, binders, such as 40 to the corresponding acyl halide of formula 7 by means of a starches, and/or glidants, such as talc or magnesium Stearate, halogenating reagent under conditions known to a skilled and if desired with stabilizers. In soft capsules the active person. Preferably, the carboxylic acid is converted to the acid ingredient is preferably dissolved or suspended in suitable oil chloride using oxalyl chloride in the presence of a catalytical excipients, such as fatty oils, paraffin oil or liquid polyethyl amount of dimethylformamide in an appropriate solvent, ene glycols, it being possible also for stabilizers and/or anti 45 bacterial agents to be added. Dyes or pigments may be added such as dichloromethane or toluene or the like. to the tablets or dragée coatings or the capsule casings, for example for identification purposes or to indicate different doses of active ingredient. Scheme 1 For parenteral administration, aqueous solutions of an 50 R1 active ingredient in water-soluble form, for example of a water-soluble salt, or aqueous injection Suspensions that con R2 POCl, DMF tain viscosity-increasing Substances and stabilizers, are espe N 0° C. to 40° C., 2h cially suitable. The active ingredient, optionally together with excipients, can also be in the form of a lyophilizate and be 55 R3 N made into a solution before parenteral administration by the R4 addition of solvents. 1 A further object of the invention is a process for preparing RI pyridoindol derivatives according to Formula I, I, I or I. CHO Compounds according to formula I of the present invention 60 R2 pyrrollidine, toluene are prepared according to the general sequence of reactions N reflux, 16 h outlined in the schemes below, wherein R', R. R. R. Rand Rare as defined in formula I, I, I, or I. The compounds 3 N obtained may also be converted into a pharmaceutically R H acceptable salt thereof in a manner known perse. 65 R4 Compounds of the invention may be manufactured by the 2 application or adaptation of known methods, by which is US 7,897,788 B2 37 -continued RI / C) Step a) R2 Br COR EtOH, rt, 16 h ^ He HNRR. DIEA R4 10 CHCl2, rt, 4h He

COR R1 15 Intermediate A-G

NC COR NaOEt, EtOH, CHCI Ho

R4 COR 4 Precursor A-G 25

OR

30 Step b)

Deprotection

Deprotection H

(COCl), CH2Cl2 DMF (cat.), rt, 16 h 45

55

The treatment of an acyl halide of formula 7 with a primary amine of formula R. NH in a suitable solvent, such as 60 dichloromethane, tetrahydrofuran, or N,N-dimethylforma mide, gives a N-substituted amide of formula 8, wherein R is COR a hydrogen atom, while a secondary amine of formula 7 NHRR gives a N,N-disubstituted amide of formula 8. Pref. Intermediate A-G 65 erably a base such as triethylamine, N,N-diisopropylethy lamine, N-ethyl-morpholine, N-methylpiperidine, or pyri dine is added to combine with the liberated hydrochloric acid. US 7,897,788 B2 39 40 Hydrolysis of the ester group Rin formula 8 can be carried Particular embodiments of the invention are described in out using routine procedures, as outlined in Scheme 2, Step the following Examples, which serve to illustrate the inven b), for example by stirring withaqueous Sodium hydroxide, or tion in more detail without limiting its scope in any way. trifluoroacetic acid to give a compound of formula (I.4). Alternatively, indolacetic acid derivatives of Formula I can EXAMPLES be synthesized in two consecutive steps as outlined in Scheme 3, starting from abovementioned Schiff base of formula 4 Temperatures are indicated in degrees Celsius (° C.). (Step c), which is reacted first with 2-cyano-acetamide of Unless otherwise indicated, the reactions take place at room formula NC CH CONRR to forman amide of Formula temperature (rt). 8. Final deprotection understandard conditions, as outlined in 10 Scheme 3, Stepb), delivers a final compound of formula (I.4). In mixtures, relations of parts of solvent or eluent or The reagent 2-cyano-acetamide of formula NC CHP reagent mixtures in liquid form are given as Volume relations CONRR is prepared from cyanoacetic acid and a primary or (v/v), unless indicated otherwise. secondary amine under conditions known to a skilled person. ABBREVIATIONS AND ACRONYMS USED Scheme 3 15 Step c) AcOH: acetic acid; NHaOH: ammonium hydroxide: BSA: bovine serum albumin; calcd: calculated; CHCl: dichlo R1 N y romethane; DIEA: N,N-diisopropylethylamine; DMF: N.N- dimethylformamide, DMSO: dimethyl sulfoxide: EDTA: R2 / ethylenediaminetetraacetic acid; EtN: triethylamine: \ Br NC1 NCONRR: EtOAc: ethyl acetate; EtOH: ethanol: g: gram; h: hour; HO: NaOEt, EtOH, CHCI water; HCl: hydrochloric acid; HEPES: 4-(2-hydroxyethyl)- R3 N-- piperazin-1-ethanesulfonic acid buffer, HPLC: high-perfor 4 N 25 mance liquid chromatography; k: kilo; KCOs: potassium R COEt carbonate; KHSO: potassium hydrogenosulfate: 1: liter; 4 MgCl2: magnesium chloride; MgSO: magnesium Sulfate; 1: Precursor A-G micro; m: milli; mol: mole; M: molar, MeOH: methanol; Me: methyl: min: minute: ESI-MS: electrospray ionization mass 30 spectrometry; N: normality of solution; NaNs: sodium azide: NaCl: sodium chloride; NaHCO: sodium hydrogenocarbon ate; NaCO: sodium carbonate; NaOH: sodium hydroxide: NaSO: sodium sulfate; PBS: phosphate buffer saline; PGD: prostaglandin D2: PMSF: phenyl methanesulfonyl 35 fluoride; POCl: phosphorous oxychloride: THF: tetrahydro furan: t: retention time; Tris: tris-(hydroxymethyl)ami nomethane buffer. Analytical HPLC Conditions as Used in the Examples Below 40 Step b) 8 LC-1: Analytical HPLC on a XterraTM MSCs column (50x2.1 mm, 5um, Waters): Linear gradient of water/0.06% formic acid (A) and aceto nitrile/0.06% formic acid (B) from 5% to 95% B over 6 min: 45 flow rate 0.25 ml/min, detection at 215 nm. LC-2: Analytical HPLC on a GromSil MSCs column (50x2.1 mm, 5um, Waters): Deprotection Linear gradient of water/0.06% formic acid (A) and aceto nitrile/0.06% formic acid (B) from 5% to 95% B over 6 min: 50 flow rate 0.25 ml/min, detection at 215 nm. LC-3: Analytical HPLC on a Waters XterraTM MS C18 column (4.6x50mm, 5 mm): Linear gradient of water/0.06% formic acid (A) and aceto nitrile/0.06% formic acid (B) from 5% to 95% B over 1 min: 55 flow rate 3 ml/min. LC-4: Analytical HPLC on a Zorbax SB-AQ column (4.6x 50 mm, 5 mm): Linear gradient of water/0.06% formic acid (A) and aceto nitrile/0.06% formic acid (B) from 5% to 95% B over 1 min: 60 flow rate 3 ml/min. LC-5: Analytical HPLC on a Zorbax SB-AQ column (50x 4.6 mm, 5 mm, Agilent 1100 equipped with a binary pump Dionex P580, a Photodiode Array Detector Dionex PDA-100 and a mass spectrometer Finnigan AQA): 65 Linear gradient of water/0.04% TFA (A) and acetonitrile (B) from 5% to 95% B over 1 min: flow rate 4.5 ml/min, detection at 210, 220, 230, 254 and 280 nm. US 7,897,788 B2 41 42 Synthesis of Precursors A-G of Formula 4 Precursor D: 1-Ethoxycarbonylmethyl-5-fluoro-3- pyrrolidin-1-ylmethylene-3H-indolium bromide Precursor A: 1-ethoxycarbonylmethyl-3-pyrrolidin 1-ylmethylene-3H-indolium bromide The title compound is prepared using a procedure analo 5 gous to the preparation procedure for Precursor B, substitut A-a) 3-Pyrrolidin-1-yl-methylene-3H-indole ing 5-fluoro-1H-indole-3-carbaldehyde for 5-bromo-1H-in dole-3-carbaldehyde. Preparation of 5-fluoro-1H-indole-3- In a round bottom flask equipped with a Dean-Starck con carbaldehyde is performed analogous to 5-bromo-1H-indole denser, 1H-indole-3-carbaldehyde (40 g, 0.275 mmol) and 3-carbaldehyde. t (LC-2) 1.45 min; ESI-MS(+): m/z,303.26 pyrrolidine (27 ml, 0.330 mmol) were suspended in toluene 10 MI" (calcd 303.35 for CHFNO"). (480 ml) and kept heating at reflux overnight. After cooling to Precursor E: 1-Ethoxycarbonylmethyl-5-methyl-3- rt, the solid was filtered off, washed with toluene and recrys pyrrolidin-1-ylmethylene-3H-indolium bromide tallized from THF (100 ml) affording subtitle compound (47.7 g) as a reddish solid in 87% yield. 15 The title compound is prepared using a procedure analo to (LC-2): 0.47 min: ESI-MS(+): m/z 199.46 M+H" gous to the preparation procedure for Precursor A. Substitut (calcd 198.26 for CHN). ing 5-methyl-1H-indole-3-carbaldehyde for 1H-indole-3- carbaldehyde. Preparation of 5-methyl-1H-indole-3- A-b) 1-Ethoxycarbonylmethyl-3-pyrrolidin-1-ylm carbaldehyde is performed analogous to 5-bromo-1H-indole ethylene-3H-indolium bromide 3-carbaldehyde. t (LC-2) 1.46 min; ESI-MS(+): m/z 299.25 MI" (calcd 299.39 for C.HNO"). Ethyl bromoacetate (6.1 ml, 55.4 mmol) was added drop Precursor F: 1-Ethoxycarbonylmethyl-6-fluoro-3- wise to a stirred solution of 3-pyrrolidin-1-yl-methylene-3H pyrrolidin-1-ylmethylene-3H-indolium bromide indole (10g, 50.4 mmol) in EtOH (40 ml) and the reaction mixture was kept stirring at rt overnight. The solid was filtered 25 The title compound is prepared using a procedure analo off, washed with small portions of EtOH and then dried in gous to the preparation procedure for Precursor A. Substitut vacuo, affording title compound (17 g) as a beige solid in 93% ing 6-fluoro-1H-indole-3-carbaldehyde for 1H-indole-3-car yield. t (LC-1): 1.45 min: ESI-MS(+): m/z 285.31 M" baldehyde. Preparation of 6-fluoro-1H-indole-3- (calcd 285.36 for C.H. BrNO"). carbaldehyde is performed analogous to 5-bromo-1H-indole 30 3-carbaldehyde. t (LC-2): 1.45 min: ESI-MS(+): m/z.303.26 Precursor B: 5-bromo-1-ethoxycarbonylmethyl-3- MI" (calcd 303.35 for CHFNO"). pyrrolidin-1-ylmethylene-3H-indolium bromide Precursor G: 1-Ethoxycarbonylmethyl-6-nitro-3- The title compound is prepared using a procedure analo pyrrolidin-1-ylmethylene-3H-indolium bromide 35 gous to Precursor A, substituting 5-bromo-1H-indole-3-car The title compound is prepared using a procedure analo baldehyde for 1H-indole-3-carbaldehyde. t (LC-2): 1.52 gous to the preparation procedure for Precursor A. Substitut min: ESI-MS(+): m/z. 365.10 M+H" (calcd 364.26 for ing 6-nitro-1H-indole-3-carbaldehyde for 1H-indole-3-car C.HBrNO"). baldehyde. Preparation of 6-nitro-1H-indole-3-carbaldehyde is performed analogous to 5-bromo-1H-indole-3-carbalde Preparation of 5-bromo-1H-indole-3-carbaldehyde 40 hyde. t (LC-2): 1.37 min: ESI-MS(+): m/z 330.26 MI" (calcd 330.36 for C, HNO"). Dry DMF (7.5 ml) is cooled to 0° C. and treated dropwise with POCl (3.66 ml, 40 mmol). After stirring at this tempera Preparation of Intermediates A-G of Formula 7 ture for 15 min, a solution of 5-bromo-1H-indole (784 mg. 4 45 Intermediate A: Ethyl 3-(2-chlorocarbonyl-2-cyano mmol) in dry DMF (2 ml) is added and the reaction mixture is vinyl)-indol-1-yl)-acetate allowed to warm to rt within 1 h. Stirring is continued at 40° C. for an additional hour, then the reaction mixture is cooled To a stirred suspension of 2-cyano-3-(1-ethoxycarbonylm to rt and poured onto ice. Aqueous NaOH solution is added to ethyl-1H-indol-3-yl)-acrylic acid (3.0 g, 10 mmol) in dry neutralize the acidic solution, adjusting to pH 6. After stirring 50 dichloromethane (120 ml), in the presence of a few drops of overnight at rt, the precipitate was collected by filtration, dry DMF, was added oxalyl chloride (1.7 ml, 20 mmol). After washed with water and dried under high Vacuum to give pure stirring at rt overnight, the volatiles were removed under Subtitle compound (932 mg) as a beige solid in quantitative reduced pressure, the residue azeotoped twice with dry tolu yield. ene and dried in vacuo, affording crude title compound (3.18 to (LC-2): 1.85 min: ESI-MS(+): m/z 226.10 M+2" 55 g) in quantitative yield. This material was stored under argon (calcd 224.05 for CHBrNO). and was used without further purification. Precursor C: 1-Ethoxycarbonylmethyl-7-methyl-3- A-c) 2-Cyano-3-(1-ethoxycarbonylmethyl-1H-indol pyrrolidin-1-ylmethylene-3H-indolium bromide 3-yl)-acrylic acid 60 To a stirred solution of Precursor A (1-ethoxycarbonylm The title compound is prepared using a procedure analo ethyl-3-pyrrolidin-1-yl-methylene-3H-indolium bromide, gous to the preparation procedure for Precursor B, substitut 4.0 g, 10.8 mmol) and tert-butyl cyanoacetate (15.0 g, 10.8 ing 7-methyl-1H-indole-3-carbaldehyde for 5-bromo-1H-in mmol) in chloroform (100 ml) was added dropwise a solution dole-3-carbaldehyde. Preparation of 7-methyl-1H-indole-3- of sodium ethylate (0.74g, 10.8 mmol) in dry EtOH (40 ml). carbaldehyde is performed analogous to 5-bromo-1H-indole 65 The reaction mixture was kept stirring at rt overnight, then 3-carbaldehyde. t (LC-1) 1.56 min: ESI-MS(+): m/z 299.47 diluted with EtOAc (60 ml) and water (30 ml), acidified to pH MI" (calcd 299.39 for C.HNO"). 3 by adding 1N aqueous HC1. After phase separation, the US 7,897,788 B2 43 44 aqueous phase was extracted twice with EtOAc. The com t (LC-2) 2.18 min (single peak): ESI-MS(+): m/z. 374.45 bined organic layers were washed with water and brine, dried M+H" (calcd373.40 for CHNO). over NaSO, and the solvent removed under reduced pres sure. The residue was dissolved in dichloromethane (20 ml) Step B) and treated with trifluoroacetic acid (8.3 ml, 108 mmol) at rt A stirred solution of crude ethyl 3-(2-cyano-2-phenylcar for 4 h. The volatiles were removed under reduced pressure bamoyl-vinyl)-indol-1-yl)-acetate (0.079 mmol) in THF (0.8 and the residue was azeotoped three times with toluene, then ml) is treated with 0.2N aqueous NaOH (0.4 ml, 0.08 mmol) re-crystallized from EtOAc affording subtitle compound at rt for 10 min. The yellow reaction mixture is diluted with (3.15 g) as a yellow solid in 97% yield: t (LC-2) 1.98 min: water (2 ml) and washed twice with diethyl ether (2 ml). The ESI-MS(+): m/z 324.35 M+Na" (calcd 298.29 for 10 aqueous phase is acidified to pH 1 by adding conc. HCl and C6H4N2O4). extracted with dichloromethane. The solvent is evaporated and the residue is recrystallized from acetonitrile yielding Intermediate B: Ethyl 3-(2-chlorocarbonyl-2-cyano pure title compound. vinyl)-5-bromo-indol-1-yl)-acetate t (LC-2) 1.91 min (single peak): ESI-MS(+): m/z 346.16 M+H" (calcd345.35 for CHNO). 15 Alternatively to re-crystallization, final purification of the The title compound is prepared using a procedure analo title compound is performed by column chromatography on gous to Intermediate A, substituting Precursor B (5-bromo silica gel (hexane/EtOAc 3:1, containing 2% of AcOH), or by 1-ethoxycarbonylmethyl-3-pyrrolidin-1-ylmethylene-3H preparative reversed-phase HPLC. indolium) for Precursor A. Alternatively, indolacetic acid derivatives of the general Formula I are prepared as described below for Example 107. Intermediate C: Ethyl 3-(2-chlorocarbonyl-2-cyano starting with the respective Precursor B and 2-cyano-aceta vinyl)-7-methyl-indol-1-yl)-acetate mide reagent of Formula NC CH CONRR. The title compound is prepared using a procedure analo Example 107 gous to Intermediate A, substituting Precursor C for Precursor A. 25 5-Bromo-3-((E)-2-cyano-2-phenylcarbamoyl-vi nyl)-indol-1-yl)-acetic acid Intermediate D: Ethyl 3-(2-chlorocarbonyl-2-cyano vinyl)-5-fluoro-indol-1-yl)-acetate Step a) Ethyl5-bromo-3-((E)-2-cyano-2-phenylcar bamoyl-vinyl)-indol-1-yl)-acetate 30 The title compound is prepared using a procedure analo A mixture of 2-cyano-N-phenyl-acetamide (122 mg, 0.14 gous to Intermediate A, substituting Precursor D for Precur mmol) and sodium ethylate (9.3 mg, 0.14 mmol) in dry etha sor A. nol (1 ml) is ultra-sonicated for 2 min and then added to a solution of Precursor B (50 mg, 0.14 mmol) in dry ethanol (1 Intermediate E: Ethyl 3-(2-chlorocarbonyl-2-cyano ml). The reaction mixture is stirred at rt for 15 min, the vinyl)-5-methyl-indol-1-yl)-acetate 35 precipitate is filtered off and washed twice with a small amount of ethanol. Pure subtitle compound is obtained as a The title compound is prepared using a procedure analo brownish solid (24 mg) in 39% yield: t (LC-2) 2.51 min: gous to Intermediate A, substituting Precursor E for Precursor ESI-MS(+): m/z 454.09 M+2" (calcd 452.30 for A. CHBrNO). Intermediate F: Ethyl 3-(2-chlorocarbonyl-2-cyano 40 Step b) vinyl)-6-fluoro-indol-1-yl)-acetate The title compound is obtained using conditions for the The title compound is prepared using a procedure analo hydrolysis of the above ester analogous to Example 1. gous to Intermediate A, substituting Precursor F for Precursor to (LC-2)2.25 min: ESI-MS(+): m/z,424.08M+H" (calcd A. 45 423.03 for CHBrNO). Intermediate G: Ethyl 3-(2-chlorocarbonyl-2-cyano Preparation of 2-cyano-acetamide reagents of For vinyl)-6-nitro-indol-1-yl)-acetate mula NC CH CONRR 2-cyano-N-phenyl-acetamide The title compound is prepared using a procedure analo 50 gous to Intermediate A, substituting Precursor G for Precur Cyanoacetic acid (1.0 g, 11.7 mmol) is added to a stirred Sor A. suspension of PC1s (2.4 g 11.7 mmol) in dry dichlo romethane (200 ml). The reaction mixture is heated to reflux Example 1 and kept stirring for 30 min. After cooling to rt, aniline (1.07 55 ml, 11.7 mmol) is added dropwise and the reaction is stirred 3-((E)-2-Cyano-2-phenylcarbamoyl-vinyl)-indol-1- at reflux for additional 2 h, then cooled to 0°C. and neutral yl-acetic acid ized by addition of aqueous saturated NaCO solution. The precipitate is filtered off, washed with water and dried under Step A: Ethyl 3-(2-cyano-2-phenylcarbamoyl-vinyl)- high vacuum to give title compound (1.54 g) as a white solid indol-1-yl)-acetate in 82% yield: t (LC-2) 1.50 min: ESI-MS(+): m/z 183.33 60 M+Na" (calcd 160.17 for CHNO). Aniline (8 ul, 0.09 mmol) is added to a stirred solution of Intermediate A (25 mg, 0.08 mmol) and DIEA (41 ul, 0.24 Other Useful 2-cyano-acetamide reagents mmol) in dry dichloromethane (1 ml). The reaction mixture is stirred at rt overnight, then is washed with 1N aqueous HCl, The following 2-cyano-acetamide reagents were prepared water and saturated aqueous NaHCO solution. The solvent 65 using a procedure analogous to the preparation of 2-cyano of the organic phase is removed yielding crude Subtitle com N-phenyl-acetamide, Substituting the appropriate amine for pound: aniline: US 7,897,788 B2 45 46

Formula tR min MS Data Compound Mol Weight (Method) m/z. M+H" 2-cyano-N-(4-fluoro-phenyl)-N-methyl- C1 OH9N2OF 1.65 193.14 acetamide 192.19 (LC-1) 2-cyano-N-cyclohexyl-N-phenyl-acetamide C15H18N2O 2.12 243.22 242.30 (LC-2) N-butyl-2-cyano-N-phenyl-acetamide C13H16N2O 2.00 217.19 216.30 (LC-2) N-benzyl-2-cyano-N-phenyl-acetamide C16H14N2O 2.02 251.18 2SO.30 (LC-2) 3-(10,11-dihydro-dibenzob.fazepin-5-yl)- C17H14N2O 2.00 263.15 3-oxo-propionitrile 262.31 (LC-2) 3-(3,4-dihydro-2H-quinolin-1-yl)-3-oxo-propionitrile C12H12N2O 1.73 20121 200.24 (LC-2) 3-(2-chloro-phenothiazin-10-yl)-3-oxo-propionitrile C15H9N2SOC 2.22 301.03 300.77 (LC-2) 2-cyano-N-phenyl-N-thiophen-3-ylmethyl-acetamide C14H12N2OS 1.01 256.89 256.33 (LC-4) 2-cyano-N-(2,2-diphenyl-ethyl)-N-phenyl-acetamide C23H2ON2O 1.15 341.97 340.42 (LC-4) 3-(6,11-dihydro-dibenzob.eazepin-5-yl)-3- C17H14N2O 1.03 363.26 oxo-propionitrile 262.31 (LC-4) 2-cyano-N-(3-fluoro-phenyl)-N-methyl-acetamide C1 OH9FN2O O.88 192.94 192.19 (LC-3) 2-cyano-N-methyl-N-(2-trifluoromethyl-phenyl)- C11H9F3N2O O.98 242.97 acetamide 242.2O (LC-3) 2-cyano-N-(3,4-dichloro-phenyl)-N-methyl-acetamide C10H8C12N2O O.99 242.98 243.09 (LC-4) 2-cyano-N-(2,4-difluoro-phenyl)-N-methyl-acetamide C10H8F2N2O O.91 210.21 210.18 (LC-3) 3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxo-propionitrile C12H12N2O O.89 2O112 200.24 (LC-4) 3-oxo-3-(7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-yl)- C13H11F3N2O 1.03 268.87 propionitrile 268.23 (LC-4) 2-cyano-N-ethyl-N-(4-trifluoromethoxy-phenyl)-acetamide C12H11F3N2O2 1.10 272.77 272.22 (LC-3) 3-(5,11-dihydrodibenzob.e. 14 oxazepin- C16H12N2O2 1.01 264.95 5-yl)-3-oxo-propionitrile 264.28 (LC-4)

35 Phenethyl-phenyl-amine give off white crystals of the title compound (1.35 g) in 72% (HNR11R12 for Example 84) yield: t (LC-2) 1.65 min: ESI-MS(+): m/z 210.70 M+H" (calcd 209.29 for CHN). Sodium triacetoxyborohydride (5.46g, 26 mmol) is added 40 in small portions to a stirred solution of aniline (2.0g, 21.5 6,11-Dihydro-5H-dibenzobelazepine (HNR11R12 mmol) and phenylacetaldehyde (2.83 g, 24 mmol) in dry for Example 89) DMF/MeOH/AcOH (87:10:3, 120 ml). After stirring at rt for 90 min, the volatiles are removed under reduced pressure. The Step i) 5.11-Dihydro-dibenzob.eazepin-6-one residue is dissolved in dichloromethane (200 ml) and 45 extracted twice with 1 NHC1. The combined aqueous layers A suspension of anhydrous aluminum chloride (319 mg. are washed with EtOAc, then ammonium hydroxide solution 2.39 mmol) in o-xylene is heated to 110°C. Then, a solution is added to pH 9, and the mixture is extracted with dichlo of 2-benzylphenylisocyanate (500 mg, 2.39 mmol) is added romethane. The solvent is evaporated, and the crude product dropwise and the brown reaction mixture is kept stirring at is purified by silica gel chromatography (hexane/EtOAc. 5:1) 50 150° C. during 1 h. After cooling to rt, the solvent is evapo affording pure title compound as a yellow oil. rated, the residue is dissolved in dichloromethane/methanol to (LC-2) 2.16 min; ESI-MS (positive ion) m/z 198.22 (19:1) and filtered through a small plug of silica gel. The M+H" (calcd 197.28 for CHN). Solvent is evaporated and the crude product is recrystallized from acetonitrile to give pure Subtitle compound as a beige 55 solid (170 mg) in 34% yield (Warawa et al., J. Med. Chem. 5,6,11,12-tetrahydro-dibenzob.fazocine 2001, 44, 372-389): t (LC-2) 1.87 min: ESI-MS(+): m/z (HNR11R12 for Example 85) 210.13 M+H" (calcd 209.24 for CHNO). To a suspension of 11,12-dihydro-5H-dibenzob.flazocin Step ii) 6-one (2.0 g, 8.96 mmol) in dry THF (20 ml) is added drop 60 wise a solution of LiAlH (1.0 N in THF, 8.96 ml) over a To a stirred solution of 55,11-dihydro-dibenzob.eazepin period of 10 min. After ceasing of gas evolution, the reaction 6-one (170 mg, 0.81 mmol) in dry THF (20 ml) is added mixture is kept stirring at reflux overnight, then quenched by dropwise a solution of LiAlH4 (1.0 N in THF, 0.81 mmol) the addition of water (0.48 ml). The precipitate is filtered off over a period of 10 min. After ceasing of gas evolution the and the filtrate is extracted twice with EtOAc. The combined 65 reaction mixture is kept stirring at reflux overnight, cooled to organic layers are dried over NaSO4, the solvent is evapo rt and poured onto water (100 ml). The mixture is extracted rated and the residue recrystallized from boiling hexane to with diethyl ether, the combined organic layers are dried over US 7,897,788 B2 47 48 NaSO and the solvent removed under reduced pressure. The twice with dichloromethane. The aqueous layer is adjusted to residue is recrystallized from boiling hexane affording title pH 9 by the addition of ammonium hydroxide solution and compound as an off white solid (130 mg) in 82% yield: to extracted with dichloromethane. Drying the combined (LC-2) 2.09 min: ESI-MS(+): m/z 197.33 M+2HI" (calcd organic layers over NaSO and evaporating the solvents give 195.26 for CHN). crude title compound as a pale yellow oil. to (LC-2) 1.40 min: ESI-MS(+): m/z 226.23 M+H" (calcd Diphenethyl-amine (HNR11R12 for Example 90) 225.33 for CHN). Examples 2-106 and 108-156 of the following Tables 1 to Sodiumtriacetoxyborohydride (8.87 g., 41.3 mmol) is 8 are prepared using a procedure analogous to that described added in small portions at 0°C. to a stirred solution of phen 10 for Example 1, Substituting the appropriate amine for aniline ethylamine (5.0 g, 41.3 mmol) and phenylacetaldehyde (4.96 and the appropriate Intermediate for Intermediate A respec g, 41.3 mmol) in methanol (50 ml). The reaction mixture is tively; or analogous to that described for Example 107, sub stirred at rt overnight, poured onto saturated aqueous KHPO, stituting the appropriate 2-cyano-acetamide for 2-cyano-N- solution and extracted twice with EtOAc. The solvent is phenyl-acetamide and the appropriate Precursor for evaporated, the residue is taken up in 1N HCl and washed Precursor B. TABLE 1. Examples 1-106 with the general structure of

I

tR MS Data Formula min mz Ex. Name R R6 Mol weight (Meth.) M + H" 1 3-((E)-2-cyano-2- H phenyl C2OH1SN3O3 1.91 346.16 phenylcarbamoyl 345.357 (LC-2) vinyl)-indol-1-yl)- acetic acid 2 3-((E)-2-cyano-2-m- H 3-methyl-phenyl C21H17N3O3 2.22 26O20 tolylcarbamoyl-vinyl)- 359.384 (LC-1) indol-1-yl)-acetic acid 3 {3-(E)-2-cyano-2-(4- H 4-methoxy- C21H17N3O4. 2.10 376.25 methoxy phenyl 375.383 (LC-1) phenylcarbamoyl)- vinyl-indol-1-yl)- acetic acid 4 {3-(E)-2-(3-bromo 3-bromo-phenyl C2OH14N3O3Br 2.34 426.OO phenylcarbamoyl)-2- 424.253 (LC-1) cyano-vinyl-indol-1- yl)-acetic acid 5 {3-(E)-2-cyano-2- cyclohexyl- C21H23N3O3 2.08 366.24 (cyclohexylmethyl methyl 365.432 (LC-2) carbamoyl)-vinyl indol-1-yl)-acetic acid 6 3-((E)-2-cyano-2- phenethyl C22H19N3O3 1.94 374.2O phenethylcarbamoyl 373.411 (LC-2) vinyl)-in acetic 7 3-((E)-2-cyano-2- isopropyl C17H17N3O3 1.73 312.34 isopropy 3.11.34 (LC-2) vinyl)-in acetic 8 3-((E)-2-cyano-2- propyl C17H17N3O3 1.73 312.23 propylcarbamoyl 3.11.34 (LC-2) vinyl)-i 800 9 3-((E)-2-cyano-2- cyclohexyl C2OH21N3O3 1.96 352.26 cyclohexylcarbamoyl 351.405 (LC-2) viny 800

US 7,897,788 B2 79 80 TABLE 8 Examples 155-156 with the general structure of

I

R4 Noon Formula I, wherein R = R = R = H.

MS Data Formula tR min Ex. Compound R 4 R R6 Mol weight (Method) {3-(E)-2-cyano methyl phenyl cyclohexyl 1.04 442.33 2-(cyclohexyl 441.529 (LC-5) phenyl-carbamoyl)- vinyl-7-methyl indol-1-yl)-acetic acid 156 (3-(E)-2-cyano methyl methyl 4-fluoro O.98 334.26 2-(4-fluoro phenyl 391401 (LC-5) phenyl)-methyl carbamoyl-vinyl 7-methyl-indol 1-yl)-acetic acid

Biological Assays Microscint-40 (Packard) are added and the bound radioactiv 35 ity is quantified by means of Topcount (Packard). Example B-1 Example B-2 Preparation of CRTH2 Membranes an Radioligand Binding Assay Intracellular Calcium Mobilization Assay (FLIPR) 40 Preparation of the membranes and radioligand binding Cells (HEK-293), stably expressing the hCRTH receptor assays are performed according to known procedures, e.g. under the control of the cytomegalovirus promotor from a Sawyer N. et al. (Br. J. Pharmacol., 2002, 137, 1163-1172). A single insertion of the expression vector pcDNA5 (Invitro clonal HEK 293 cell line, expressing high level of recombi gen), are grown to confluency in DMEM (low glucose, nant hCRTH2 receptor, is selected for the preparation of 45 Gibco) medium supplemented with 10% fetal calf serum membranes. Cells are detached from culture plates in 5 ml (both Bioconcept, Switzerland) under standard mammalian buffer A per plate (5 mM Tris, 1 mM MgClx6HO, 0.1 mM cell culture conditions (37°C. in a humidified atmosphere of PMSF, 0.1 mM phenanthroline) using a police rubber and 5% CO). Cells are detached from culture dishes using a transferred into centrifugation tubes and frozen at -80° C. dissociation buffer (0.02% EDTA in PBS, Gibco) for 1 min, After thawing, the cells are centrifuged at 500 g for 5 min and 50 and collected by centrifugation at 200 g at rt for 5 minin assay then resuspended in buffer A. Cells are then fragmented by buffer (equal parts of Hank's BSS (HBSS, Bioconcept) and homogenization with a Polytron homogenizer for 30s. The DMEM (low glucose, without phenol red, Gibco)). After membrane fragments are centrifuged at 3000 g for 40 minand incubation for 45 min (37°C. and 5% CO) in the presence of resuspended in membranes in buffer B (50 mM Tris, 25 mM 1 uM Fluo-4 and 0.04% Pluronic F-127 (both Molecular MgCl, 250 mM saccharose, pH 7.4) and aliquots are stored 55 Probes), 20 mM HEPES (Gibco) in assay buffer, the cells are frozen. washed with and resuspended in assay buffer, then seeded Binding assay is performed in a total volume of 250 ul. In onto 384-well FLIPRassay plates (Greiner) at 50,000 cells in each well, 75ul buffer C (50 mM Tris, 100 mM. NaCl, 1 mM 66 ul per well), and sedimented by centrifugation. EDTA, 0.1% BSA (protease free), 0.01% NaNs, pH 7.4) was Stock Solutions of test compounds are made up at a con mixed with 50 ul{H}-PGD (at 2.5 nM (220,000 dpm per 60 centration of 10 mM in DMSO, and serially diluted in assay well) from Amersham, TRK734), 100 ul CRTH2 membranes buffer to concentrations required for inhibition dose response to give 80 ug per well and 25ul of test compound in buffer C curves. Prostaglandin D. (Biomol, Plymouth Meeting, Pa.) is containing 1% DMSO. For unspecific binding, PGD2 is used as an agonist. added to the reaction mixture at 1 uM final concentration. A FLIPR384 instrument (Molecular Devices) is operated This binding assay mix is incubated at rt for 90 min and then 65 according to the manufacturer's standard instructions, adding filtered through a GF/C filter plate. The filter is washed three 4 ul of test compound dissolved at 10 mM in DMSO and times with ice cold binding buffer. Then, 40 ul per well diluted prior to the experiment in assay buffer to obtain the US 7,897,788 B2 81 82 desired final concentration. 10 ul of 80 nM prostaglandin D. carbonyl-aryl or aryloxy-aryl, or R and R', together (Biomol, Plymouth Meeting, Pa.) in assay buffer, supple with the nitrogen atom to which they are attached, form mented with 0.8% bovine serum albumin (fatty acid con a heterocyclic ring system; tent<0.02%, Sigma), is then added to obtain a final concen or a salt of the compound of formula I; tration of 10 nM and 0.1%, respectively. Changes in 5 with the proviso that the compound is not: fluorescence are monitored before and after the addition of {3-(E)-2-cyano-2-(4-fluoro-phenylcarbamoyl)-vinyl-in test compounds at 488 nm and 540 nm. Emission dol-1-yl)-acetic acid; peak values above base level after prostaglandin D addition 3-((E)-2-cyano-2-m-tolylcarbamoyl-vinyl)-indol-1-yl)- are exported after base line subtraction. Values are normal acetic acid; ized to high-level control (no test compound added) after 10 {3-(E)-2-(3-bromo-phenylcarbamoyl)-2-cyano-vinyl Subtraction of base line value (no prostaglandin D added). The program XLlfit 3.0 (IDBS) is used to fit the data to a indol-1-yl)-acetic acid; single site dose response curve of the equation (A+((B-A)/ 3-((E)-2-cyano-2-phenylcarbamoyl-vinyl)-indol-1-yl)- (1+((C/x) D)))) and to calculate the ICs values. acetic acid; 15 3-((E)-2-benzylcarbamoyl-2-cyano-vinyl)-indol-1-yl)- BIOLOGICAL RESULTS acetic acid; 3-((E)-2-cyano-2-o-tolylcarbamoyl-vinyl)-indol-1-yl)- The following results have been obtained using the proce acetic acid; dures given above (biological tests B1 and B2) for the above 3-((E)-2-cyano-2-p-tolylcarbamoyl-vinyl)-indol-1-yl)- mentioned example compounds: acetic acid; {3-(E)-2-(4-bromo-phenylcarbamoyl)-2-cyano-vinyl indol-1-yl)-acetic acid; {3-(E)-2-cyano-2-(4-ethyl-phenylcarbamoyl)-vinyl-in CRTH2 binding ICs (nM) CRTH2 FLIPRICs (nM) Example No. (method B1 above) (method B2 above) dol-1-yl)-acetic acid; 25 {3-(E)-2-cyano-2-(4-methoxy-phenylcarbamoyl)-vinyl 12 29 90 indol-1-yl)-acetic acid; 29 42 151 45 7 48 {3-(E)-2-cyano-2-(4-ethoxy-phenylcarbamoyl)-vinyl 46 11 61 indol-1-yl)-acetic acid; 47 9 S4 3-((E)-2-cyano-2-isopropylcarbamoyl-vinyl)-indol-1- 49 35 146 30 yl-acetic acid; S4 18 98 64 40 61 {3-(E)-2-cyano-2-(3-ethoxy-phenylcarbamoyl)-vinyl 70 76 58 indol-1-yl)-acetic acid: 87 12 57 {3-(E)-2-cyano-3-2-(1H-indol-3-yl)ethylaminol-3- 89 6 114 oxo-1-propenyl-indol-1-yl)-acetic acid; 94 10 181 35 99 16 159 {3-(E)-2-cyano-2-(4-chloro-phenylcarbamoyl)-vinyl 101 15 182 indol-1-yl)-acetic acid; 113 9 66 {3-(E)-2-cyano-3-(4-methyl-piperidin-1-yl)-3-oxo-pro 141 17 47 penyl-indol-1-yl)-acetic acid; 149 49 253 {3-(E)-2-(3-chloro-4-methyl-phenylcarbamoyl)-2-cy 40 ano-vinyl-indol-1-yl)-acetic acid: {3-(E)-2-cyano-2-(3-phenyl-propylcarbamoyl)-vinyl The invention claimed is: indol-1-yl)-acetic acid; 1. A compound of formula I {3-(E)-2-cyano-2-(2,3-dichloro-phenylcarbamoyl)-vi nyl-indol-1-yl)-acetic acid; 45 {3-(E)-2-(5-chloro-2-methyl-phenylcarbamoyl)-2-cy ano-vinyl-indol-1-yl)-acetic acid: {3-(E)-2-cyano-2-(4-methoxy-benzylcarbamoyl)-vinyl indol-1-yl)-acetic acid; {3-(E)-2-cyano-2-(2-fluoro-phenylcarbamoyl)-vinyl-in 50 dol-1-yl)-acetic acid; or {3-(E)-2-cyano-3-oxo-3-(4-phenyl-piperazin-1-yl)-pro penyl-indol-1-yl)-acetic acid. 2. The compound according to claim 1, wherein the groups R and R do not form a heterocyclic ring system together 55 with the nitrogenatom to which they are attached; or a salt of the compound. 3. The compound according to claim 2, wherein R is aryl and R is alkyl, cycloalkyl, alkenyl, cyanoalkyl, diphenyla wherein lkyl, heteroaryl-alkyl, aryl-alkyl or aryl; or a salt of the com A represents cyano; 60 pound. B represents hydrogen; 4. The compound according to claim 2, wherein R is R", R. RandR'independently represent hydrogen, alkyl, aryl-alkyl and R is alkyl, aryl or aryl-alkyl; or a salt of the halogen, nitro, cyano or formyl; and compound. R and R independently represent hydrogen, alkyl, 5. The compound according to claim 1, wherein the groups cycloalkyl, cycloalkyl-alkyl, heteroaryl, heteroaryl 65 RandR form a heterocyclic ring system together with the alkyl, alkenyl, carboxyalkyl, cyanoalkyl, diphenylalkyl, nitrogen atom to which they are attached; or a salt of the aryl, aryl-alkoxy-aryl, aryl-alkyl, aryl-alkyl-aryl, aryl compound.

US 7,897,788 B2 87 88 3-((E)-2-cyano-3-dibenzob.fazepin-5-yl-3-oxo-prope attached, then said heterocyclic ring system is neitheran nyl)-6-methyl-indol-1-yl)-acetic acid; unsubstituted or Substituted piperidine nor an unsubsti {3-(E)-2-cyano-3-(6,11-dihydro-dibenzob.elazepin-5- tuted or Substituted piperazine; or a salt of the com yl)-3-oxo-propenyl-6-methyl-indol-1-yl)-acetic acid; pound. {3-(E)-2-cyano-3-(10,11-dihydro-dibenzob.fazepin-5- 5 8. A pharmaceutical composition comprising at least one yl)-3-oxo-propenyl-6-methyl-indol-1-yl)-acetic acid; compound according to claim 1 and a pharmaceutically {3-(E)-2-(benzyl-phenyl-carbamoyl)-2-cyano-vinyl-6- acceptable carrier. methyl-indol-1-yl)-acetic acid; 9. A method for treating chronic or acute allergic immune {3-(E)-2-cyano-2-(cyclohexyl-phenyl-carbamoyl)-vi disorders comprising the administration of a therapeutically nyl-6-methyl-indol-1-yl)-acetic acid; 10 (3-(E)-2-cyano-2-(4-fluoro-phenyl)-methyl-carbam effective amount of the compound according to claim 1, oyl-vinyl-6-methyl-indol-1-yl)-acetic acid; wherein the disorder is allergic asthma, rhinitis, chronic {3-(E)-2-(butyl-phenyl-carbamoyl)-2-cyano-vinyl]-6- obstructive pulmonary disease (COPD), dermatitis, inflam methyl-indol-1-yl)-acetic acid; matory bowel disease, rheumatoid arthritis, allergic nephritis, {3-(E)-2-cyano-2-(cyclohexyl-phenyl-carbamoyl)-vi 15 conjunctivitis, atopic dermatitis, bronchial asthma, food nyl-7-methyl-indol-1-yl)-acetic acid; or allergy, anaphylactic shock, urticaria, eczema, itching, (3-(E)-2-cyano-2-(4-fluoro-phenyl)-methyl-carbam inflammation, ischemia-reperfusion injury, pleuritis, ulcer oyl-vinyl-7-methyl-indol-1-yl)-acetic acid; or ative colitis, Churg-Strauss syndrome, sinusitis, basophilic a salt of the compound. leukemia, or basophilic leukocytosis. 10. The compound of claim 1, wherein the compound is 7. The compound according to claim 1, wherein the com {3-(E)-2-cyano-3-(3,4-dihydro-2H-quinolin-1-yl)-3-oxo pound is of formula I propenyl-indol-1-yl)-acetic acid. 11. The compound of claim 1, wherein: A is cyano; B is hydrogen; 25 R", R, R and Rare all hydrogenatoms or one of R', R, RandR is halogen while the others are all hydrogen; and at least one of RandR is chosen from the group consist ing of heteroaryl, heteroaryl-alkyl, diphenylalkyl, aryl, 30 aryl-alkoxy-aryl, aryl-alkyl, aryl-alkyl-aryl, arylcarbo nyl-aryl and aryloxy-aryl; or R and R', together with the nitrogen atom to which they are attached, form a heterocyclic ring system; or a salt of the compound. 12. A method for treating chronic or acute allergic immune 35 disorders comprising the administration of a therapeutically wherein effective amount of the compound according to claim 11, A represents cyano; wherein the disorder is allergic asthma, rhinitis, chronic B represents hydrogen; obstructive pulmonary disease (COPD), dermatitis, inflam R", R. RandR'independently represent hydrogen, alkyl, 40 matory bowel disease, rheumatoid arthritis, allergic nephritis, halogen, nitro, cyano or formyl; and conjunctivitis, atopic dermatitis, bronchial asthma, food R and R independently represent hydrogen, alkyl, allergy, anaphylactic shock, urticaria, eczema, itching, cycloalkyl, cycloalkyl-alkyl, heteroaryl, heteroaryl inflammation, ischemia-reperfusion injury, pleuritis, ulcer alkyl, alkenyl, carboxyalkyl, cyanoalkyl, diphenylalkyl, ative colitis, Churg-Strauss syndrome, sinusitis, basophilic aryl, aryl-alkoxy-aryl, aryl-alkyl, aryl-alkyl-aryl, aryl leukemia, or basophilic leukocytosis. carbonyl-aryl or aryloxy-aryl, or R and R, together 45 13. The method for treating chronic or acute allergic with the nitrogen atom to which they are attached, form immune disorders comprising the administration of a thera a heterocyclic ring system; peutically effective amount of the compound according to provided that at least one of the following conditions must claim 6, wherein the disorder is allergic asthma, rhinitis, be met: 50 chronic obstructive pulmonary disease (COPD), dermatitis, one of R', R, R and R is different from a hydrogen inflammatory bowel disease, rheumatoid arthritis, allergic atom; or nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, when Rand Rare such that they do not form a hetero food allergy, anaphylactic shock, urticaria, eczema, itching, cyclic ring system together with the nitrogen atom to inflammation, ischemia-reperfusion injury, pleuritis, ulcer which they are attached, then both R and -R are 55 ative colitis, Churg-Strauss syndrome, sinusitis, basophilic different from hydrogen and one of R and R is dif leukemia, or basophilic leukocytosis. ferent from alkyl; or when RandR are such that they form a heterocyclic ring system together with the nitrogenatom to which they are