MX2008006758A - Novel vinylogous acids derivatives - Google Patents

Abstract

The invention is concerned with novel vinylogous acids derivatives of formula (I) wherein A and R1to R6are as defined in the description and in the claims, as well as physiologically acceptable salts thereof. These compounds inhibit chymase and can be used as medicaments.

Description

NEW DERIVATIVES OF ACIDS VINYLLOGS DESCRIPTION OF THE INVENTION The present invention relates to new vinyl acid derivatives of the formula (I), (i) wherein A is -CH2-, -0- or -NR'-, wherein R 'is hydrogen or C? _6 alkyl, or R' and R4 form a C2_5 alkylene; R1 is hydrogen, halogen, nitro, cyano, amino, C? _6 alkyl, heteroalkyl, C3_7 cycloalkyl, C2_6 alkenyl, C2_6 alkynyl, hydroxy, C? -6 alkoxy, -NR'R ", - (C0_6 alkylene) ) -NR'R ", in which R 'and R" independently of each other are selected from the group consisting of hydrogen, C? _6 alkyl, heteroalkyl, formyl, C? -6 alkylcarbon, optionally substituted C3_7 cycloalkylcarbonyl, arylcarbonyl optionally substituted, optionally substituted heteroarylcarbonyl, optionally substituted heterocyclylcarbonyl, C 1-6 alkylsulfonyl, C 3 cycloalkylsulfonyl, optionally REF.: 193224 substituted, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl and optionally substituted heterocyclylsulfonyl, or - (alkylene Co-e) _0R ', wherein R' is hydrogen, C? _6 alkyl, heteroalkyl, formyl or C? _6 alkylcarbonyl; R2, R2 'and R2 independently from each other are hydrogen, halogen, cyano, nitro, amino, amino mono- or disubstituted by C? -6 alkyl, C? _6 alkyl, C2_6 alkenyl, C2_6 alkynyl, heteroalkyl, hydroxy or Ci-β alkoxy; R3 is hydrogen, halogen, cyano, nitro, amino, amino mono- or disubstituted by C? -6 alkyl, C? -6 alkyl, C2-6 alkenyl, C2_6 alkynyl, heteroalkyl, hydroxy, C? -6 alkoxy, C3_7 cycloalkyl optionally substituted, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C3-7 cycloalkyl-C6-alkyl, optionally substituted arylalkyl -6, optionally substituted heteroaryl-C6-6alkyl, or heterocyclyl-C-alkyl? _6 optionally substituted; R 4 is hydrogen, halogen, cyano, nitro, amino, amino mono- or disubstituted by C 1-6 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroalkyl, hydroxy, C 1-6 alkoxy, optionally substituted C 3-7 cycloalkyl, aryl optionally substituted, optionally substituted heteroaryl, optionally substituted heterocyclyl, C3_7 cycloalkyl optionally substituted C6_6 alkyl, optionally substituted C6_6 arylalkyl, optionally substituted C6_6 heteroaryl_alkyl, or optionally substituted C6_6 heterocyclylC_6alkyl; R5 is hydrogen or C6-alkyl; or R 4 and R 5, together with the carbon atom to which they are attached, form an optionally substituted C 3 cycloalkyl ring or an optionally substituted heterocyclyl ring; R6 is hydrogen or C6-alkyl; and prodrugs and pharmaceutically acceptable salts thereof. The invention further relates to a process and an intermediate compound for the preparation of the above compounds, to pharmaceutical preparations containing the compounds, to the use of these compounds for the manufacture of pharmaceutical preparations as well as to a process for the preparation of the intermediate compound . The compounds of the formula (I) inhibit chymase. Chymase is a serine proteinase of an expression model limited strictly to a subpopulation of mast cells (MCt mast cells). • Chymase is only activated after activation and degranulation of mast cells which restricts the activity of the enzyme to positive tissues. of MCt- Chymase breaks down a large number of substrates pathologically relevant (Raymond, WW, SW Ruggles et al., JBC 278 (36), 34517-34524, 2003), thereby activating angiotensin II, endothelin, TGFb, 111, SCF, collagenase and degrading thrombin-like proteins, FN, APO Al, 2. This model makes chymase an attractive target for allergic, inflammatory and fibrotic diseases It is true that a large number of studies of chymase inhibitors have been successful in animals and have proved their effectiveness in animals atopics, vascular lesions and atherosclerosis (Doggrell, SA, Wanstall JC, Can. J. Physiol. Pharmacol. 83 (2), 123-30, February 2005; Lindstedt K.A., Kovanen P.T., Curr. Opin. Lipidol. 15 (5), 567-73, Oct. 2004; Reed CE., Kita H., J. Allergy. Clin. I munol. 114 (5), 997-1008, Nov. 2004; Takai S. et al., Eur. J. Pharmacol. 501 (1-3), 1-8, 6 oct. 2004; Takai S. et al., Trends Pharmacol. Sci. 25 (10), 518-22, Oct. 2004; Takai S., Miyazaki M., Curr. Vasc. Pharmacol. 1 (2), 217-24, Jun. 2003. Therefore, the inhibition of chymase seems to be a useful modality for the treatment of allergy, asthma, peripheral arterial occlusive disease, ischemia of a critical limb, patients with vulnerable atherosclerotic plaque, unstable angina, congestive heart failure, left ventricular hypertrophy , reperfusion injury of ischemia, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, bowel disease irritable, Crohn's disease, wound healing (burns / ulcers in dies / CLI). The present invention provides novel compounds of formula (I), which are inhibitors of chymase. Unless indicated otherwise, the following definitions are established to illustrate and delimit the meanings and scope of the various terms used to describe the invention. The term "halogen" or "halo" means fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred. The term "C?-6 alkyl", alone or in combination with other groups, means a monovalent, straight or branched chain alkyl radical having from one to six carbon atoms. This term is further exemplified by terms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl. C 4 alkyl is more preferred. The term "heteroalkyl" means C? _6 alkyl substituted by one or more substituents independently selected from the group consisting of nitro, hydroxy, halogen, cyano, C? _6 alkoxy, formyl, C? _6 alkylcarbonyl, carboxyl, C-6 alkylthio , C 1 -C 6 alkylsulfinyl, C 6 alkylsulfonyl, amino and mono- or disubstituted amino by C 6 -alkyl. This term is further exemplified by radicals such as 2-hydroxyethyl, perfluoromethyl, C?-6 alkyls substituted by a hydroxy group or from one to three identical or different halogen atoms are preferred. The term "C3_7 cycloalkyl", alone or in combination with other groups, means a saturated monovalent cyclic hydrocarbon radical of three to seven ring carbon atoms, for example, cyclopropyl, cyclobutyl, cyclohexyl. The term "C 1-6 alkoxy", alone or in combination with other groups, means the group R'-O-, wherein R 'is a C-6 alkyl. The term "C2_6 alkenyl", alone or in combination with other groups, means a straight or branched chain hydrocarbon residues containing an olefinic bond and having from two to six carbon atoms, for example, ethenyl, 2-propenyl. The term "C2-6 alkynyl", alone or in combination with other groups, means a straight or branched chain hydrocarbon residue containing a triple bond and having from two to six carbon atoms, for example, ethynyl, 2-propynyl. The term "alkylene Co-e" means a divalent saturated, straight-chain or branched aliphatic hydrocarbon bond or chain of 1 to 6 carbon atoms. Alkylene Co means a bond.

The term "aryl", alone or in combination with other groups, means a phenyl or naphthyl radical, preferably a phenyl radical. The term "heterocyclyl", alone or in combination with other groups, means non-aromatic mono- or bicyclic radicals, of three to eight ring atoms, in which one or two ring atoms are heteroatoms chosen from N, 0 and S (0) n (where n is an integer between 0 and 2), the other ring atoms are C. The term "heteroaryl" means a monocyclic or bicyclic radical, of 5 to 12 atoms in the ring, which has at least one aromatic ring containing one, two or three heteroatoms in the ring selected from N, 0 and S, the other ring atoms are C. The point of attachment of the heteroaryl radical will preferably be located in the aromatic ring. The terms "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted heterocyclyl" and "optionally substituted C3_ cycloalkyl" mean aryl, heteroaryl, heterocyclyl and C3- cycloalkyl, respectively, optionally substituted by one or more substituents independently chosen from if between the group consisting of halogen, nitro, cyano, amino, C6 alkyl, C2-6 alkenyl, C2_6 alkynyl, hydroxy, C6_6 alkoxy, amino mono- or disubstituted by C6_6 alkyl and heteroalkyl. The preferred radicals of the chemical groups, whose definitions have been presented above, are those specifically exemplified in the examples. The compounds of the formula (I) can form pharmaceutically acceptable acid addition salts. Examples of such pharmaceutically acceptable salts are the salts of the compounds of the formula (I) with physiologically compatible inorganic acids, for example hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid.; or with organic acids, for example methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The term "pharmaceutically acceptable salts" means this type of salts. The compounds of the formula (I), in which a COOH group is present, can also form salts with bases. Examples of such salts are the alkali metal, alkaline earth metal and ammonium salts, for example, the Na, K, Ca and trimethylammonium salt. The term "pharmaceutically acceptable salts" also indicates this type of salts. The aforementioned acid addition salts are preferred. "Optional" or "optionally" means that the event or circumstance described below may occur but not necessarily and that the description includes the cases in which the event or circumstance occurs and the cases in which it does not occur. For example, "aryl group optionally substituted with an alkyl radical" means that the alkyl radical may be present but not necessarily and the description includes situations in which the aryl group is substituted by an alkyl group and the situations in which the group aryl is not substituted by the alkyl group. "Pharmaceutically acceptable excipient" means an excipient that is useful for the manufacture of a pharmaceutical composition, which is generally safe, non-toxic and non-disruptive in a biological sense or in any other sense and includes the excipient that is acceptable for veterinary use and also for human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the description and claims includes both one and more than one excipient. Compounds that have the same molecular formula but differ in the nature or binding sequence of their atoms or in the configuration of their atoms in space are termed "isomers". The isomers that differ in the ordering of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are called "diastereomers" and those that are non-overlapping mirror images are called "enantiomers". When a compound has an asymmetric center, for example, when a carbon atom is attached to four different radicals, the existence of a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and described by the R and S sequencing rules of Cahn, Ingold and Prelog or by the way in which the molecule rotates the plane of polarized light and is then called dextrorotatory. or levorotatory (that is, isomer (+) and (-), respectively). A chiral compound can exist in the form of an individual enantiomer or in the form of a mixture of enantiomers. A mixture containing the same proportion of both enantiomers is called a "racemic mixture." The compounds of the formula (I) may have one or more asymmetric centers. Unless otherwise indicated, both enantiomers and mixtures thereof, racemic or of the type, are included in the description or mention of a particular compound in the description or in the claims. Methods for the determination of stereochemistry and separation of stereoisomers are well known in the art (see chapter 4 of "Advanced Organic Chemistry", 4th edition, J. March, John Wiley &Sons, New York, 1992) . In the above, the definition has been described more of this invention, but certain compounds of the formula (I) are preferred. i) A preferred compound of the invention is a compound of the formula (I), wherein R3 is C6_6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-C6_6alkyl or optionally substituted heteroaryl alkyl C? _6. ii) Another preferred compound of the invention is a compound of the formula (I), wherein R3 is C6-C6 alkyl; phenyl-C_6 alkyl; phenyl optionally substituted by one to three fluorine atoms; or heteroaryl optionally substituted by one to three fluorine atoms, the heteroaryl is a monocyclic aromatic radical of 5 or 6 ring atoms, containing one or two nitrogen atoms in the ring or a sulfur atom in the ring. iii) Another preferred compound of the invention is a compound of the formula (I), wherein R3 is phenyl. iv) Another preferred compound of the invention is a compound of the formula (I), wherein R1 is C6-6 alkyl, - (C06 alkylene) -NR'R ", wherein R 'and R" independently of each other are selected from the group consisting of hydrogen, C? _6 alkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, arylsulfonyl optionally substituted and optionally substituted heteroarylsulfonyl or - (alkylene Co-e) -OR ', wherein R' is hydrogen or C 1 -C 6 alkylcarbonyl) Another preferred compound of the invention is a compound of the formula (I), in which wherein R1 is C6-6 alkyl, - (C2_6 alkylene) -NR'R ", wherein R 'and R" independently from each other are selected from the group consisting of hydrogen, acetyl, arylcarbonyl, in which aryl is optionally substituted by one or two perfluoromethyl and arylsulfonyl or - (C2_d alkylene) -OR ', wherein R' is hydrogen or acetyl. vi) Another preferred compound of the invention is a compound of the formula (I), wherein R 1 is 2-aminoethyl, 2-acetylaminoethyl, 2-acetylamino-2,2-dimethylethyl, methyl, isopropyl or 2-hydroxyethyl. vii) Another preferred compound of the invention is a compound of the formula (I), in which R2, R2 'and R2"independently of each other are hydrogen, halogen, C-6 alkyl or C-6 alkoxy. Preferred compound of the invention is a compound of the formula (I), wherein two of R2, R2 'and R2"are hydrogen and the other is hydrogen, halogen, C? -6 alkyl or C? -6 alkoxy. ix) Another preferred compound of the invention is a compound of the formula (I), in which two of R2, R2 'and R2"are hydrogen and the other is hydrogen, chlorine, fluorine, methyl, ethyl or methoxy x) Another preferred compound of the invention is a compound of formula (I), in which two of R2, R2 'and R2"are hydrogen and the other occupies position 5 or 6 of the indole ring and is selected from the group consisting of hydrogen, chlorine, fluorine, methyl and ethyl. xi) Another preferred compound of the invention is a compound of the formula (I), wherein R6 is hydrogen. xii) Another preferred compound of the invention is a compound of the formula (I), wherein R4 is hydrogen, C6-6 alkyl, C3-optionally substituted cycloalkyl, optionally substituted aryl, C3_7 cycloalkyl-optionally substituted C6_6alkyl or optionally substituted C6-arylalkyl and R5 is hydrogen or C-β alkyl; or R4 and R5, together with the carbon atom to which they are attached form an optionally substituted C3_7 cycloalkyl ring. xiii) Another preferred compound of the invention is a compound of the formula (I), wherein A is -CH2-. xiv) Another preferred compound of the invention is a compound of the formula (I), wherein A is -CH 2 -, R 4 is phenyl and R 5 is hydrogen. xv) Another preferred compound of the invention is a compound of the formula (I), wherein A is -NR'-, wherein R 'is hydrogen or C-6 alkyl. xvi) Another preferred compound of the invention is a compound of the formula (I), wherein A is -NR'-, wherein R 'is hydrogen or methyl, R4 is isopropyl and R5 is hydrogen. xvii) Another preferred compound of the invention is a compound of the formula (I), wherein A is -0-. xviii) Another preferred compound of the invention is a compound of the formula (I), wherein A is -0-, R4 is hydrogen, phenyl, C6 alkyl, C3_7 cycloalkyl-optionally substituted C6-alkyl or aryl optionally substituted C? _6 alkyl and R5 is hydrogen or C? -6 alkyl, - or R4 and R5, together with the carbon atom to which they are attached form an optionally substituted C3-7 cycloalkyl ring. xix) Another preferred compound of the invention is a compound of the formula (I), wherein A is -0-, R4 is phenyl, benzyl, isobutyl, 2-cyclohexylethyl or phenethyl and R5 is hydrogen or methyl. xx) Another preferred compound of the invention is a compound of the formula (I), wherein R3 is C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, aryl optionally substituted C_6 alkyl or optionally substituted heteroaryl C_6 alkyl; R3 is preferably C6_6 alkyl, phenyl optionally substituted by one to three fluorine atoms, heteroaryl optionally substituted by one to three fluorine atoms, heteroaryl is a monocyclic aromatic radical of 5 or 6 ring atoms, which contains one or two nitrogen atoms in the ring, or phenyl C? -6 alkyl, especially phenyl; R1 is C6-6 alkyl, - (C6-6 alkylene) -NR'R ", wherein R 'and R" independently from each other are selected from the group consisting of hydrogen, C6-6 alkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted arylsulfonyl and optionally substituted heteroarylsulfonyl or - (alkylene Co-β) -OR ', wherein R' is hydrogen or (Ci-β alkyl) -carbonyl; R1 is preferably C6_6 alkyl, - (C2_6 alkylene) -NR'R ", wherein R 'and R" independently from each other are selected from the group consisting of hydrogen, acetyl, arylcarbonyl, the aryl is optionally substituted by one or two perfluoromethyl and arylsulfonyl or - (C2-d alkylene) -OR ', wherein R' is hydrogen or acetyl, especially 2-aminoethyl, 2-acetylaminoethyl, 2-acetylamino-2,2-dimethylethyl, methyl , isopropyl or 2-hydroxyethyl; R2, R2 'and R2"independently of each other are hydrogen, halogen, C? _6 alkyl or C? -6 alkoxy, with two preference of R2, R2 'and R2"are hydrogen and the other is hydrogen, halogen, C6_6alkyl or C6alkoxy, more preferably two of R2, R2' and R2" are hydrogen and the other is hydrogen, chlorine, fluorine, methyl, ethyl or methoxy, in particular two of R2, R2 'and R2"are hydrogen and the other occupies position 5 or 6 of the indole ring and is selected from the group consisting of hydrogen, chlorine, fluorine, methyl and ethyl R6 is hydrogen, R4 is hydrogen, C6-6 alkyl, optionally substituted C3-7 cycloalkyl, optionally substituted aryl, optionally substituted C-6 cycloalkyl, optionally substituted C6-alkyl or optionally substituted C6-alkyl, R5 is hydrogen or alkyl -e; or R4 and R5, together with the carbon atom to which they are attached form an optionally substituted C3_7 cycloalkyl ring: xxi) A preferred compound of group xx) is a compound of the formula (I), wherein A is -CH2- When A is -CH2-, R4 is preferably phenyl and R5 is hydrogen, xxii) Another preferred compound A group of formula (I), in which A is -NR'-, wherein R 'is hydrogen or C? _6 alkyl, preferably hydrogen or methyl. When A is -NR'-, wherein R 'is hydrogen or methyl, R4 is preferably isopropyl and R5 is hydrogen. xxiii) Another preferred compound of group xx) is a compound of the formula (I), wherein A is -0-. When A is -0-, R4 is preferably hydrogen, phenyl, C6 alkyl, C3_7 cycloalkyl optionally substituted C6_6 alkyl or optionally substituted C6_6 aryl alkyl, and R5 is hydrogen or C6_6 alkyl; or R4 and R5, together with the carbon atom to which they are attached form an optionally substituted C3-7 cycloalkyl ring. When A is -0-, R4 is more preferably phenyl, benzyl, isobutyl, 2-cyclohexylethyl or phenethyl and R5 is hydrogen or methyl. xxiv) Another preferred compound of the invention is a compound of the formula (I), wherein A is -CH2-, -0- or -NR'-, wherein R 'is hydrogen or C? -6 alkyl. xxv) Another preferred compound of the invention is a compound of the formula (I), wherein A is -NR'-, wherein R 'and R4 form a C2-5 alkylene. xxvi) Another preferred compound of the invention is a compound of the formula (I), which is 3- [(5-fluoro-3-methyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy- 5-isopropyl-l, 5-dihydro-pyrrol-2-one, 3- [(5-fluoro-3-methyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5-isopropyl- l-methyl-l, 5-dihydro-pyrrol-2-one, 4-hydroxy-5-isopropyl-3- [(3-methyl-lH-indol-2-yl) - phenyl-methyl] -1,5-dihydro-pyrrol-2-one, 3- [(5-fluoro-3-isopropyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5-isopropyl -l, 5-dihydro-pyrrol-2-one, N- (2- { 2- [(5-benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl) - phenyl-methyl] -6-fluor-lH-indol-3-yl.} - ethyl) -acetamide, 5-benzyl-3-. { [6-fluoro-3- (2-hydroxy-ethyl) -lH-indol-2-yl] -phenyl-methyl} -4-hydroxy-5H-furan-2-one, 3-. { [3- (2-Amino-ethyl) -6-fluor-lH-indol-2-yl] -phenyl-methyl} -5-benzyl-4-hydroxy-5H-furan-2-one; salt with acetic acid, 5-benzyl-3- [(5-fluoro-3-methyl-lH-indol-2-yl) -phenyl-methyl] - -hydroxy-5H-furan-2-one, (2-. {6-fluoro-2- [(4-hydroxy-5-methyl-2-oxo-5-phenyl-2,5-dihydro-furan-3-yl) -phenyl-methyl] -indol-3-yl} -ethyl) -acetamide, (2- { 2- [(4-hydroxy-5-isobutyl-2-oxo-2, 5-dihydro-furan-3-yl) -phenyl-methyl] -indol- 3-yl.] -ethyl) -acetamide, N- [2- (2 { [5- (2-cyclohexyl-ethyl) -4-hydroxy-2-oxo-2,5-dihydro-furan- 3-yl] -phenyl-methyl.} - 6-fluor-lH-indol-3-yl) -ethyl] -acetamide, N- (2-. {6-fluoro-2- [(4-hydroxy) 2-oxo-5-phenethyl-2, 5-dihydro-furan-3-yl) -phenyl-methyl] -lH-indol-3-yl}. -ethyl) -acetamide, N- (2- { 2- [(2-hydroxy-5-oxo-3-phenyl-cyclopent-1- enyl) -phenyl-methyl] -lH-indol-3-yl} ethyl) -acetamide, N- (2-. {6-fluor-2- [(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl) -phenyl-methyl] -lH-indole- 3-yl.] -ethyl) -acetamide, N- (2- (5-ethyl-2- [(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl) -phenyl-methyl] - lH-indol-3-yl.}.-ethyl) -acetamide, N- (2-. {2- [(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl) -phenyl-methyl] ] -5-methyl-lH-indol-3-yl.}.-Ethyl) -acetamide, 2- { [3- (2-amino-ethyl) -6-ethyl-lH-indol-2-yl] phenyl-methyl.} - 3-hydroxy-4-phenyl-cyclopent-2-enone or N- (2- (6-chloro-2 - [(2-hydroxy-5-oxo-3-phenyl-cyclopentyl) 1-enyl) -phenyl-methyl] -lH-indol-3-yl.} -1, 1-dimethy1-ethyl) -acetamide The compounds of the present invention can be obtained, for example, by the general synthetic methods which are described below.

General Synthetic Procedures Abbreviations: DMSO: dimethyl sulfoxide LDA: lithium diisopropylamide THF: tetrahydrofuran I) The compounds of the formula (I) can be obtained according to the following reaction scheme 1: Reaction Scheme 1 III IV A, R1, R2, R¿ R¿ R3, R- and R have the meanings defined above. The addition of a vinyl alcohol III, an aldehyde IV and an indole V on a vinyl alcohol I can be carried out in a solvent, for example CH3CN or an acid, for example a carboxylic acid, for example, formic acid or preferably acetic acid a a temperature comprised in a range between 20 and 100 ° C, preferably at 70 ° C for 1-20 h.

II) -i) The starting materials of the formula III (A = O) can be obtained according to the following reaction scheme 2: Reaction Scheme 2 JL COOMe VI III R4 and R5 have the meanings defined above. The aldehydes or ketones VI can be reacted with methyl 3 (E) -methoxy acrylate (Miyata, Okiko; Schmidt, Richard R.; Angewandte Chemie _9_4 (8), 651-2, 1982), in solvents of the ether type of diethyl or THF, in the presence of a base of the lithium diisopropylamide type, at a temperature comprised in a range between -100 ° C and -50 ° C, preferably around -80 ° C, to obtain the methyl ester of the acid tetronic II (A = O). The cleavage of the methoxy group in II (A = O) can be carried out with a strong inorganic acid, for example Hl, HBr or HCl, preferably HBr, in water and acetic acid, at a temperature comprised in a range between 20 ° C and 100 ° C, preferably at 40 ° C, to obtain the tetronic acid III (A = O).

II) -ii) The starting materials of the formula III (A = NH or A = N-alkyl C? _6) can be obtained according to the following reaction scheme 3 as described by Hofheinz, Werner et al., Helvética Chimica Acta 60 (2), 660-9, 1977, or Hilpert, Hans et al., publ. request pat. U.S. (2005), US2005119329: Reaction Scheme 3 j Vil -; 0 VIICI - The methyl ester of amino acid VII can be reacted with chlorocarbonyl-ethyl acetate in solvents of the type of diethyl ether, THF or preferably dichloromethane in the presence of an alkylamine-type base, preferably triethylamine, at a temperature comprised between 0 ° C and 60 ° C, preferably at 22 ° C, to obtain malonamide VIII (A = NH or A = N-C C-C6 alkyl). The deletion of malonamide VIII can be carried out with a strong base, for example, sodium t-amylate, potassium t-butoxide or preferably potassium hexamethyldisilazide in a solvent, for example diethyl ether, THF, benzene or preferably toluene, at a temperature comprised in a range between 0 ° C and 60 ° C, preferably at 22 ° C, to obtain the tetrahydric acid derivative IX (A = NH or A = N-C 1 -C 6 -alkyl). The decarboxylation of the tetrahydric acid derivative IX can be carried out in the presence of a weak or strong acid, example acetic acid or trifluoroacetic acid, between 22 ° C and 100 ° C, preferably at 80 ° C, to obtain the tetrámico acid III (A = NH or A = N-C6 alkyl).

II) -iii) The starting materials of the formula III (A = CH2) can be obtained according to Nguyen, Hanh Nho et al., Journal of the American Chemical Society 125 (39), 11818-11819, 2003; or Hamer, Neil K. et al., Tetrahedron Letters 27 (19), 2167-8, 1986.

II) -iv) The starting materials of the formula III can also be obtained according to the methods described in the citations of the technical literature: 11) Hofheinz, Werner et al., Helvética Chimica Acta 60 (2), 660-9 , 1977; 12) Galeotti, Nathalie et al., Journal of Organic Chemistry 58 (20), 5370-6, 1993; 13) Hilpert, Hans et al., Publ. request pat. U.S. (2005), US2005119329.; 14) Krepski, Larry R. et al., Tetrahedron Letters 26 (8), 981-4, 1985; 15) Compain, Philippe et al., Synlett (11), 943-5, 1994; 16) Nguyen, Hanh Nho et al., Journal of the American Chemical Society 125 (39), 11818-11819, 2003; 17) Hamer, Neil K. et al., Tetrahedron Letters 27 (19), 2167-8, 1986; 18) Matsuo, Keizo et al., Chemical & Pharmaceutical Bulletin 32 (9), 3724-9, 1984; 19) Mizuno, Hatsuhiko et al., Chemical & Pharmaceutical Bulletin 23 (3), 527-37, 1975.

III) All starting materials of formula IV are commercial products.

IV) The starting materials of formula V are commercial products or compounds obtainable according to methods described in the following citations of the technical literature: 1) Ho, Beng T. et al., Journal of Medicinal Chemistry 4 (6), 1971; 2) Hasegawa, Masakazu et al., Heterocycles 51 (12), 2815-2821, 1999; 3) Contour-Galcera, Marie-Odile et al., Bioorganic & Medicinal Chemistry Letters 5 (15), 3555-3559, 2005; 4) Khalil, Ehab M. et al., Journal of Biological Chemistry 273 (46), 30321-30327, 1998; 5) Nenajdenko, Valentine G. et al., Tetrahedron 60 (51), 11719-11724, 2004; 6) Cheve, Gwenael et al., Medicinal Chemistry Research 11 (7), 361-379, 2002; 7) Mor, Marco et al., Journal of Medicinal Chemistry 41 (20), 3831-3844, 1998; 8) Heath-Brown, B. et al., Journal of the Chemical Society, abstracts (dic), 7165-78, 1965; 9) Bastían, Jolie Anne et al., Public. request pat. WO 2003/016307, (2003); 10) D. Nagarathnam et al., Synthetic Communications 23 (14), 2011-2017, 1993; 20) Hengartner, Urs et al., Journal of Organic Chemistry 44_ (22), 3741-7, 1979; 21) Yang, Shyh-Chyun et al., Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry 38B (8), 897-904, 1999; 22) Tsuchiya, Michihiro et al., International patent application WO 82/00032 (1982). 23) Pfister, Jurg R. et al., US patent application US5436264 (1995). As described above, the compounds of formula (I) are active compounds and inhibit chymase. Accordingly, these compounds prevent the activation of angiotensin II, endothelin, TGFb, 111, SCF, collagenase and the degradation of thrombin-type proteins, FN, APO Al, 2.

Therefore, they can be used for the treatment and / or prevention of allergic, inflammatory and / or fibrotic, such as allergy, asthma, peripheral arterial occlusive disease, critical ischemia of extremities, patients with vulnerable atherosclerotic plaque, unstable angina, congestive heart failure, left ventricular hypertrophy, reperfusion injury due to ischemia, stroke, cardiomyopathy, restenosis, rheumatoid arthritis , diabetic nephropathy, irritable bowel disease, Crohn's disease, atherothrombosis and / or burns / ulcers in diabetes / CLI. The preferred indication is the prevention and / or treatment of allergic, inflammatory or fibrotic diseases, in particular of atherothrombosis or asthma. The invention thus relates to pharmaceutical compositions containing the above defined compound and a pharmaceutically acceptable excipient. The invention also encompasses compounds described above for use as therapeutically active substances, especially as therapeutically active substances for the treatment and / or prophylaxis of allergic, inflammatory and / or fibrotic diseases, in particular as therapeutically active substances for the treatment and / or or prophylaxis of allergy, asthma, peripheral arterial occlusive disease, critical limb ischemia, patients with vulnerable atherosclerotic plaque, unstable angina, congestive heart failure, left ventricular hypertrophy, reperfusion injury due to ischemia, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable bowel disease, Crohn's disease, atherothrombosis and / or burns / ulcers in diabetes / CLI. The invention also relates to the use of the compounds described above for the manufacture of medicaments for the therapeutic and / or prophylactic treatment of allergic, inflammatory and / or fibrotic diseases, in particular to the therapeutic and / or prophylactic treatment of allergy, asthma, peripheral arterial occlusive disease, critical ischemia of extremities, patients with vulnerable atherosclerotic plaque, unstable angina, congestive heart failure, left ventricular hypertrophy, reperfusion injury due to ischemia, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, Irritable bowel, Crohn's disease, atherothrombosis and / or burns / ulcers in diabetes / CLI. Such medications contain a compound that has already been described in previous pages. The invention also relates to the process and intermediary compounds for the preparation of the compounds of the formula (I) as well as to the process for the preparation of the intermediate compounds. The inhibition of chymase with the compounds of the present invention can be demonstrated by the test of Peptide substrate described below. For chymase, a substrate containing the 4 amino acid peptide AAPF is chosen as the standard substrate for chymotrypsin-like compounds (succinyl-Ala-Ala-Pro-Phe [7-amino-4-methylcoumarin]; Lockhart BE et al., "Recombinant human mast-cell chymase: an improved procedure for expression in Pichia pastoris and purification of the highly active enzyme", Biotechnol Appl. Biochem, published as an immediate publication on May 26, 2004 as manuscript BA2004007). The peptide is synthesized with a purity of 95% in the company Bachem, Bubendorf, Switzerland). Purified chymase from human skin mast cells is obtained from the Calbiochem company (Merck Biosciences, San Diego, California, USA). The test buffer is 0.15 M NaCl, 0.05 M Tris-HCl, 0.05% CHAPS (3- [(3-colamidopropyl) -dimethylammonium] -1-propanesulfonate), 0.1 mg / ml heparin (sodium heparin, Sigma, intestinal mucosa porcine), 0.02 mM AAPF substrate, 1 nM chymase at pH 7.4. The assay is carried out in 96-well plates (Packard Optiplate), with a volume of 0.05 ml, at room temperature. The activity of the chymase is indicated with the initial ratio of fluorescence increase at 340/440 nm (excitation / emission) of free 7-amino-4-methylcoumarin released from the substrate. The inhibition of the activity caused by the inhibitory compounds is read after 30 min of pre-incubation with chymase at room temperature in assay buffer without AAPF substrate. The assay is then started with the addition of the indicated concentration of AAPF substrate. The IC50 values of the active compounds of the present invention are preferably between (1000) and (1) nM, especially between (30) and (1) nM.

The compounds of formula I and / or their pharmaceutically acceptable salts can be used as medicaments, for example, in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, for example, in the form of tablets, coated tablets, dragees, hard or soft gelatine capsules, solutions, emulsions or suspensions, rectally, for example, in the form of suppositories, via parenteral, for example, in form of injectable solutions or suspensions or solutions for infusion, or topically, for example, in the form of ointments, creams or oils. Oral administration is preferred. The production of the pharmaceutical preparations can be carried out in a manner which is familiar to any person skilled in the art and which consists of incorporating the described compounds of the formula I and / or their pharmaceutically acceptable salts, optionally in combination with other substances therapeutically valuable, to the form of galenic administration together with suitable or non-toxic, inert, therapeutically compatible liquid or solid carrier materials or excipients, and, if desired, the usual pharmaceutical adjuvants. The suitable excipient materials are not only the inorganic excipient materials, but also the organic excipient materials. Accordingly, there can be used, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts as excipient materials of tablets, coated tablets, dragees and hard gelatine capsules. Suitable excipient materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (however, depending on the nature of the active ingredient, it may not be necessary to use them in the case of soft gelatine capsules). Suitable excipient materials for the manufacture of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. The suitable excipient materials for injectable solutions are, for example, water, alcohols, polyols, glycerin and vegetable oils. The excipient materials suitable for suppositories are, for example, natural and hydrogenated oils, waxes, fats and semi-liquid and liquid polyols. Suitable excipient materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives. As pharmaceutical adjuvants, stabilizers, preservatives, wetting and emulsifying agents, consistency improving agents, flavor improving agents, salts for varying the osmotic pressure, buffering substances, solubilizers, dyes and masking agents as well as usual antioxidants are taken into consideration. The dosage of the compounds of the formula (I) can vary within wide limits depending on the disease to be controlled, the age and health condition of the patient and the mode of administration and obviously conform to the individual requirements of each particular case. For adult patients a daily dosage of 1 to 1000 mg, especially 1 to 300 mg, is taken into consideration. Depending on the severity of the disease and the particular pharmacokinetic profile, the compound may be administered in one or several daily dosage units, for example, in 1-3 dosage units. The pharmaceutical preparations will conveniently contain 1-500 mg, preferably 1-100 mg, of a compound of the formula I. The following examples serve to illustrate the present invention in greater detail. However, with them it is not intended in any way to limit the scope of it.

General procedure A: Preparation of methyl esters of tetronic acids II (A = O) To a solution of 20 ml of LDA (2M in THF) and 130 ml of THF is added between -95 ° C and -100 ° C during 1 min a solution of 5.47 g of methyl 3 (E) -methoxy-acrylate in 4.5 ml of THF, stirring is continued at the same temperature for 5 min, then the addition is carried out for 2 min of a pre-cooled solution (- 78 ° C) of the aldehyde (33 mmoles) in 4.5 ml of THF and stirring is continued at -100 ° C for 30 min and at -78 ° C for 1 h. The cold solution is poured on 130 ml of ice-water, the pH is adjusted to 4 with 6.5 ral of HCl aqueous (37%) and the phases are separated. The aqueous phase is extracted twice with dichloromethane, the organic phases are washed with brine, dried and concentrated. The residue was chromatographed on silica gel (n-heptane / AcOEt, various proportions), obtaining methyl esters of tetronic acids II (A = 0).

General procedure B: Preparation of tetronic acids III (A = 0) A mixture of the tetronic acid methyl ester II (A = O, 10 mmol) and 15 ml of aqueous HCl (from HCl) is stirred at 40 ° C until the completion of the reaction. 37%). The suspension is filtered and the residue is washed with ice-cold water and dried. The oily reaction mixture is extracted with dichloromethane, the organic phases are washed with brine, dried and concentrated. The residue is triturated with AcOEt / hexane or chromatographed with dichloromethane / MeOH (various proportions), obtaining tetronic acids III (A = O).

General Procedure C: Preparation of the tetrahedral acids III (A = NH or A = N-C C-6 alkyl) To a mixture of the methyl ester of amino acid VII (A = NH 2 or A = N (H) (C C-6 alkyl) ), 18 mmol) in dichloromethane (60 ml) were added successively at 0 ° C triethylamine (56 mmoles) and the chlorocarbonyl-ethyl acetate (21.5 mmol) and stirring is continued overnight. The suspension is filtered, the filtrate is concentrated and the residue is partitioned between dilute aqueous hydrochloric acid and ethyl acetate. The organic phase is dried, concentrated and the residue is chromatographed on silica gel using cyclohexane / ethyl acetate (2: 1), thereby obtaining malonamide VIII (A = NH or A = N-C-alkyl). ? -6). A mixture of malonamide VIII (A = NH or A = N-C 6 -alkyl, 7 mmol) in toluene (12 ml) is treated with a solution of potassium hexamethyldisilazide in THF (0.9 M, 7 mmol) and stirring continues for 1-16 h. The suspension is filtered and the residue is dried, yielding the tetrahydric acid derivative IX (A = NH or A = N-C? _6 alkyl). A mixture of the tetrahydric acid derivative IX (A = NH or A = N-C 1-6 alkyl, 7 mmol) in acetic acid (40 ml) and trifluoroacetic acid (4 ml) is heated at reflux for 1-5 h. The mixture is concentrated by evaporation and the residue is chromatographed on silica gel using diethyl ether, thus obtaining tetrahydric acid III (A = NH or A = N-C_5 alkyl).

Example A Preparation of 4-hydroxy-5-methyl-5-phenyl-5H-furan-2-one Al. Applying the general procedure A, acetophenone is reacted with methyl 3 (E) -methoxy-acrylate, obtaining the rac- 4-methoxy-5-methyl-5-phenyl-5H-furan-2-one as a colorless solid. MS = 204.1 ([M] +). A2. Rac-4-methoxy-5-methyl-5-phenyl-5H-furan-2-one (0.50 g) is obtained on a Chiralpack AD column using 9: 1 n-heptane / ethanol., in this way (S) -4-methoxy-5-methyl-5-phenyl-5H-furan-2-one is obtained (0.24 g as the peak that elutes more rapidly and the (R) -4-methoxy- 5-methyl-5-phenyl-5H-furan-2-one (0.24 g) as peak eluting more slowly A3 Using general procedure B, (S) -4-methoxy-5-methyl-5 is hydrolysed phenyl-5H-furan-2-one, obtaining (S) -4-hydroxy-5-methyl-5-phenyl-5H-furan-2-one as a colorless solid EM = 190.2 ([M] + ). [a] 365nm = -420.4 ° (1%, CHC13). A4. Using the general procedure B the (R) -4-methoxy-5-methyl-5-phenyl-5H-furan-2-one is hydrolyzed, obtaining the (R) -4-hydroxy-5-methyl-5-phenyl- 5H-furan-2-one as a colorless solid. MS = 190.2 ([M] +). [a] 365nm = + 441.5 ° (1%, CHC13).

Example B Preparation of rac-5- (2-cyclohexyl-ethyl) -4-hydroxy-5H-furan-2-one Bl. Using general procedure A, cyclohexanopropanal (Stratakis, Manolis et al., Journal of Organic Chemistry 67 (25), 8758-8763, 2002) is reacted with methyl 3 (E) -methoxy-acrylate, obtaining the rac- 5- (2-Cyclohexyl-ethyl) -4-methoxy-5H-furan-2-one as a colorless solid. MS = 225.2 ([M + H] +). B2. Using general procedure B, rac-5- (2-cyclohexyl-ethyl) -4-methoxy-5H-furan-2-one is hydrolyzed, obtaining rac-5- (2-cyclohexyl-ethyl) -4-hydroxy- 5H-furan-2-one in the form of a brown oil. MS = 211.1 ([M + H] +).

EXAMPLE C Preparation of rac-l-hydroxy-7a-methyl-5, 6, 7, 7a-tetrahydro-pyrrolizin-3-one Using the general procedure C the methyl rac-2-methyl-pyrrolidine-2-carboxylate is converted in the title compound, which is obtained as a yellow solid. MS = 154.3 ([M + H] +).

Example D Preparation of (R) -5-benzyl-4-hydroxy-5-methyl-1, 5-dihydro-pyrrol-2-one Using the general procedure C, the (R) -2-amino-2 is converted methyl-3-phenyl-propionate in the title compound, which is obtained as a white solid. MS = 204.1 ([M + H] +).

Example E Preparation of (R) -4-hydroxy-5-isopropyl-5-methyl-1, 5-dihydro-pyrro1-2-one Using the general procedure C, the (R) -2-amino-2,3-dimethyl-butyrate methyl in the title compound, which is obtained as a white solid. MS = 156.3 ([M + H] +).

Example F Preparation of (R) -4-hydroxy-5-methyl-5-phenyl-1,5-dihydro-pyrrol-2-one Using the general procedure C the (R) -2-amino-2-phenyl-propionate methyl in the title compound [Lit. 19] which is obtained in the form of a colorless oil. MS = 190.3 ([M + H] 0. [A] 365nm = +360.9 ° (c = 1%, CHC13).

General procedure D: Addition of vinyl III acid to aldehyde IV and indole V A solution of vinylogous acid (1 mmol), aldehyde (1.3 mmol) and indole (1 mmol) in acid are stirred at 70 ° C for 16 h. acetic acid (2 ml). The suspension is filtered and the residue washed with MeOH / Et20 (1:10). If no precipitate forms, the solution is purified by preparative HPLC (RP-18, gradient of CH3CN / H20).

Example 1 N- (2- { 2- [(4-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-lH-pyrrol-3-yl) -phenyl-methyl] -lH-indole 3-yl.}.-Ethyl) -acetamide Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one is reacted (technical literature (hereinafter abbreviated as Lit.) 11) with benzaldehyde and N- [2- (lH-indol-3-yl) -ethyl] -acetamide, the title compound being obtained as a pale yellow solid. MS = 432.5 ([M + H] +).

Example 2 N- (2- {2- [(3-Fluoro-phenyl) - (4-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-lH-pyrrol-3-yl) -methyl) ] -lH-indol-3-yl.}.-ethyl) -acetamide Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one is reacted (Lit. 11) with 3-fluoro-benzaldehyde and N- [2- (lH-indol-3-yl) -ethyl] -acetamide, the title compound being obtained as a yellow solid. MS = 450.1 ([M + H] +).

EXAMPLE 3 N- (2- { 2- [(4-Fluoro-phenyl) - (-hydroxy-5-isopropyl-2-oxo-2, 5-dihydro-lH-pyrrol-3-yl) -methyl] -lH-indol-3-yl.}. -ethyl) -acetaraide Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Lit.11) is reacted with 4-fluoro-benzaldehyde and N- [2- (lH-indol-3 -il) - ethyl] -acetamide, obtaining the title compound as a yellow solid. MS = 450.3 ([M + H] +).

Example 4 N- (2- (2 - [(3,5-difluorophenyl) - (4-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-lH-pyrrol-3-yl) -methyl) ] -lH-indol-3-yl.}.-ethyl) -acetamide Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one is reacted (Lit. 11) with 3, 5-difluor-benzaldehyde and N- [2- (lH-indol-3-yl) -ethyl] -acetamide, the title compound being obtained as a yellow solid. MS = 468.0 ([M + H] +).

Example 5 Acetate of 2-. { 2- [(-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-lH-pyrrol-3-yl) -phenyl-methyl] -lH-indol-3-yl} -ethyl Using the general procedure C is done reacting 4-hydroxy-5-isopropyl-l, 5-dihydro-pyrrol-2-one (Lit. 11) with benzaldehyde and 2- (1H-indol-3-yl) -ethanol, the title compound being obtained in the form of orange foam. MS = 433.3 ([M + H] 0.

Example 6 4-hydroxy-3-. { [3- (2-hydroxy-ethyl) -lH-indol-2-yl] -phenyl-methyl} -5-isopropyl-l, 5-dihydro-pyrrol-2-one A solution of 2- acetate is stirred at 22 ° C for 30 min. { 2- [(4-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-lH-pyrrol-3-yl) -phenyl-methyl] -lH-indol-3-yl} ethyl (40 mg) and LiOH (8.5 mg) in MeOH (0.5 ml) and concentrated by evaporation. The residue is partitioned between aqueous 0.1 N HCl and AcOEt and the organic phase is dried and concentrated. The residue is chromatographed on silica gel using CH2Cl2 / MeOH (10: 3), thereby obtaining the title compound as an orange foam. MS = 391.1 ([M + H] +).

Example 7 N- (2- {2- [(4-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-lH-pyrrol-3-yl) -phenyl-methyl] -lH-indole 3-yl.}.-Ethyl) -benzamide Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Lit. 11) is reacted with benzaldehyde and N- [2- (lH-indol-3-yl) - ethyl] -benzamide, obtaining the title compound as a gray solid. MS = 494.3 ([M + H] +).

Example 8 N- (2- { 2- [(4-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-lH-pyrrol-3-yl) -phenyl-methyl] -lH-indole 3-yl.}. -ethyl) -3,5-bis-trifluoromethyl-benzamide 8. 1. Preparation of N- [2- (lH-indol-3-yl) -ethyl] -3,5-bis-trifluoromethyl-benzamide To a solution of 2- (lH-indol-3-yl) -ethylamine (1.0 g) in CH2C12 is added at 22 ° C the NEt3 (1.74 ml) and 3, 5-bis-trifluoromethyl-benzoyl chloride (1.24 ml) and stirring is continued at 22 ° C for 16 h. The mixture is washed with aqueous NaHC03 and brine, the organic phase is dried and concentrated, obtaining the title compound as a brown solid. MS = 401.3 ([M + H] 0. 8.2) Using general procedure C, 4-hydroxy-5-isopropyl-l, 5-dihydro-pyrrol-2-one (Lit. 11) is reacted with benzaldehyde and N- [2- (lH-indol-3-yl) -ethyl] -3,5-bis-trifluoromethyl-benzamide, yielding N- (2-. {2 - [(4-hydroxy-5-isopropyl-2- oxo-2, 5-dihydro-lH-pyrrol-3-yl) -phenyl-methyl] -lH-indol-3-yl}. -ethyl) -3,5-bis-trifluoromethyl-benzamide as a red solid EM = 630.2 ([M + H] +).

Example 9 (2- { 2- [(4-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-lH-pyrrol-3-yl) -phenyl-methyl] -lH-indole-3- Naphthalene-2-sulfonic acid amide) Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one is reacted (Lit. 11) with benzaldehyde and naphthalene-2-sulfonic acid [2- (lH-indol-3-yl) -ethyl] -amide (Lit. 1), obtaining the compound of the title in the form of an orange solid. EM 580.3 ([M + H] 0.

Example 10 3- [(5-Fluoro-3-methyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5-isopropyl-l, 5-dihydro-pyrrol-2-one Using the general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Lit. 11) is reacted with benzaldehyde and 5-fluoro-3-methyl-1H-indole, obtaining the compound of the title in the form of a yellow solid. MS = 377.1 ([M-H] ").

EXAMPLE 11 3- [(5-Fluoro-3-methyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5-isopropyl-1-methyl-1, 5-dihydro-pyrrole-2- ona Using the general procedure C, 4-hydroxy-5-isopropyl-1-methyl-1, 5-dihydro-pyrrole- 2-one (Lit. 12) with benzaldehyde and 5-fluoro-3-methyl-1H-indole, the title compound being obtained as a yellow solid. MS = 391.3 ([M-H] ").

Example 12 4-Hydroxy-5-isopropyl-3- [(3-methyl-lH-indol-2-yl) -phenyl-methyl] -1,5-dihydro-pyrrol-2-one Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one is reacted (Lit. 11) with benzaldehyde and 3-methyl-lH-indole, the title compound being obtained as a yellow solid. EM = 361. 0 ([M + H] 0.

Example 13 3- [(5-Fluoro-3-isopropyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5-isopropyl-l, 5-dihydro-pyrrol-2-one 13. 1. The 5-fluoro-3-isopropyl-1H-indole is obtained from mode similar to that described in Lit. 10 in the form of brownish oil, MS = 177.0 ([M] +). 13.2. Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Lit. 11) is reacted with benzaldehyde and 5-fluoro-3-isopropyl-1H-indole, whereby 3-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Lit. - [(5-Fluoro-3-isopropyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5-isopropyl-l, 5-dihydro-pyrrol-2-one in the form of an orange solid. MS = 405.2 ([M-H] ").

EXAMPLE 14 N- (2-. {2- [(-hydroxy-2-oxo-2,5-dihydro-furan-3-yl) -phenyl-methyl] -lH-indol-3-yl}. ethyl) -acetamide Using general procedure C, 4-hydroxy-5H-furan-2-one is reacted with benzaldehyde and N- [2- (lH-indol-3-yl) -ethyl] -acetamide, whereby the title compound is obtained in the form of orange foam. EM = 391.1 ([M + H] 0.

EXAMPLE 15 N- (2- {2- [(5-benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl) -phenyl-methyl] -1H-indole-3- il.}.-ethyl) -acetamide Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) is reacted with benzaldehyde and N- [2- (lH-indol-3-yl) -ethyl] -acetamide. , the title compound being obtained as a white solid. MS = 481.0 ([M + H] +).

EXAMPLE 16 N- (2-. {2- [(5-benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl) -phenyl-methyl] -6-fluoro-lH- indol-3-yl.}.-ethyl) -acetamide 16. 1. N- [2- (6-fluor-lH-indol-3-yl) -ethyl] -acetamide To a solution of 2- (6-fluor-lH-indol-3-yl) Ethylamine (0.88 g) and NEt3 (2.27 ml) in CH2C12 (8 ml) were added with acetic anhydride (0.43 ml) and stirring was continued at 22 ° C for 1 h. The mixture is washed with 1N aqueous HCl, the organic phase is dried and concentrated. The residue is chromatographed on silica gel using CH2Cl2 / MeOH (25: 1), thereby obtaining the title compound as a pale yellow oil. MS = 219.1 ([MH] ") 16.2 Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) is reacted with benzaldehyde and N- [2- (6 -fluor-lH-indol-3-yl) -ethyl] -acetamide, obtaining N- (2. {2- [(5-benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan- 3-yl) -phenyl-methyl] -6-fluor-lH-indol-3-yl}. -ethyl) -acetamide as a white solid, MS = 497.4 ([M-HD.

Example 17 N- (2- { 2- [(5-benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl) -phenyl-methyl] -5-chloro-lH- indol-3-yl.}.-ethyl) -acetamide Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one is reacted (Lit. 13) with benzaldehyde and N- [2- (5-chloro-lH-indol-3-yl) -ethyl] -acetamide (Lit.2), obtaining the title compound as a white solid. MS = 513.1 ([M-H] ").

Example 18 and 19 5-benzyl-3-. { [6-fluoro-3- (2-hydroxy-ethyl) -lH-indol-2-yl] -phenyl-methyl} -4-hydroxy-5H-furan-2-one and 2- acetate. { 2- [(5-Benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl) -phenyl-methyl] -6-fluoro-lH-indol-3-yl} -ethyl Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) is reacted with benzaldehyde and 2- (6-fluor-lH-indol-3-yl) -ethanol (Lit. . 3). The mixture was separated by HPLC, obtaining the first title compound as a pale brown solid. MS = 456.3 ([M-H] ") The second fraction contains the second title compound as an orange solid, MS = 498.1 ([M-H] -).

Example 20 N- (2- { 2- [1- (5-benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl) -2-methyl-propyl] -lH- indol-3-yl.}.-ethyl) -acetamide Using the general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) is reacted with 2-methyl-propionaldehyde and N- [2- (lH-indol-3-yl) - ethyl] -acetamide), the title compound being obtained as a yellow solid. MS = 445.1 ([M-H] ").

Example 21 N- (2- { 2- [1- (5-benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl) -3-methyl-butyl] -lH- indol-3-yl.}.-ethyl) -acetamide Using the general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) is reacted with 3-methyl-butyraldehyde and N- [2- (lH-indol-3-yl) - ethyl] -acetamide), the title compound being obtained as a yellow solid. MS = 459.1 ([M-H] ").

EXAMPLE 22 N- (2- { 2- [1- (5-benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl) -pentyl] -lH-indole-3- il.}.-ethyl) -acetamide Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) is reacted with pentanal and N- [2- (lH-indol-3-yl) -ethyl] -acetamide. ), obtaining the title compound as a white solid. MS = 459.3 ([M-H] ").

Example 23 N- (2- { 2- [1- (5-benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl) -2-phenyl-ethyl] -lH- indol-3-yl.}.-ethyl) -acetamide Using the general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) is reacted with phenyl-acetaldehyde and N- [2- (lH-indol-3-yl) -ethyl] -acetamide), obtaining the title compound as a solid White. MS = 493.0 ([M-H] ").

Example 24 N- (2- { 2- [1- (5-benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl) -3-phenyl-propyl] -lH- indol-3-yl.}.-ethyl) -acetamide Using the general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) is reacted with 3-phenyl-propionaldehyde and N- [2- (lH-indol-3-yl) - ethyl] -acetamide), the title compound being obtained as a yellow solid. MS = 507.2 ([M-H] ").

Example 25 N- (2- { 2- [(5-benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl) - (2-fluoro-phenyl) -methyl] - lH-indol-3-yl.}. -ethyl) -acetamide Using the general procedure C is done react 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) with 2-fluoro-benzaldehyde and N- [2- (lH-indol-3-yl) -ethyl] -acetamide), obtaining the title compound as a white solid. MS = 497.3 ([M-H] ").

Example 26 3-. { [3- (2-Amino-ethyl) -6-fluor-lH-indol-2-yl] -phenyl-methyl} -5-benzyl-4-hydroxy-5H-furan-2-one; salt with acetic acid Using the general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) is reacted with benzaldehyde and 2- (6-fluor-lH-indol-3-yl) -ethylamine, obtaining the title compound in the form of a pale red foam. MS = 457.1 ([M + H] 0.

Example 27 N- (2- { 2- [(5-benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl) -phenyl-methyl] -lH-indole-3- il.}. -ethyl) -N-methyl-acetamide Using the general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) is reacted with benzaldehyde and N- [2- (lH-indol-3-yl) -ethyl] -N -methyl-acetamide (Lit. 4), obtaining the title compound as a pale yellow solid. MS = 493.3 ([M-H] ").

Example 28 N- (2- { 2- [(5-benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl) -phenyl-methyl] -5-fluoro-lH- indol-3-yl.}.-ethyl) -acetamide Using the general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) is reacted with benzaldehyde and N- [2- (5-fluor-lH-indol-3-yl) - ethyl] -acetamide (Lit. 5), obtaining the title compound as a pale yellow solid. MS = 497.4 ([M-H] ").

Example 29 N- (2- { 2- [(5-benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl) -phenyl-methyl] -l-methyl-1H- indol-3-yl.}.-ethyl) -acetamide 29. 1. N- [2- (l-Methyl-lH-indol-3-yl) -ethyl] -acetamide is obtained from 2- (l-methyl-lH-indol-3-yl) -ethylamine by Acylation as described in Example 16.1, yielding a pale green oil, MS = 217.4 ([M + H] +). 29.2. Using the general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) is reacted with benzaldehyde and N- [2- (l-methyl-lH-indol-3-yl) - ethyl] -acetamide, giving N- (2- { 2- [(5-benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl) -phenyl-methyl] -l -methyl-lH-indol-3-yl.}. -ethyl) -acetamide as a red solid. MS = 493.3 ([M-H] ").

Example 30 5-Benzyl-3- [(5-fluoro-3-methyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5H-furan-2-one Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) is reacted with benzaldehyde and 5-fluoro-3-methyl-1H-indole, obtaining the title compound in the form of colorless solid. EM = 426.1 ([M-H] ").

Example 31 N- (2-. {6-fluor-2- [(4-hydroxy-2-oxo-5-phenyl-2,5-dihydro-furan-3-yl) -phenyl-methyl] -lH- indol-3-yl.}.-ethyl) -acetamide Using general procedure C, 4-hydroxy-5-phenyl-5H-furan-2-one (Lit. 14) is reacted with benzaldehyde and N- [2- (6-fluor-lH-indol-3-yl) - ethyl] -acetamide (example 18.1.), obtaining the title compound in form of pale brown solid. MS = 485.0 ([M + H] Example 32 3-. { [3- (2-Amino-ethyl) -6-ethyl-lH-indol-2-yl] -phenyl-methyl} -4-hydroxy-5-phenyl-5H-furan-2-one Using general procedure C, 4-hydroxy-5-phenyl-5H-furan-2-one (Lit. 14) is reacted with benzaldehyde and 2- (6-ethyl-lH-indol-3-yl) -ethylamine (Lit. 8), obtaining the title compound as a white solid. MS = 453.3 ([M + H] +).

Example 33 N- (2-. {6-fluoro-2- [(4-hydroxy-5-methyl-2-oxo-5-phenyl-2,5-dihydro-furan-3-yl) -phenyl-methyl) ] -lH-indol-3-yl.}.-ethyl) -acetamide Using general procedure C, 4-hydroxy-5-methyl-5-phenyl-5H-furan-2-one is reacted (example A2) with benzaldehyde and N- [2- (6-f luor-1H-indol-3 -i 1) -eti 1] -acetylamide (example 18.1.), obtaining the title compound as a solid pale brown. MS = 499.5 ([M + H] +).

EXAMPLE 34 N- (2- { 2- [(4-hydroxy-5-isobutyl-2-oxo-2,5-dihydro-furan-3-yl) -phenyl-methyl] -1H-indole-3- il.}.-ethyl) -acetamide Using general procedure C, 4-hydroxy-5-isobutyl-5H-furan-2-one (Lit. 14) is reacted with benzaldehyde and N- [2- (lH-indol-3-yl) -ethyl] -acetamide. , the title compound being obtained as a white solid. MS = 441.1 ([M + H] 0.

Example 35 2- acetate. { 2- [(4-hydroxy-5-isobutyl-2-oxo-2,5-dihydro-furan-3-yl) -phenyl-methyl] -lH-indol-3-yl} -ethyl Using the general procedure C, 4-hydroxy-5-is obu-1 -5 H-furan-2 -one (Lit. 14) is reacted with benzaldehyde and 2- (1H-i-1 -3-yl) - Ethanol, obtaining the title compound as an orange solid. MS = 448.1 ([M + H] +).

Example 36 N- (2- { 2- [(4-hydroxy-2-oxo-l-oxa-spiro [4, 5] dec-3-en-3-yl) -phenyl-methyl] -lH- indol-3-yl.}.-ethyl) -acetamide Using general procedure C, 4-hydroxy-1-oxa-spiro [4.5] dec-3-en-2-one (Lit. 15) is reacted with benzaldehyde and N - [2 - (1H-i ndo 1 - 3 -i 1) - eti 1] - to ce t amide, the title compound being obtained as a white solid. MS = 459.1 ([M + H] +).

Example 37 N- (2- { 2- [(5-cyclohexylmethyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl) -phenyl-methyl] -6-fluor-1H- indol-3-yl.}.-ethyl) -acetamide Using general procedure C, 5-cyclohexylmethyl-4-hydroxy-5H-furan-2-one (Lit. 13) is reacted with benzaldehyde and N- [2- (6-fluor-lH-indol-3-yl) - ethyl] -acetamide (example 18.1.), obtaining the title compound as a pale red solid. MS = 503.0 ([M-Hl ").

EXAMPLE 38 N- [2- (2- { [5- (2-Cyclohexyl-ethyl) -4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl] -phenyl-methyl. .6-fluor-lH-indol-3-yl) -ethyl] -acetamide Using the general procedure is done reacting 5- (2-cyclohexyl-ethyl) -4-hydroxy-5H-furan-2-one (example B2) with benzaldehyde and N- [2- (6-fluor-lH-indol-3-yl) -ethyl] -acetamide (example 18.1.), obtaining the title compound as a pale green solid. MS = 517.2 ([M-H] ").

Example 39 N- (2-. {6-fluoro-2- [(4-hydroxy-2-oxo-5-phenethyl-2,5-dihydro-furan-3-yl) -phenyl-methyl] -lH- indol-3-yl.}.-ethyl) -acetamide Using the general procedure C is reacted -hydroxy-5-phene t i 1 -5H-furan-2 -one (Lit. 13) with benzaldehyde and N- [2 - (6- f luor-1H-indol-3- i 1) -e ti 1] -acetamide (example 18.1.), Obtaining the title compound as a pale red solid.

MS = 511.1 ([M-H] ").

EXAMPLE 40 N- [2- (6-Fluoro-2 { [4-hydroxy-2-oxo-5- (3-phenyl-propyl) -2,5-dihydro-furan-3-yl] -phenyl) -methyl.}.-lH-indol-3-yl] ethyl] -acetamide Using the general procedure C, 4-hydroxy-5- (3-phenyl-propyl) -5H-furan-2-one (Lit. 13) with benzaldehyde and N- [2- (6-fluor-lH-indol-3-yl) -ethyl] -acetamide (example 18.1.), The title compound being obtained as a pale red solid. MS = 525.2 ([M-H] ").

EXAMPLE 41 N- (2-. {2- [(2-hydroxy-5-oxo-cyclopent-1-enyl) -phenyl-methyl] -lH-indol-3-yl] -ethyl) -acetamide Using the general procedure C, 3-hydroxy-cyclopent-2-enone (Lit. 16) is reacted with benzaldehyde and N- [2- (lH-indol-3-yl) -ethyl] -acetamide, obtaining the title compound in the form of solid rose.

MS = 387.4 ([M-H] EXAMPLE 42 N- (2- {2- [(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl) -phenyl-methyl] -lH-indol-3-yl} -ethyl ) -acetamide Using the general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) is reacted with benzaldehyde and N- [2- (lH-indol-3-yl) -ethyl] -acetamide, obtaining the title compound as a pink solid. MS = 465.0 ([M + H] 0.

Example 3 N- (2-. {6-fluoro-2- [(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl) -phenyl-methyl] -lH-indol-3-yl} -ethyl) -acetamide Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone is reacted (Lit. 17) with benzaldehyde and N- [2- (6-fluor-lH-indol-3-yl) -ethyl] -acetamide (Example 18.1.), obtaining the title compound as a pink solid. MS = 483.5 ([M + H] +).

Example 44 N- (2- { 2- [(2-hydroxy-5-oxo-3-pheny1-cyclopent-1-enyl) -pyridin-2-yl-methyl] -lH-indol-3-yl} -ethyl) -acetamide Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) is reacted with pyridine-2-carbaldehyde and N- [2- (lH-indol-3-yl) -ethyl] -acetamide, obtaining the title compound as a white solid. MS = 466.3 ([M + H] +).

Example 45 N- (2- { 2- [(2-hydroxy-5-oxo-3-phenyl-cyclopent-l-enyl) -pyridin-3-yl-methyl] -lH-indol-3-yl} -ethyl) -acetamide Using the general procedure C, 3-hydroxy-4-phenyl-1-cyclopent-2-enone (Lit. 17) is reacted with pyridine-3-carbaldehyde and N- [2 - (1H-indol-3 -i 1) -e ti 1] -acetamide, the title compound being obtained as a pale brown solid. MS = 466.3 ([M + H] +).

Example 46 N- (2 - {2 - [(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl) - (1H-imidazol-4-yl) -methyl] -lH- indol-3-yl.}.-ethyl) -acetamide Using general procedure C, 3-hydroxy-4-phenyl-1-cyclopent-2-enone is reacted (Lit. 17) with 3H-imide zol-4 -carbaldehyde and N- [2 - (1H-indol-3i 1) -e t i 1] -acetylamide, obtaining the title compound as a pale brown solid. EM = 455.0 ([M + H] +).

Example 47 N- (2- { 2- [(2-hydroxy-5-oxo-3-pheny1-cyclopent-1-enyl) - (1H-imidazol-2-yl) -methyl] -lH-indole 3-yl.}.-Ethyl) -acetamide Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) is reacted with lH-imidazole-2-carbaldehyde and N- [2- (lH-indol-3-yl) - ethyl] -acetamide, the title compound being obtained as a pale brown solid. MS = 455.0 ([M + H] +).

Example 48 N- (2- (5-ethyl-2- [(2-hydroxy-5-oxo-3-pheny1-cyclopent-1-enyl) -phenyl-methyl] -lH-indol-3-yl}. -ethyl) -acetamide Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) is reacted with benzaldehyde and N- [2- (5-ethyl-lH-indol-3-yl) -ethyl] -acetamide (Lit. 6), obtaining the title compound in the form of solid orange MS = 493.4 ([M + H] +) Example 49 2-. { [3- (2-Amino-ethyl) -5-methyl-lH-indol-2-yl] -phenyl-methyl} -3-hydroxy-4-phenyl-cyclopent-2-enone Using the general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) is reacted with benzaldehyde and 2- (5-ethyl-1H-indol-3-yl) -ethylamine, obtaining the compound of the title in the form of an orange solid. MS = 437.1 ([M + H] +).

Example 50 N- (2- { 2- [(2-hydroxy-5-oxo-3-pheny1-cyclopent-1-enyl) -phenyl-methyl] -5-methyl-1H-indol-3-yl} -ethyl) -acetamide Using the general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) is reacted with benzaldehyde and N- [2- (5-methyl-lH-indol-3-yl) -ethyl] -acetamide (Lit. 7), obtaining the title compound as an orange solid. MS = 479.0 ([M + H] 0.

Example 51 2-. { [3- (2-Amino-ethyl) -6-ethyl-lH-indol-2-yl] -phenyl-methyl} -3-hydroxy-4-phenyl-cyclopent-2-enone Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) is reacted with benzaldehyde and 2- (6-ethyl-1H-indol-3-yl) -ethylamine (Lit. ), obtaining the title compound as a pale brown solid. MS = 451.0 ([M + H] 0.

Example 52 N- (2-. {6-ethyl-2- [(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl) -phenyl-methyl] -lH-indol-3-yl} -ethyl) -acetamide 52. 1 N- [2- (6-ethyl-lH-indol-3-yl) - is obtained ethyl] -acetamide from 2- (6-ethyl-lH-indol-3-yl) -ethylamine (Lit. 8) as described in example 16.1. 52.2. Using the general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) is reacted with benzaldehyde and N- [2- (6-ethyl-lH-indol-3-yl) -ethyl] -acetamide, obtaining N- (2-. {6-ethyl-2- [(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl) -phenyl-methyl] -lH-indole-3 -yl.}. -ethyl) -acetamide in the form of a pale brown solid. MS = 493.1 ([M + H] 0.

Example 53 2-. { [3- (2-amino-2-methyl-propyl) -6-chloro-lH-indol-2-yl] -phenyl-methyl} -3-hydroxy-4-phenyl-cyclopent-2-enone Using the general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) is reacted with benzaldehyde and 2- (6-chloro-lH-indol-3-yl) -1,1-dimethyl. -ethylamine (obtained by a method similar to that described in Lit. 9), obtaining the title compound as a pale yellow solid. MS = 485.4 ([M + H] +).

Example 54 N- (2-. {6-chloro-2- [(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl) -phenyl-methyl] -lH-indol-3-yl} -l, 1-dimethyl-ethyl) -acetamide 54. 1. N- [2- (6-chloro-lH-indol-3-yl) -1,1-dimethyl-ethyl] -acetamide is obtained from 2- (6-chloro-lH-indol-3 -yl) -1,1-dimethyl-ethylamine (obtained in a manner similar to that described in Lit. 9) by acylation as described in example 16.1. 54.2. Using the general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) is reacted with benzaldehyde and N- [2- (6-chloro-lH-indol-3-yl) -1, 1-dimethyl-ethyl] -acetamide, obtaining N- (2. {6-chloro-2- [(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl) -phenyl-methyl] -lH-indol-3-yl.} -1, 1-dimethyl-ethyl) -acetamide as a pale yellow solid. MS = 527.3 ([M + H] +).

Example 55 H- (2-. {6-chloro-2- [(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl) -phenyl-methyl] -5-methoxy-1H-indole 3-yl.} -ethyl) acetamide Using the general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) is reacted with benzaldehyde and N- [2- (6-chloro-5-methoxy-1H-indol-3-yl ) -ethyl] -acetamide, the title compound being obtained as a pale red solid. MS = 529.3 ([M + H] +).

Example 56 N- (2- { 2- [(2-hydroxy-5-oxo-3-pheny1-cyclopent-1-enyl) -phenyl-methyl] -6-methoxy-1H-indol-3-yl} -ethyl) -acetamide Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone is reacted (Lit. 17) with benzaldehyde and N- [2- (6-methoxy-lH-indol-3-yl) -ethyl] -acetamide (Lit. 7), obtaining the title compound as a pale red solid. MS = 495.5 ([M + H] +).

Example 57 N- (2- { 2- [(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl) -phenyl-methyl] -5-methoxy-1H-indol-3-yl} -ethyl) -acetamide Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) is reacted with benzaldehyde and N- [2- (5-methoxy-lH-indol-3-yl) -ethyl] -acetamide, obtaining the title compound as a pale red solid. MS = 495.4 ([M + H] +).

Example 58 3-. { [6-fluoro-3- (2-hydroxy-ethyl) -lH-indol-2-yl] -phenyl-methyl} -4-hydroxy-5-isopropyl-l, 5-dihydro-pyrrol-2-one Using the general procedure D is done react rac-4-hydroxy-5-isopropyl-l, 5-dihydro-pyrrol-2-one (Lit. 11) with benzaldehyde and 2- (6-fluor-lH-indol-3-yl) -ethanol, obtaining the composed of the title in the form of a pale yellow solid. MS = 409.1 ([M + H] +).

Example 59 2- [(5-Fluoro-3-methyl-lH-indol-2-yl) -phenyl-methyl] -1-hydroxy-7a-methyl-5, 6, 7, 7a-tetrahydro-pyrrolizin-3 ona Using the general procedure D, rac-l-hydroxy-7a-methyl-5,6,7,7-tetrahydro-pyrrolizin-3-one (Example C) is reacted with benzaldehyde and 5-fluoro-3-methyl-1H- indole, obtaining the title compound as a red solid. MS = 391.1 ([M + H] 0.

Example 60 3- [(5-Fluoro-3-methyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5,5-dimethyl-l, 5-dihydro-pyrrol-2-one Using the general procedure D, rac-4-hydroxy-5,5-dimethyl-l, 5-dihydro-pyrrol-2-one is reacted (Lit. 18) with benzaldehyde and 5-fluoro-3-methyl-1H-indole, the title compound being obtained as a yellow solid. MS = 365.1 ([M + H] +).

Example 61 (R) -5-Benzyl-3- [(5-fluoro-3-methyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5-methyl-1, 5-dihydro- pyrrol-2-one Using the general procedure D, (R) -5-benzyl-4-hydroxy-5-methyl-1,5-dihydro-pyrrol-2-one (Example D) is reacted with benzaldehyde and 5-fluoro-3-methyl- 1H-indole, the title compound being obtained as a yellow solid. MS = 441.1 ([M + H] +).

Example 62 (R) -3- [(5-Fluoro-3-methyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5-isopropyl-5-methyl-1, 5-dihydro- pyrrol-2-one Using the general procedure D, (R) -4-hydroxy-5-isopropyl-5-methyl-1,5-dihydro-pyrrol-2-one (Example E) is reacted with benzaldehyde and 5-fluoro-3-methyl- 1H-indole, the title compound being obtained as a pale yellow solid. MS = 393.1 ([M + H] +).

Example 63 N-. { 2- [((R) -4-hydroxy-5-methyl-2-oxo-5-phenyl-2, 5-dihydro-lH-pyrrol-3-yl) -phenyl-methyl] -6-methyl-lH- Indole-3-ylmethyl} -acetamide 63. 1. 6-Methyl-lH-indole-3-carbaldehyde oxime To a solution of 6-methyl-lH-indole-3-carbaldehyde (0.96 g, Lit. 20) in ethanol (30 ml) is added at 22 ° C the hydroxylamine hydrochloride (0.46 g) and sodium acetate (0.54 g) and the mixture is stirred for 3 h. The mixture is concentrated by evaporation, the residue is triturated with water and dichloromethane / n-heptane (1: 1) and dried, obtaining the title compound (0.96 g) as a pink solid. MS = 175.3 ([M + H] 0. 63.2 C- (6-methyl-lH-indol-3-yl) -methylamine To a mixture of the oxime of 6-methyl-lH-indole-3 carbaldehyde (0.66 g) and NiCl2-6 H20 (0.97 g) in methanol (60 ml) is added at 22 ° C in portions sodium borohydride (3.04 g). The suspension is filtered and the filtrate is concentrated. The residue was partitioned between aqueous NH3 (1%) and ethyl acetate, the organic phase was dried and concentrated to give the crude title compound as a yellow semi-solid (0.68 g). 63.3. N- (6-Methyl-lH-indol-3-ylmethyl) -acetamide To a solution of C- (6-me thi 1-lH-indol-3-yl) -methylamine (0.24 g) in dichloromethane (4 ml ) was added acetic anhydride (0.14 ml) and pyridine (0.13 ml) and stirring was continued at 22 ° C for 20 min.

The mixture is washed with aqueous HCl (1N), the organic phases are dried and concentrated. The residue is chromatographed on silica gel using dichloromethane / methanol (70: 1), thereby obtaining the title compound as a colorless foam. (0.15 g). MS = 203.1 ([M + H] +). 63.4. Using the general procedure D, (R) -4-hydroxy-5-methyl-1-phenyl-1,5-dihydro-pi rr-ol-2 -one (Example F) is reacted with benzaldehyde and N- ( 6-methyl-lH-indol-3-ylmethyl) -acetamide, the title compound being obtained as a white solid. MS = 478.4 ([M-H] ").

Example 64 (R) -4-hydroxy-5-methyl-3- [(3-methyl-lH-indol-2-yl] phenyl-methyl] -5-phenyl-1, 5-dihydro-pyrrol-2-one Using the general procedure D, (R) -4-hydroxy-5-methyl-5-phenyl-1,5-dihydro-pyrrol-2-one (obtained according to Lit. 11, see also Lit. 19) is reacted with benzaldehyde and 3-methyl-1H-indole, the title compound being obtained as a yellow foam. MS = 409.2 ([M + H] 0.

Example 65 (R) -3- [(3,5-Dimethyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5-methyl-5-phenyl-1,5-dihydro-pyrrol- 2-one Using the general procedure D, (R) -4-hydroxy-5-methyl-5-phenyl-1,5-dihydro-pyrrol-2-one (obtained according to Lit. 11, see also Lit. 19) is reacted with benzaldehyde and 3, 5-dimethyl-lH-indole (Lit. 21), obtaining the title compound as a yellow foam. MS = 423.3 ([M + H] +).

Example 66 (R) -3- [(3,6-Dimethyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5-methyl-5-phenyl-1,5-dihydro-pyrrol- 2-one Using the general procedure D, (R) -4-hydroxy-5-methyl-5-phenyl-1,5-dihydro-pyrrol-2-one (obtained according to Lit. 11, see also Lit. 19) is reacted with benzaldehyde and 3,6-dimethyl-1H-indole (Lit. 22), obtaining the title compound as a yellow foam. MS = 423.3 ([M + H] +).

Example 67 (R) -3- [(5-Fluoro-3-methyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5-methyl-5-phenyl-1,5-dihydro- pyrrol-2-one Using the general procedure D is done react (R) -4-hydroxy-5-methyl-5-phenyl-1, 5-dihydro-pyrrol-2-one (obtained according to Lit. 11, see also Lit. 19) with benzaldehyde and 5-fluoro- 3-methyl-lH-indole, the title compound being obtained as a pale yellow foam. MS = 425.4 ([M-H] ").

Example 68 5-Benzyl-3- [(5-fluoro-3-methyl-1H-indol-2-yl) -thiophen-2-yl-methyl] -4-hydroxy-5H-furan-2-one Using general procedure D, rac-5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) is reacted with thiophene-2-carbaldehyde and 5-fluoro-3-methyl-1H-indole, obtaining the title compound as a red solid.

MS = 434.3 ([M + H] 0.

Example 69 5-Benzyl-3- [(5-fluoro-3-methyl-1H-indol-2-yl) -thiophen-3-yl-methyl] -4-hydroxy-5H-furan-2-one Using the general procedure D is done react rac-5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) with thiophene-3-carbaldehyde and 5-fluoro-3-methyl-1H-indole, obtaining the title compound as colorless solid. MS = 434.3 ([M + H] +).

Example 70 N- (2-. {6-chloro-2- [(-hydroxy-5-methyl-2-oxo-5-phenyl-2,5-dihydro-furan-3-yl) -phenyl-methyl] -lH-indol-3-yl.} -1, 1-dimethyl-ethyl) -acetamide 70. 1. N- [2- (6-Chloro-lH-indol-3-yl) -1,1-dimethyl-ethyl] -acetamide The 2- (6-chloro-lH-indol-3-yl) - acylates 1,1-dimethyl-ethylamine (obtained in a manner similar to that described in Lit. 9) in the manner described in Example 63.3, obtaining the title compound as a brown semisolid. 70.2. Using the general procedure D reacts rae-4-hydroxy-5-methyl-5-phenyl-5H-furan-2-one (obtained according to Example A3) with benzaldehyde and N- [2- (6-chloro-lH-indol-3-yl) -1,1-dimethyl-ethyl] -acetamide, the title compound being obtained as a solid pale brown. MS = 543.3 ([M + H; EXAMPLE 71 N- (2- {5-Chloro-2- [(4-hydroxy-5-methyl-2-oxo-5-pheny1-2,5-dihydro-furan-3-yl) -phenyl-methyl) ] -lH-indol-3-yl.} -1, 1-dimethyl-ethyl) -acetamide 71. 1. N- [2- (5-Chloro-lH-indol-3-yl) -1,1-dimethyl-ethyl] -acetamide Acylation of 2- (5-chloro-lH-indol-3-yl) - 1,1-dimethyl-ethylamine (Lit.23) in the manner described in Example 63.3, giving the title compound as a colorless solid. MS = 263.1 ([MH] "). 71.2 Using general procedure D, rac-4-hydroxy-5-methyl-5-phenyl-5H-furan-2-one (obtained according to Example A3) is reacted with benzaldehyde and N- [2- (5-chloro-lH-indol-3-yl) -1,1-dimethyl-ethyl] -acetamide, the title compound being obtained as a pale brown solid EM = 543.3 ([M + H] +).

Example 72 N- (2- [((R) -4-hydroxy-5-methyl-2-oxo-5-phenyl-2, 5-dihydro-furan-3-yl) -phenyl-methyl] -6-methyl -lH-indol-3-ylmethyl.} - acetamide Using general procedure D, (R) -4-hydroxy-5-methyl-5-phenyl-1,5-dihydro-pyrrol-2-one (Example A4) is reacted with benzaldehyde and N- (6-methyl-1H) -indol-3-ylmethyl) -acetamide (from Example 63.3), obtaining the title compound as a yellow solid. MS = 479.4 ([M-H] ").

Example 73 N-. { 2- [((S) -4-hydroxy-5-methyl-2-oxo-5-phenyl-2,5-dihydro-furan-3-yl) -phenyl-methyl] -6-methyl-1H-indole 3-ylmethyl} -acetamide Using the general procedure D is reacted (S) -4-hydroxy-5-methyl-5-phenyl-1,5-dihydro-pyrrol- 2-one (Example A3) with benzaldehyde and N- (6-methyl-lH-indol-3-ylmethyl) -acetamide (from Example 63.3), obtaining the title compound as a yellow solid. MS = 479.4 ([M-H] ").

Example 74 (R) -4-hydroxy-5-methyl-3- [(3-methyl-lH-indol-2-yl) -phenyl-methyl] -5-phenyl-5H-furan-2-one Using general procedure D, (R) -4-hydroxy-5-methyl-5-phenyl-1,5-dihydro-pyrrol-2-one (Example A4) is reacted with benzaldehyde and 3-methyl-1H-indole, obtaining the title compound as a yellow solid. MS = 408.4 ([M-H] ").

Example 75 (R) -3- [(3,5-dimethyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5-methyl-5-phenyl-5H-furan-2-one Using general procedure D, (R) -4-hydroxy-5-methyl-5-phenyl-1,5-dihydro-pyrrol-2-one (Example A4) is reacted with benzaldehyde and 3,5-dimethyl-1H- indole (Lit. 21), obtaining the title compound as a pale brown solid. MS = 422.5 ([M-H] ").

Example 76 (R) -3- [(3,6-Dimethyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5-methyl-5-phenyl-5H-furan-2-one Using the general procedure D, (R) -4-hydroxy-5-methyl-5-phenyl-1,5-dihydro-pyrrol-2-one (Example A4) is reacted with benzaldehyde and 3,6-dimethyl-1H- indole (Lit. 22), obtaining the title compound as a pale brown solid. MS = 422.4 ([M-H] ").

Example 77 (R) -3- [(5-Fluoro-3-methyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5-methyl-5-phenyl-5H-furan-2- ona react (R) -4-hydroxy-5-methyl-5-phenyl-1,5-dihydro-pyrrol-2-one (Example A4) with benzaldehyde and 5-fluoro-3-methyl-1H-indole, obtaining the compound of the title in the form of a yellow solid. MS = 426.1 ([M-H] ").

Example 78 3-hydroxy-2- [(3-methyl-lH-indol-2-yl) -phenyl-methyl] -4-phenyl-cyclopent-2-enone Using general procedure D, rac-3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) is reacted with benzaldehyde and 3-methyl-1H-indole, obtaining the title compound as a red solid. EM = 394.1 ([M + H] 0.

Example 79 2- [(5-Fluoro-3-methyl-lH-indol-2-yl) -phenyl-methyl] -3-hydroxy-4-phenyl-cyclopent-2-enone Using general procedure D, rac-3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) is reacted with benzaldehyde and 5-fluoro-3-methyl-1H-indole, obtaining the title compound in the form of solid red. MS = 412.0 ([M + H] +).

Example A Films coated with a film, containing the following ingredients, can be manufactured in conventional manner: Ingredients per core tablet: compound of the formula (I) 10.0 mg 200.0 mg microcrystalline cellulose 23.5 mg 43.5 mg lactose hydrated 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg sodium starch glycolate 12.5 mg 17.0 mg magnesium stearate 1.5 mg 4.5 mg (core weight) 120.0 mg 350.0 mg coating film: hydroxypropyl methyl cellulose 3.5 mg 7.0 mg polyethylene glycol 6000 0.8 mg 1.6 mg talc 1.3 mg 2.6 mg iron oxide (yellow) 0.8 mg 1.6 mg titanium dioxide 0.8 mg 1.6 mg The active ingredient is screened and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is mixed with sodium starch glycolate and magnesium stearate and compressed to obtain cores of 120 and 350 mg, respectively. The cores are varnished with an aqueous solution / suspension of the aforementioned film.

Example B Capsules containing the following ingredients can be manufactured in a conventional manner: Ingredients per capsule compound of formula (I) 25.0 mg lactose 150.0 mg corn starch 20.0 mg talc 5.0 mg The components are sieved, mixed and packed in size 2 capsules.

Example C Injectable solutions can have the following composition: compound of the formula (I) 3.0 mg polyethylene glycol 400 150.0 mg acetic acid, sufficient quantity up to the final pH of 5.0 water for injectable solutions up to 1.0 ml The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (one part). The pH is adjusted to 5.0 with acetic acid. The volume is adjusted to 1.0 ml by addition of the remaining amount of water. The solution is filtered, packaged in vials using an appropriate excess and sterilized.

Example D In a conventional manner, soft gelatin capsules containing the following ingredients can be manufactured: capsule content Compound of the formula (I) 5.0 mg yellow wax 8.0 mg hydrogenated soybean oil 8.0 mg vegetable oils partialm. Hydrogen 34.0 mg soybean oil 110.0 mg capsule content weight: 165.0 mg gelatin capsule gelatin 75.0 mg 85% glycerin 32.0 mg Karion 83 8.0 mg (dry matter) titanium dioxide 0.4 mg yellow iron oxide 1.1 mg The active ingredient is dissolved in a melt of the other ingredients and the mixture is filled into soft gelatin capsules of the appropriate size. The soft gelatin capsules and their contents are treated according to the usual procedures.

Example E Sachets containing the following ingredients can be manufactured in a conventional manner: compound of the formula (I) 50.0 mg lactose, fine powder 1015.0 mg microcrystalline cellulose (AVICEL PH 102) 1400.0 mg sodium carboxymethyl cellulose 14.0 mg polyvinylpyrrolidone K 30 10.0 mg magnesium stearate 10.0 mg flavoring additives 1.0 mg The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and It is granulated with a mixture of polyvinylpyrrolidone and water. The granulate is mixed with magnesium stearate and the flavoring additives and packaged in sachets. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (27)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Compounds of the formula (I) (i) characterized in that A is -CH2-, -O- or -NR'-, wherein R 'is hydrogen or C6_6 alkyl, or R' and R4 form a C2_5 alkylene; R1 is hydrogen, halogen, nitro, cyano, amino, C? -6 alkyl, heteroalkyl, C3_7 cycloalkyl, C2-6 alkenyl, C2_6 alkynyl, hydroxy, C-6 alkoxy, -NR'R ", - (C0-6 alkylene) ) -NR'R ", wherein R 'and R" independently of each other are selected from the group consisting of hydrogen, C? _6 alkyl, heteroalkyl, formyl, C_6 alkylcarbonyl, C3 optionally substituted cycloalkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted heterocyclylcarbonyl,

C 1 -C 6 alkylsulfonyl, optionally substituted C 3 cycloalkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl, and optionally substituted heterocyclylsulfonyl, or - (alkylene Co-e) ~ 0R ', wherein R' is hydrogen, C 6 -alkyl, heteroalkyl, formyl or (C 1 -C 6 alkylcarbonyl; R2, R2 'and R2"independently of each other are hydrogen, halogen, cyano, nitro, amino, amino mono- or disubstituted by C6_6 alkyl, C6 alkyl, C2_6 alkenyl, C2_6 alkynyl, heteroalkyl, hydroxy or C-alkoxy ? 6; R3 is hydrogen, halogen, cyano, nitro, amino, amino mono- or disubstituted by C? -6 alkyl, C? _6 alkyl, C2_6 alkenyl, C2_6 alkynyl, heteroalkyl, hydroxy, C? -6 alkoxy, cycloalkyl Optionally substituted C3_, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C6_7 cycloalkyl, optionally substituted C6_6 alkyl, optionally substituted arylalkyl, optionally substituted C6_6 heteroarylalkyl or optionally substituted C6_6 heterocyclylalkyl R 4 is hydrogen, halogen, cyano, nitro, amino, amino mono- or disubstituted by C 1-6 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroalkyl, hydroxy, C 1-6 alkoxy, optionally substituted C 3-7 cycloalkyl, arilo optionally substitute uido, heteroaryl optionally substituted, optionally substituted heterocyclyl, C3-7 cycloalkyl optionally substituted C6-6alkyl, optionally substituted arylalkyl C6, optionally substituted heteroaryl-C6alkyl, or optionally substituted heterocyclylC6alkyl; R5 is hydrogen or C6-alkyl; or R4 and R5, together with the carbon atom to which they are attached, form an optionally substituted C3_7 cycloalkyl ring or an optionally substituted heterocyclyl ring; R6 is hydrogen or C6_6alkyl; and prodrugs and pharmaceutically acceptable salts thereof; wherein the term "heteroalkyl" means C? -6 alkyl substituted by one or more substituents independently chosen from the group consisting of nitro, hydroxy, halogen, cyano, C? _ alkoxy, formyl, C? _6 alkylcarbonyl, carboxyl, alkylthio C6-6, alkylsulfinyl C6-6, alkylsulfonyl C6-6, amino and amino mono- or disubstituted by C6-alkyl; the term "aryl" means a phenyl or naphthyl radical; The term "heteroaryl" means a monocyclic or bicyclic radical, of 5 to 12 ring atoms, which has at least one aromatic ring containing one, two or three heteroatoms in the ring chosen from N, 0 and S, the other ring atoms are C, assuming that the point of attachment of the heteroaryl radical is located in the ring aromatic; the term "heterocyclyl" means non-aromatic mono- or bicyclic radicals, having three to eight ring atoms, in which one or two ring atoms are heteroatoms chosen from N, 0 and S (0) n (wherein n is an integer from 0 to 2), the other ring atoms are C; the terms "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted heterocyclyl" and "optionally substituted C3-7 cycloalkyl" mean aryl, heteroaryl, heterocyclyl and C3-7 cycloalkyl, respectively, optionally substituted by one or more substituents independently chosen from the group consisting of halogen, nitro, cyano, amino, C6 alkyl, C2_6 alkenyl, C2_6 alkynyl, hydroxy, C alkoxy ? 6, amino mono- or disubstituted by C6 alkyl and heteroalkyl. 2. Compounds according to claim 1, characterized in that R3 is C6_6alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-C6_6alkyl or optionally substituted C6_6 heteroaryl-alkyl.

3. Compounds according to any of claims 1 and 2, characterized in that R3 is C6 alkyl; phenyl alkyl C? -e; phenyl optionally substituted by one to three fluorine atoms; or heteroaryl optionally substituted by one to three fluorine atoms, the heteroaryl is a monocyclic aromatic radical of 5 or 6 ring atoms, containing one or two nitrogen atoms in the ring or a sulfur atom in the ring.

4. Compounds according to any one of claims 1 to 3, characterized in that R3 is phenyl.

5. Compounds according to any one of claims 1 to 4, characterized in that R1 is C6 alkyl, - (C06 alkylene) -NR'R ", wherein R 'and R" independently of each other are chosen from the group consisting of hydrogen, C-6 alkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted arylsulfonyl, and optionally substituted heteroarylsulfonyl or - (alkylene Co-β) -OR ', wherein R' is hydrogen or alkylcarbonyl C ? -

6. 6. Compounds according to any one of claims 1 to 5, characterized in that R1 is C6_6 alkyl, - (C2_6 alkylene) -NR'R ", wherein R 'and R" independently of each other are selected from the group consisting of hydrogen, acetyl, arylcarbonyl, the aryl is optionally substituted by one or two perfluoromethyl and arylsulfonyl or - (C2_6 alkylene) -OR ', wherein R' is hydrogen or acetyl.

7. Compounds according to any one of claims 1 to 6, characterized in that R1 is 2-aminoethyl, 2-acetylaminoethyl, 2-acetylamino-2, 2-dimethylethyl, methyl, isopropyl or 2-hydroxyethyl.

8. Compounds according to any of claims 1 to 7, characterized in that R2, R2 'and R2"independently of each other are hydrogen, halogen, C6_6 alkyl or C6_6-9 alkoxy. Compounds in accordance with any of claims 1 to 8, characterized in that two of R2, R2 'and R2"are hydrogen and the other is hydrogen, halogen, C6-6 alkyl or C6-6 alkoxy. Compounds in accordance with any of the claims 1 to 9, characterized in that two of R2, R2 'and R2"are hydrogen and the other is hydrogen, chlorine, fluorine, methyl, ethyl or methoxy 11. Compounds according to any of claims 1 to 10, characterized in that two of R2, R2 'and R2"are hydrogen and the other occupies position 5 or 6 of the indole ring and is selected from the group consisting of hydrogen, chlorine, fluorine, methyl and ethyl. 12. Compounds in accordance with any of the claims 1 to 11, characterized in that R6 is hydrogen. 13. Compounds according to any one of claims 1 to 12, characterized in that R4 is hydrogen, C? -6 alkyl, optionally substituted C3_ cycloalkyl, optionally substituted aryl, (C3_7 cycloalkyl)-optionally substituted C? -6 alkyl or arylalkyl Optionally substituted C? -6 and R 5 is hydrogen or C-6 alkyl, - or R 4 and R 5, together with the carbon atom to which they are attached form an optionally substituted C 3_ cycloalkyl ring. 14. Compounds according to any of claims 1 to 13, characterized in that A is -CH2-. 15. Compounds according to any one of claims 1 to 14, characterized in that A is -CH2-, R4 is phenyl and R5 is hydrogen. 16. Compounds according to any one of claims 1 to 13, characterized in that A is -NR'-, wherein R 'is hydrogen or C-6 alkyl. 17. Compounds according to any one of claims 1 to 13 and 16, characterized in that A is -NR'-, wherein R 'is hydrogen or methyl, R4 is isopropyl and R5 is hydrogen. 18. Compounds in accordance with any of the claims 1 to 13, characterized in that A is -0-. 1

9. Compounds according to any one of claims 1 to 13 and 18, characterized in that A is -0-, R4 is hydrogen, phenyl, C6 alkyl, (C3_7 cycloalkyl)-optionally substituted C-6 alkyl or arylalkyl C? _6 optionally substituted and R5 is hydrogen or C? -6 alkyl; or R4 and R5, together with the carbon atom to which they are attached form an optionally substituted C3_ cycloalkyl ring. 20. Compounds according to any one of claims 1 to 13, 18 and 19, characterized in that A is -O-, R4 is phenyl, benzyl, isobutyl, 2-cyclohexylethyl or phenethyl and R5 is hydrogen or methyl. 21. Compounds according to claim 1, characterized in that they are: 3- [(5-fluoro-3-methyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5-isopropyl-1, 5-dihydro-pyrrol-2-one, 3- [(5-fluoro-3-methyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5-isopropyl-1-methyl-1, 5-dihydro-pyrrol-2-one, 4-hydroxy-5-isopropyl-3- [(3-methyl-lH-indol-2-yl) -phenyl-methyl] -1,5-dihydro-pyrrole-2- ona, 3- [(5-fluoro-3-isopropyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5-isopropyl-l, 5-dihydro-pyrrol-2-one, N- (2- {2- [(5-benzyl-4-hydroxy-2-oxo-2, 5-dihydro-furan-3-yl) -phenyl-methyl] -6-fluoro-lH-indol-3} il.}.-ethyl) - acetamide, 5-benzyl-3-. { [6-fluoro-3- (2-hydroxy-ethyl) -lH-indol-2-yl] -phenyl-methyl} -4-hydroxy-5H-furan-2-one, 3-. { [3- (2-Amino-ethyl) -6-fluor-lH-indol-2-yl] -phenyl-methyl} -5-benzyl-4-hydroxy-5H-furan-2-one; salt with acetic acid, 5-benzyl-3- [(5-fluoro-3-methyl-lH-indol-2-yl) -phenyl-methyl] -4-hydroxy-5H-furan-2-one, (2- {6-Fluoro-2- [(4-hydroxy-5-methy1-2-oxo-5-phenyl-2,5-dihydro-furan-3-yl) -phenyl-methyl] -indol-3-yl. .).-ethyl) -acetamide, (2- (2- [(4-hydroxy-5-isobutyl-2-oxo-2,5-dihydro-furan-3-yl) -phenyl-methyl] -indol-3 -yl.}.-ethyl) -acetamide, N- [2- (2- { [5- (2-cyclohexyl-ethyl) -4-hydroxy-2-oxo-2,5-dihydro-furan-3 -yl] -phenyl-methyl.} .6-fluor-lH-indol-3-yl) -ethyl] -acetamide, N- (2-. {6-fluoro-2- [(4-hydroxy-2) -oxo-5-phenethi-2-, 5-dihydro-furan-3-yl) -phenyl-methyl] -1H-indol-3-yl}. -ethyl) -acetamide, N- (2- { 2 - [(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl) -phenyl-methyl] -lH-indol-3-yl}. -ethyl) -acetamide, N- (2-. { 6-Fluoro-2- [(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl) -phenyl-methyl] -lH-indol-3-yl.} -ethyl) -acetamide, N - (2- { 5-ethyl-2- [(2-hydroxy-5-oxo-3-phenyl-cyclopent- 1-enyl) -phenyl-methyl] -1H-indol-3-yl} ethyl) -acetamide, N- (2- { 2- [(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl) -phenyl-methyl] -5-methyl-1H-indole 3-yl.) -ethyl) -acetamide, 2- ([3- (2-amino-ethyl) -6-ethyl-lH-indol-2-yl] -phenyl-methyl.} - 3-hydroxy- 4-phenyl-cyclopent-2-enone or N- (2- {6-chloro-2- [(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl) -phenyl-methyl] - 1H-indol-3-yl.) -1, 1-dimethyl-ethyl) -acetamide 22. Process for the preparation of compounds of the formula (I), characterized in that it consists of the step of adding a compound of the formula (III) (III), a compound of the formula (IV) R3 I CHO (IV) and a compound of the formula (V) wherein A, R1, R2, R2 ', R2'0 R3, R4, R5 and R6 have the meanings defined in accordance with claim 1. 23. Pharmaceutical compositions, characterized in that they comprise a compound according to any of the claims from 1 to 21 and a pharmaceutically acceptable excipient. 24. Compounds according to any one of claims 1 to 21, characterized in that they are for use as therapeutically active substances. 25. Compounds according to any one of claims 1 to 21, characterized in that they are for use as therapeutically active substances intended for the treatment and / or prophylaxis of allergic, inflammatory or fibrotic diseases. 26. Use of compounds according to any of claims 1 to 21, for the manufacture of medicaments for the therapeutic and / or prophylactic treatment of allergic, inflammatory or fibrotic diseases. 27. Use according to claim 26, wherein the disease is allergy, asthma, peripheral arterial occlusive disease, critical extremity ischemia, patients with vulnerable atherosclerotic plaque, unstable angina, congestive heart failure, hypertrophy left ventricular, reperfusion injury due to ischemia, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable bowel disease, Crohn's disease, atherothrombosis or burns / ulcers in diabetes / CLI.