MXPA98008546A - Specific binders of immunophylin as antimatic, immunosupreso - Google Patents

Abstract

The new immunophilin-specific ligands of the general formula (1) possess anti-asthmatic and immunosuppressive effect and are suitable for the preparation of medicament.

Description

SPECIFIC INMUNOPHILINES LIKE ANTI-ASMATIC, IMMUNOSUPPRESSIVE The invention relates to new specific ligands of the immunofilin of formula The radicals R.sub.1, R.sub.3, R.sub.4, X, Y, A, B and D have the following meaning: hydrogen RL, (C! -C12) -alkyl or (C2-C6) -alkoxy groups, where the alkyl group can be straight or branched chain and can be substituted by a mono or bicyclic heteroaryl with 1-4 heteroatoms, preferably N, S, O, such as morpholine, piperazine, piperidine, indole, indazole, phthalazine, thiophene, furan, imidazole, or a more times for a phenyl ring. This phenyl ring in turn can be substituted by halogen, -alkyl, (C3-C7) -cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight or branched chain (Ci-Cg) alkanes, carbamoyl groups, trifluoromethyl, hydroxyl , methoxy, ethoxy, benzoyloxy, amino, which in turn are replaced by benzyl, benzoyl, acetyl.

Rx can also be an amino residue of the following amino acid methyl esters: histidine, leucine, valine, serine (Bzl), threonine, pipecoliniso acid, 4-ieridi nc a rboxí 1 ico acid, 3-piperidinesarboxílico acid, e-NH2- lysine, eZ-NH-lysine, e (2C1-Z) -NH-lysine, 2-pyridylalanine, phenylalanine, tryptophan, glutamic acid, arginine (Cough), asparagine, citrulline, homocitrulin, ornithine, proline, 2- i ndol acid incarboxylic acid, hydrocarboxylic acid, tetrahydroisoquinolinecarboxylic acid, 5-aminovaleric acid, 8-aminooctanoic acid, R 2 hydrogen, (C 1 -C 12) -alkyl or (C 2 -C 6) -alkyloxy groups, wherein alkyl group is straight or branched chain and may be substituted by a mono or bicyclic heteroaryl with 1-4 heteroatoms, preferably N, S, 0, co or morpholine, piperazine, piperidine, indole, indazole, phthalazine, thiophene, furan, imidazole , or once or twice for a phenyl ring. This phenyl ring in turn can be substituted one or more times by halogen, -alkyl, (C3-C7) -cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight or branched chain (Ci-Cg) alkanols, groups carbamoyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, benzyloxy, amino, which in turn are substituted by benzyl, benzoyl, acetyl. R3 is hydrogen, butyloxycarbonyl, carboxybenzyl, carbonylaryl or carbonyl-heteroaryl with 1-4-10 heteroatoms, preferably N, S, O, mono- or tricyclics, where the aryl or, where appropriate, heteroaryl, in turn may be substituted or more times by halogen, (Cx-C6) -alkyl, (C3-C7) -cycloalkyl, carboxyl groups, groups carboxyl esterified with straight or branched chain alkanols, carbamoyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, benzyloxy, amino groups, which in turn are substituted by benzyl, benzoyl, acetyl. In addition R3 can is carboxy (Ci-Cg) -alkyl, wherein the alkyl group can be straight or branched chain and can be substituted by a mono or bicyclic heteroaryl with 1-4 heteroatoms, preferably N, S, O, as morpholine, piperazine, piperidine, indole, indazole, phthalazine, thiophene, furan, imidazole or, where appropriate, one or more times for a phenyl ring, where this phenyl ring in turn may be substituted one or more times by halogen, (Cx) - C6) -alkyl, (C3-C7) -cycloalkyl, by carboxyl groups, by carboxyl groups esterified with straight or branched chain (Ci-Cg) -alkanols, by carbamoyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, benzyl groups ? i, amino, which in turn are replaced for benzyl, benzoyl, acetyl. R3 can also be an acidic residue of the following amino acids: histidine, leucine, valine, serine (Bzl), threonine, pipecolinic acid, 4-piperidinecarboxylic acid, 3-piperidinecarboxylyl acid, e-NH2-lysine, eZ-NH-lysine, e- (2C1-Z) -NH- 1 is ina, 2-pyridylalanine, phenylalanine, tryptophan, glutamic acid, arginine (Cough), asparagine, citrulline, homocitrulin, ornithine, proline, aceid 2 - indole insarboxy 1 iso, acidic ostahydroindolinesarboxyse, acid tetrahydroisoquinolinecarboxylic acid, 5-aminovaleric acid, 8-aminooctanoic acid, where the N-terminus of amino acids may * be substituted by butyloxycarbonyl, carboxybenzyl or by the acid moiety of aryl or heteroarylcarboxylic acids with 1-4 heteroatoms, preferably N, S, 0, mono, bi or tricyclic, such as methoxyphenylacetic acid, naphthylacetic acid, pyridylacetic acid, quinazolinonylacetic acid, indazolylacetic acid , indoliglioxílico acid, fenilglioxílico acid, isobutylglyoxylic acid, 2-aminotiazol-4-glioxíliso acid or, in his saso, by carboxi- - alkyl, carboxisiclopentano, carboxiciclohexane, benzoílo, that can be substituted one or more times by halogen, methoxy groups, amino, carbamoyl, trifluoromethyl, carboxyl, carboxyl groups esterified with (Cx-C6) - straight or branched chain alkanols. R4 H, F, 0R5 R5 = hydrogen, (C3-C7) -cycloalkyl, -alkyl or carboxy- (CL-Cg) -alkyl, wherein the alkyl group may be straight or branched chain and may be substituted by a carbonylaryl or carbonylheteroaryl with 1-4 heteroatoms, preferably N, S, O mono, bi or tricyclics, wherein the aryl or, where appropriate, the heteroaryl in turn may be substituted one or more times by halogen, -alkyl, (C3-C7) ) - cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight or branched chain alkanols, carbamoyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, benzyloxy, amino groups, which in turn are substituted by benzyl, benzoyl, acetyl. A = aromatic, non-aromatic, aromatic heterocyclic with 1-2 heteroatoms, preferably N, S, 0, non-aromatic heterocyclic with 1-2 heteroatoms, preferably N, S, O, B = CH2 D = CHD BD = CH = CX = O, S, H2 Y = C, single bond In addition, the invention relates to the physiologically tolerable salts of the compounds according to formula I, the processes for the preparation of the compounds according to formula I and their pharmaceutical application. Cyclosporin A (CsA) or FK 506 are natural immunosuppressive substances formed by fungi, which inhibit the signaling pathway dependent on Ca + 2 in some cell types. In T cells both agents inhibit the transcription of a series of genes, including the gene for IL-2, which is activated by stimulating the T cell (TCR) receptors. FK 506 and CsA both bind with high affinity with proteins of soluble receptor (G. Fischer et al., Nature 337, 476-478, 1989; MW Harding et al., Nature 341, 755-760, 1989). The FK 506 receptor was called FKBP, the receptor for CsA was called cyclophilin (Cyp). Both proteins catalyze the isomerization of amin and cis trans-linker rotamers of peptides and are also often called immunophilins. The molecule composed of CsA-Cyp or, where appropriate, FK 506-FKBP binds to calcineurin (CN) and inhibits its phosphatase activity. The phosphorylated cytosolic component of the NF-AT transcription factor was resolved as the target DNA molecule of the CN, which lacks the asthmaticness of the CN for the efesto in the cell nucleus, it can not be dephosphorylated and in this way the complex can not be dismantled. astive of transsription in the IL-2 promoter. (MK Rosen, SL Schreiber, Angew, Chem. 104 (1992), 413-430, G. Fischer, Angew.Chem. 106 (1994), 1479-1501; Allergic asthmatic diseases are due to an inflammatory reactions conducted by T-cells and their mediators: Corticosteroids still represent the remedy of choice in the treatment of many allergic diseases, and CsA and FK 506 proved to be favorable therapeutic agents both in the experiment with animals and in clinical studies for asthma. bronchial and the inflammation that is due In the experiment with animals it was possible to demonstrate the blockade of various cytokines such as IL-2, IL-4 and IL-5, which cause allergen-induced inflammation.

Despite multiple attempts to identify new active inhibitors of immunophilins until now, or could be elaborated or, where appropriate, isolated structures more effective than CsA, FK 506, Rapamycin or, where appropriate, derivatives of these natural substances. However, the high inhibitory potential of CsA, FK 506, Rapamycin is considerably reduced by the multiple side effects, especially in the kidneys and neurotoxicity.

(N. H. Sigal et al., J .. Ezxp. Med. 173, 619-628, 1991). The cause of this fact is what is not specified in the interaction between immunophilin-binders and cell-specific binding proteins. For this reason, the known medicinal-therapeutic effect of these immunosuppressants is considerably limited. In addition, especially in long-time therapy, the lack of selectivity of the compounds proves problematic. The invention is based on the objective of finding new compounds with valuable pharmacological properties and providing said compounds by selective synthesis. A completely new class of substances that surprisingly specifically binds immunophilins and surprisingly inhibits the proliferation of IL-2, is represented by the compounds according to the invention, of formula I. This class of compounds and their pharmaceutically acceptable salts has a high affinity to immunophilins such as CypA, CypB, CypC and FKBP12. Those compounds of formula I which contain asymmetric carbon atoms and are therefore generally produced in the form of racemates can be separated into the optically active isomers in a manner known per se, for example with an optically active acid. However, it is also possible to use optically active starting substances from the start, the corresponding optically active compounds or, as the case may be, diastereoisomers being obtained as the final product. The invention then comprises compounds of formula I, which contain an asymmetric carbon atom, the R form, the S form and mixtures of R and S, as well as, in the case of several asymmetric carbon atoms, the diastereomeric forms. Depending on the conditions of the preparation and the starting substances, the compounds of formula I can be obtained in the form of free compounds or in the form of their salts. The salts obtained can be converted in a known manner into the bases or, where appropriate, free acids, for example, with acids, alkalis or ion exchangers. The compounds of formula I thus liberated can be transformed with acids or, where appropriate, inorganic or organic bases into the corresponding salts by the addition of physiologically tolerable acids. Both the free bases and their salts are biologically active. The compounds of formula I can be administered both in free form, as well as in salt form they are an acid or, where appropriate, physiologically tolerable base. The administration can be oral, parenteral, intravenous, transdermal or inhalation. Furthermore, the invention relates to pharmaceutical preparations with a content of at least one compound of formula I or its salts with acids or, where appropriate, physiologically tolerable inorganic or organic bases, and, where appropriate, of support substances or vehicles. and auxiliary substances, pharmaceutically usable. As administration forms are suitable, for example, tablets or dragees, capsules, solutions or, where appropriate, ampoules, suppositories, patches or powdered preparations can be placed in inhalers. The dosage of the pharmaceutical preparations described above depends on the condition of the patient and the method of administration. The daily dose of active substance is between 0.01 and 100 mg per Kg of body weight per day. The preparation of the compounds represented by the formula I is achieved, for example, by the synthesis in solid phase according to B. Merrifield, preferably in an insoluble polymer., for example, a polystyrene resin hinshable in an organic solvent, in the form of beads (for example, a polystyrene sopolymer and 1% divinylbensen), by means of standard methods of peptide cleavage of peptide solid phase synthesis. The compounds of general formula I are prepared by first providing two of the functions (α-amino group, optionally e-amino and α-carboxylic acid) of protecting groups and then appropriately transforming the third function, which is free. If necessary, intermediate protective groups can also be introduced in the first step, where this leads to better results, and changing them in the second step for the desired function. Suitable protecting groups and methods for introducing them are known in the art. Examples of protecting groups are described in "Princip-Les of Peptide Synthesis", Editorial Springer (1984), in the manual "Solid Phase Peptide Synthesis" JM Stewart and JD Young, Pierce Chem. Company, Rockford, III, 1984, and in G. Barany and RB Merrifield "The Peptides", chapter 1, p. 1-285, 1979, Academic Press Inc. Step-by-step construction is effected, for example, by first covalently ligating the amino acid with carboxy terminal, whose amino group located in position is protected, to an insoluble support customary for this, the protective group of the a-amino group of this amino acid, binds with this free amino group obtained with the following protected amino acid, by means of its carboxy group and in this way the other amino acids of the peptide to be synthesized are linked step by step, in the Correct sequence and, if necessary, other existing protective groups of collateral functions are separated and after the binding of all the amino acids the finished binder is analyzed as an immobilized compound to detect the binding to the Cyp or, where appropriate, to the FKBP. The step-by-step condensation is carried out in a customary manner by synthesis from the corresponding amino acids protected in the usual manner. It is also possible to use automatic peptide synthesizers, for example, of the Labortec SP 650 type from Bachem, Switzerland, using the protected amino acids obtainable commercially. As examples of compounds of formula I we will state: Example 1 [S- (N-e-Boc) -lisinmethyl] acid ester amide N- [1-Boc-piperidyl-4-carbonyl] -indolin-2- (R, S) -carboxylic Example 2 [S- (e-NH 2) -lisinmethyl] ester amide of N- [piperidyl-4-acid] carbonyl] -indolin-2- (R, S) -carboxylic Example 3 [S- (Ne-Boc) -lysinmethyl] acid ester amide N- [1-Boc-indolin-2- (R, S) -sarbonyl] -indolin-2- (R, S) -carboxylic Example 4 [S- (e-NH 2) -lysinmethyl] N-acid ester amide - [indolin-2 - (R, S) -carbonyl] -indole 2- (R, S) -carboxylic acid Example 5 (S- (NeZ) -lysinmethyl) amide of N- [1-Boc] acid indolin-2- (R, S) -sarbonyl] -indolin-2- (R, S) -sarboxylyl Example 6: Ester amide (S- (NeZ) -lysinmethyl) of 1-Bos-indoline-2- (R) , S) -carboxylic Example 7 Amide of the (S-phenylalanymethyl) ester of l-Boc-indolin-2- (R, S) -carboxylic acid Example 8 Methyl ester of N- [N '- (4-methoxyphenylacetyl) - piperidyl-4-carbonyl] -indolin-2- (R, S) -carboxylic acid (as a preliminary step for the preparation of an amide of general formula I) Example 9 N- (4-methoxyphenylacetyl) -indoline-2-methyl ester - (R, S) -carboxylic acid (As a preliminary step for the preparation of an amide of general formula I) Example 10 4-Piperidyl-amide of N-Boc-indolin-2- (R, S) -carboxylic acid Example 11 [Piperazineacetic acid-morpholide] -N-Boc-indolin-2- (R, S) -carboxylic acid amide Example 12 [Piperazineacetic acid-morpholide] -amide acid N- [l-Bos-pipéridil-4-sarbonyl] -indolin-2- (R, S) -carboxylic Example 13 [N- [N '- (4-methoxyphenylacetyl)] N-[N- (4-methoxy-phenylacetyl ) -piperidyl-4-carbonyl] -indoline-2- (R, S) -carboxylism Correspondingly to the present invention, the compounds of formula I can also be prepared by the following procedure. lll IV V VI Vil VIII According to the invention, compounds of formula I in which R 1 R2, R 3, R 4, A, B, D, X and Y have the stated meaning are prepared by transforming an indole derivative of formula II, wherein R 4, A, B , D, X and Y have the meaning enunciated, with an alkanol III of chain length to obtain an alkyl ester of indole derivative IV, where R4, A, B-, D, X and Y have the signified enunsiado, transforming to this ester IV, following the reaction, with a compound V, where R3, X and Y have the enunciated meaning, to obtain a compound VI, where R3, R4, A, B, D, X and Y have the stated meaning, a then subjecting this compound VI to a saponification to obtain a compound VII, wherein R3, R4, A, B, D, X and Y have the stated meaning, and then transforming compound VII with a compound VIII, wherein Rx and R2 have the enunciated meaning, to obtain the target compound I. To prepare the physiologically tolerable salts, the compounds of formula I are converted in a known manner with inorganic or organic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, lactic acid or embonic acid, or with inorganic or organic bases. The pharmaceutical preparations contain at least one compound of general formula I or its salts are acids or physiologically tolerable inorganic or organic bases and, optionally, support substances or vehicles and pharmaceutically usable auxiliaries. The compounds of formula I can be administered in free form or in the form of a salt with an acid or a base physiologically tolerable orally, parenterally, intravenously, transdermally or inhalatively. Suitable forms of application are, for example, tablets or dragees, capsules, solutions or, where appropriate, ampoules, suppositories, patches or powder preparations for placement in inhalers.

The dosage of the pharmaceutical preparations listed above depends on the condition of the patient and the manner of application. The daily dose of active substance is between 0.01 and 100 mg per Kg of body weight. The compounds according to the invention according to formula (I) are distinguished by the binding to immunophilins and inhibit their isomerase activity. This prolylisomerase activity is evaluated according to the widely used enzymatic assay: G .. Fischer, H. Bang, A. Schellenberger, Biochim. Biophys. Acta, 791, 87-97, 1984; D. H. Rich et al., J. Med. Chem. 38, 4164-4170, 1995). Without influencing in all cases the activity of peptidyl-cis-trans-isomerase of the immunophilins, such compounds surprisingly specifically inhibit the proliferation of IL-2 from mastoid cells, macrophages and activated T cells. The compounds according to the invention such as cyclosporin A (Sandimmun®, CsA), FK 506 or, where appropriate, Rapamycin (Tacrolimus) as immunosuppressants can be used (RY Calne et al., Br. Med. J. 282, 934 -936, 1981), for the treatment of autoimmune diseases (RH Wiener et al., Hepatology 7, 1025, Abst. 9, 1987); L Fry, J. "Autoimmun., 5, 231-240, 1992, G. J Feutren." Autoi mun. 5, 183-195, 1992, EP 610,743), of allergic inflammations (P. Zabel et al., Lancet 343, 1984), asthma (C. Bachert, Atemw.-Lungenkrkh., 20, 59, 1994), diabetes mellitus insulin-dependent (CR Stiller, Science, 223, 1362-1367, 1984), sepsis and also in combination with known immunophilin binders such as CsA, FK 506 or Rapamycin. (M. J. Wyvratt, N, H. Sigal, Perspectives in Drug Discovery, and Design, Immunosupression, 2, 1, 1994, WO 92/21313, US 5 330 993). The invention will be explained in more detail with the aid of examples of embodiments. The abbreviations used for this are: AcOEt ethyl acetate Boc terbutyloxycarbonyl (Boc) 20 terbutyloxycarbonyl anhydride CN calcineurin CsA cyclosporin A Cyp cyclophilin DMAP N, N-dimethylaminopyridine EA elemental analysis EE - ethyl acetate FKBP binding protein FK 506 HPLC chromatography high pressure liquid i. OPV vacuum by oil pump Lsg. Solution MeOH methanol PPlase peptidyl-proline-cis-trans-isomerase i. &V on the rotary evaporator i. V in the vessel RT ambient temperature rae racemic enantio TFA trifluoroacetic acid Z benzyloxycarbonyl Ej-sanplí-LL: Synthesis of: [S- (Ne-Boc) -lysinmethyl] amide of N- [1-Boc-piperidyl-] 4-carbonyl] -indolin-2- (R, S) -carboxylyl Step 1: (R, S) -indolin-2-carboxylic acid methyl ester x C1H In a three-man 100 ml balloon, 5.3 g (32.5 mmol) of (R, S) -2-indolinecarboxylic acid was dissolved in 70 g. ml of water-free methanol and 4.25 g (35.75 mmoles) of thionyl chloride were added at room temperature. The yellow scavenging mixture was heated for 5 hours at reflux and then, after cooling, it was freed of the solvent under vacuum in the rotary evaporator. After drying under vacuum by an oil pump, the crude product was obtained in the form of a crystalline solid, which was stirred with diethyl ether and separated by filtration by suction. Yield: 5.4 g (78%) Step 2: Boc-piperidine-4-carboxylic acid In a 250 ml balloon from a mouth, 7 g (54 mmol) of piperidine-4-carboxylic acid were dissolved in 50 ml of dioxane and 40.5 ml of 2N NaOH and it was cooled to 0 ° C. To this, 12.99 g (59.4 mmoles) of (Boc) 20 dissolved in 30 ml of dioxane were added dropwise over the course of 30 min. It was then stirred for 24 h at room temperature. A white precipitate occurred. The dioxane was removed under vacuum in the rotary evaporator and the residue was added to a saturated solution of KHS04. The aqueous phase was extracted twice with EE. The organic phase was washed once with saturated NaCl solution and dried over MgSO4. After removing the solvent under vacuum in the rotary evaporator, 11.93 g (96%) of a white powder was obtained. 1 H-NMR (DMSO-d 6, 270 MHZ): 1.25-1.5 (m, 11, Boc, 2-Pip); 1.8 (m, 2 Pip); 2.4 (m, 1, H-C4); 2.8 (t, 2, H-C3, H-C5); 3.8 (d, 2, H-C2, H-C6); 12.25 (s, 1, COOH). EA: calculated for C ^ H ^ N ^ (229.1): C 57.62; H 8.29; N 6.11 found: C 57.89; H 8.36; N, 5.86 Step 3: N- [1-Boc-piperidyl-4-sarbonyl] -indolin-2- (R, S) -carboxylic acid methyl ester 4.6 g (22 mmol) of methyl ester of acid (R, S) -indolin-2-carboxylism x HCl and 7.4 g (32 mmoles) of Boc-piperidin-4-carboxylic acid in 50 ml of CH2C12 and were added dropwise in the course of 30 min at room temperature to a suspension of 9.27 g (36 mmol) of 2-chloro-1-methylpyridinium iodide and 8.06 ml (58 mmol) of triethylamine in 40 ml of CH2C12. It was then boiled under reflux for 8 h. The solvent was removed in the rotary evaporator, the residue was added to 200 ml of EE and the organic phase was washed once with water, twice with half-saturated aqueous solution of KHS04, twice with 2N aqueous NaOH solution and one once with saturated solution saturated with NaCl. The solvent was removed in the rotary evaporator and the residue was purified by chromatography on 400 g of silica gel with CH2Cl2 / MeOH 95: 5. After removing the solvent under vacuum in the rotary evaporator and drying under vacuum by an oil pump, 4.61 g (54% J of a light brown powder was obtained.) PF: 54-56 ° Thin layer chromatography: CH2Cl2 / MeOH 95 : Rf = 0.61 XH-NMR (DMSO-d6, 270 MHz): 1.35-1.85 (m, 15, Boc, 6 Pip); 2.7-2.8 (m, 2, H) -C3, H-C5), 3.25 (m, 1, H-C3-Ind), 3.65 (m, 1, H-C3'-Ind); 3.8 (s, 3, C00CH3); 3.95 (m, 2, H-C6-pip); .45 (d, 1, H-C2-Ind); 7.05 (m, 1, Ar); 7.1-7.3 (m, 2, Ar); 8.1 (d, 1, Ar). EA: calculated for C ^ H ^ aOs (388.47): C 64.92; H 7.27; N 7.21 found: C 65.20; H 7.49; N, 7.38. MS: (ESI +): calculated 388.3, found 389.2 Step 4: N- [l-Boc-piperidyl-4-carbonyl] -indolin-2- (R, S) -carboxylic acid In a 50 ml one-pass balloon, 3.3 g (8.51 mmol) was dissolved of N- [1-Boc-piperidyl-4-carbonyl] -indolin-2- (R, S) -carboxylic acid methyl ester in 25 ml of MeOH, 2.14 g (51 mmol) of LiOH x H20 were added and it was stirred for 2.5 h at room temperature. The solution was acidified to pH 5 with semi-saturated aqueous solution of KHS04 and extracted twice with EE. The organic phase was washed once with saturated NaCl solution, dried over MgSO4 and the solvent was removed under vacuum in the rotary evaporator. After drying under vacuum by an oil pump, 3.09 g (97%) of a light brown powder were obtained. PF: 118-119 ° Thin layer chromatography: CH2Cl2 / MeOH 95: 5 Rf = 0.14 XH-NMR (DMSO-d6, 270 MHz): 1.35-1.85 (m, 15, Boc, 6 Pip ); 2.7-2.85 (m, 2, H-C3, H-C5); 3.2 (m, 1, H-C3-Ind); 3.65 (m, 1, H-C3'-Ind); 3.95 (m, 2, H-C6-Pip); 5.45 (d, 1, H-C2-Ind); 7.05 (m, 1, Ar); 7.1-7.3 (m, 2, Ar); 8.1 (d, 1, Ar); 13.0-13.3 (s, 1, COOH). MS: (ESI +): calculated 374.3; Found: 375.1 Step 5: Amide of the N- [1 -Boc-piperidyl-4-carbonyl] -indolin-2- (R, S) -carboxylic acid ester (S- (Ne-Boc) -lysinmethyl] 2 g (5 g) was dissolved , 35 mmoles) of N- [1-Boc-piperidyl-4-carbonyl] -indolin-2- (R, S) -carboxylic acid and 1.59 g (5.35 mmol) of Ne-Boc-lysine methyl ester x HCl in 20 ml of CH2C12 and added dropwise at room temperature over the course of 30 min to a suspension of 2.81 g (11 mmol, 2.73 g) of 2-chloro-1-methylpyridinium iodide and 1.62 g (16 mmol) of triethylamine in 30 ml of CH2C12. It was then boiled for 8 hours at reflux. The solvent was removed under vacuum in the rotary evaporator, the residue was added to 200 ml of EE and the organic phase was washed once with water, twice with half-saturated aqueous solution of KHS04, twice with 2N aqueous NaOH solution and one once with saturated aqueous NaCl solution. The solvent was removed under vacuum in the rotary evaporator and the residue was purified by chromatography on 400 g of silica gel with CH2Cl2 / MeOH 95: 5. After again removing the solvent under vacuum in the rotary evaporator and drying under vacuum by an oil pump, 2.61 g (79%) of a light brown powder was obtained. P.F: 83-84 ° Thin layer chromatography: CH2Cl2 / MeOH 95: 5 Rf = 0.48 FT-IR (KBr): 3365 w (N-H); 2976w (C-H); 1744m (C = 0); 1684S (CONH); 1540w (C-O); 1407m (C-H); 1170S (C-O); 755m (C = C); -NR (DMSO-d6, 270 MHz): 1.25-1.9 (m, 28, 18 Boc + 3CH2-Lys + 4 Pip); 2.7-3.05 (m, 5, e-CH2-Lys + H-C3-Ind + 2 Pip); 3.55-3.7 (m, 3, COOMe); 3.9-4.1 (m, 2, Pip); 4.15-4.3 (m, 1, H-C3-Ind); 5.15 (m, 1, HC2-Ind); 6.8 (m, 1, Ar-Ind); 7.0 (m, 1, Ar-Ind); 7.1-7.3 (m, 2, Ar-Ind + a-NHCO); 8.1 (d, 1, Ar-Ind); 8.7-8.9 (dd, 1, NHCO-Boc). MS: (ESI +): calculated 616.4, found: 617.5 HPLC: 2 peaks in 24.25 and 24.63 min EA: (calculated for C32H48N40a: 616.4): C 62.34; H 7.47; N 9.09 found: C 62.08; H 7.67; N, 8.86 Example 2 Synthesis of: [S- (e-NH2) -lysinmethyl] -amide ester of N- [1-piperidyl-4-carbonyl] -indolin-2- (R, S) -carboxylic acid 500 mg (0.812 mmol) of ester amide was dissolved [S- (Ne-Boc) -lysinmethyl] of N- [l-Boc-piperidyl-4-carbonyl] -indolin-2- (R, S) -carboxylic acid in a 25 ml balloon from a mouth, in 2 , 8 ml of CH2C12. To this, 15 equivalents (0.0122 mol, 0.93 ml) of trifluoroacetic acid were added and stirred for two hours at room temperature. They added ml of diethyl ether was added to the solution, a white precipitate was produced which was filtered off by suction and washed 6 times with diethyl ether. After drying under vacuum by an oil pump, 513 mg (98%) of a white powder was obtained. P.F: 164-165 ° Thin layer chromatography (RP): CH3CN / H20 1: 1, 1% TFA ^ 'Rf = 0.61 FT-IR (KBr): 3435W (N-H); 3049w (C-H); 1740w (C = 0); 1676s (CONH); 1420m (C-H); 1205m, 1135s (C-O); 4I-NMR (DMSO-d6, 270 MHz): 1.2-2.05 (m, 10.3 CH2-Lys + 4 Pip); 2.7-3.15 (m, 5, e-CH2-Lys + HC3-Ind + 2 Pip); 3.55-3.7 (m, 3, COOMe); 4.1-4.25 (m, 1, C3-Ind); 5.15 (d, 1, H-C2-Ind); 6.95 (m, 1, Ar-Ind); 7.1-7.3 (m, 2, Ar-Ind); 7.7-7.85 (s, 3, NH3 +); 8.1 (d, 1, Ar-Ind); 8.7-8.9 (m, 2, NH2 +). MS: (ESI +): calculated 418.2, found: 417.3 and 209.1 for m / 2 HPLC: 2 peaks at 11.54 and 12.65 min Example 3 Synthesis of: [S- (Ne-Boc) -lysinmethyl] amide ester of N- [1-Boc-indolin-2- (R, S) -carbonyl] -indolin-2- (R, S) -carboxylic Step 1: Boc- (R, S) -indole-carboxylic acid In a 250 ml balloon from a mouth, 5 g were dissolved (30.8 mmol) of (R, S) -indolin-2-carboxylic acid in 30 ml of dioxane and 23 ml of 2N NaOH and cooled to 0 ° C. To this a solution of 7.39 g (33.9 mmol) of (Boc) 20 in 20 ml of dioxane was added dropwise over the course of 30 min and stirred for 24 h at room temperature. There was a white presipitate. The dioxane was removed under vacuum in the rotary evaporator, the residue was added to a saturated solution of KHS04 and extracted twice with EE. The organic phase was washed once with saturated NaCl solution and dried over MgSO4. After removing the solvent under vacuum in a rotary evaporator and drying under vacuum by an oil pump, 7.76 g (96%) of brown powder were obtained. Thin layer chromatography: CH2Cl2 / MeOH 95: 5 + 1% NEt3 RE = 0.91 - MR (DMSO-d6, 270 MHz): 1.4-1.7 (s, 9, Boc); 3.1 (m, 1, H-C3); 3.5 (m, 1, H-C3 '); 4.9 (m, 1, H-C2); 7.0 (m, 1, Ar); 7.1-7.3 (m, 2, Ar); 7.5-7.9 (m, 1, Ar) 11.5 (m, 1, COOH) EA: calculated for C 14 H 17 N x 04 (263.2) C 63.88; H 6.46; N 5.32 found: C 64.05; H 6.53; N, 5.41 Step 2: Methyl ester of N- [1-Boc-indolin-2- (R, S) -carbonyl] -indolin-2- (R, S) -carboxylic acid. 5 g (0.023 mol) of methyl ester were dissolved. (R, S) -indolin-2-carboxylic acid x HCl and 12.11 g (46 mmoles) of Bos-indolin-2 (R, S) -carboxylic acid in 40 ml of CH2C12 and were added dropwise at room temperature in the 30 min. to a suspension of 12.92 g (51 mmol) of 2-chloro-1-methylpyridinium iodide and 10.23 ml (74 mmol) of triethylamine in 40 ml of CH2C12. It was then boiled for 8 hours at reflux. The solvent was removed under vacuum in the rotary evaporator, the residue was added to 200 ml of EE and the organic phase was washed once with water, twice with half-saturated aqueous solution of KHS04, 2 times with 2N aqueous NaOH solution and one once with saturated aqueous NaCl solution. The solvent was removed under vacuum in the rotary evaporator and the residue was purified by chromatography on 400 g of silica gel with CH 2 Cl 2 / MeOH 95: 5. After removing the solvent under vacuum in the rotary evaporator and drying under vacuum by an oil pump, 5.01 g (51%) of a dark brown powder was obtained. P.F: 86 ° C Thin layer chromatography: CH2Cl2 / MeOH 95: 5 Rf = 0.67 and 0.7 FT-IR (KBr): 3448w (N-H); 2976w (C-H); 1751s, 1707s (C = 0); 1680s (CONH); 1485s (C-H); 1168m (C-O); 1020m (C-O); 752s (C = C); MS: (ESI +) calculated: 422.4, found: 423.3 EA (calcined to (422.4)): C 68.25; H 6.16; N 6.64 found: C 67.96; H 6.17; N 6.4 Step 3 N- [l-Boc-indolin-2- (R, S) -carbonyl] -indolin-2- (R, S) -carboxylic acid In a 50 ml one-mouth balloon, 2.84 g was dissolved ( 6.77 mmole) of N- [1-Boc-indolin-2- (R, S) -carbonyl] -indolin-2- (R, S) -carboxylic acid methyl ester in 20 ml of MeOH. To this was added 1.71 g (41 mmol) of LiOH x H20 and stirred for 2.5 h at room temperature. The solution was then acidified to pH 5 with half-saturated solution of KHS04 and extracted twice with EE. The organic phase was washed once with saturated NaCl solution, dried over MgSO4 and the solvent was removed under vacuum in the rotary evaporator. After drying under vacuum by an oil pump, 2.71 g (98%) of a dark brown powder was obtained. P.F: 118-119 ° Thin layer chromatography: CH2Cl2 / Me0H 95. 5 Rf = 0, 14 MS: (ESI +) calculated: 408.2, found: 409.3 Step 4: N- [1-Boc-indolin-2- (R, S) -carbonyl] -indolin-2- (R, S) -carboxylic acid ester [S- (Ne-Boc) -lysinmethyl] acid 2 g (4.9 mmoles) of N- [1-Boc-indolin-2- (R, S) -carbonyl] -indolin-2- (R, S) -carboxylic acid and 1.45 (4, 9 mmol) of Ne-Boc-S-lysine methyl ester x HCl in 20 ml of CH2C12 and were added dropwise at room temperature over the course of 30 min to a suspension of 2.51 g (9.8 mmol) of 2- iodide. chloro-l-methylpyridinium and 2.04 ml (14.7 mmol) of triethylamine in 30 ml of CH2C12. It was then heated to reflux for 8 h. The solvent was removed under vacuum in the rotary evaporator, the residue was added to 200 ml of EA and the organic phase was washed once with water, twice with half-saturated aqueous solution of KHS04, twice with 2N aqueous NaOH solution and one once with saturated aqueous NaCl solution. The solvent was removed under vacuum in the rotary evaporator and the residue was purified by chromatography on 400 g of silica gel with CH 2 Cl 2 / MeOH 95: 5. After removing the solvent under vacuum in the rotary evaporator and drying under vacuum by an oil pump, 2.21 g (69%) of a brown powder was obtained. P.F: 78-80 ° Thin layer chromatography: CH2Cl2 / Me0H 95: 5 Rf = 0.51 FT-IR (KBr): 3504w (N-H); 2975w (C-H); 1749s, 1690s (CONH, C = 0); 1490S (C-H); 1407m (C-H); 1170s (C-O); 757m (C = C); XH-NMR (DMSO-d6, 270 MHz): 1.2-1.8 (m, 24, 18 Boc, 3 CH2-Lys); 2.8-3.0 (m, 3, e-CH2-Lys, H-C3-Ind); 3.0-3.2 (m, 1, H-C3-Ind); 3.4-3.5 (m, 1, H-C3-Ind); 3.5-3.7 (m, 3, COOMe); 4.2-4.3 (m, 1, H-C3-Ind); 4 ', 7-4, 9 (m, 1, H-C2-Ind); 5.0-5.5 (m, 1, H-C2-Ind); 6.7-6.8 (m, 1, Ar-Ind); 6.85-7.3 (m, 6, Ar-Ind); 7.7-8.9 (m, 3, NHCO, Ar-Ind, a-NHCO). MS: (ESI +) calculated: 650.2, found: 651.4. HPLC: 4 peaks in 24.82 min, 29.9 min, 30.3 min, 31.2 min.

Example 4 Synthesis of: [S- (e-NH2) -lysinmethyl] amide of N- [indolin-2- (R, S) -carbonyl] -indolin-2- (R, S) -carboxylic acid dissolved 500 mg (0.812 mmol) of ester amide [S- (Ne-Boc) -lysinmethyl] of N- [l-Boc-indolin-2- (R, S) -carbonyl] -indolin-2 (R, S) -carboxylic acid in a 25 ml. one mouth in 2.8 ml of CH2C12. To this, 15 equivalents (0.0122 mol, 0.93 ml) of trifluoroacetic acid were added and stirred for two hours at room temperature. 10 ml of diethyl ether were added to the solution, a white precipitate was produced which was separated by suction filtration and washed 6 times with diethyl ether. After drying in vacuo by asement pump, 513 mg (98%) of a wet powder was obtained. P.F: 164-165 ° Thin layer chromatography (RP): CH3CN / H20 1: 1, 1% TFA RE = 0.61 FT-IR (KBr): 3435w (N-H); 3049w (C-H); 1740w (C = 0); 1676s (CONH); 1420m (C-H); 1205m, 1135S (C-O); XH-NMR (DMSO-d6, 270 MHz): 1.2-2.05 (m, 10.3 CH2-Lys + 4 Pip); 2.7-3.15 (m, 5, e-CH2-Lys + H-C3-Ind + 2 Pip); 3.55-3.7 (m, 3, COOMe); 4.1-4.25 (m, 1, C3-Ind); 5.15 (d, 1, H-C2-Ind); 6.95 (m, 1, Ar-Ind); 7.1-7.3 (m, 2, Ar-Ind); 7.7-7.85 (s, 3, NH3 +); 8.1 (d, 1, Ar-Ind); 8.7-8.9 (m, 2, NH2 +). MS: (ESI +): calculated 418.2, found: 417.3 and 209.1 for m / 2 HPLC: 2 floors at 11.54 and 12.65 min Example 5; Synthesis of: Ester amide (S- (NeZ) -lysinmethyl) of N- [l-Boc-indolin-2- (R, S) -carbonyl] -indolin-2- (R, S) -carboxylic acid were dissolved 2.5 g (6.13 mmoles) of N- [1-Boc-indolin-2- (R, S) -carbonyl] -indolin-2- (R, S) -carboxylyl acid and 2.03 g (6.13 g) mmoles) of NeZ-lisinmethyl ester x HCl in 20 ml of CH2C12 and dropwise added at room temperature over the course of 30 min to a suspension of 2.35 g (9.2 mmol) of 2-chloro-1-methylpyridinium iodide and 2.13 ml (15 mmol) of triethylamine in 30 ml of CH2C12. It was then boiled for 8 hours at reflux. The solvent was removed under vacuum in the rotary evaporator, the residue was added to 200 ml of EE and the organic phase was washed once with water, twice with semi-saturated solution KHS04, twice with 2N NaOH solution and once with solution saturated with NaCl. The solvent was removed under vacuum in the rotary evaporator and the residue was purified by chromatography on 400 g of silica gel with CH2Cl2 / MeOH 95: 5. After removing the solvent under vacuum in the rotary evaporator and drying under vacuum by an oil pump, 2.57 g (61%) of a brown powder was obtained. P.F: 68 ° Thin layer chromatography: CH2Cl2 / MeOH 95: 5 Rf = 0.48 FT-IR (KBr): 3329w (N-H); 2935w (C-H); 1701S (C = 0); 1485s (C-H); 1260m (C-O); 1149m, 1020m (C-O); 753m (C = C); MS: (ESI +) calc'd: 684.5, found: 685.4 EA (calculated for C38H44N4? 8 (684.5)): C 66.67; H 6.43; N 8.19 found: C 64.15, H 6.5, N 7.88; Example 6 Synthesis of: Amide of the ester (S- (NeZ) -lysinmethyl) of 1-Boc-indolin-2- (R, S) -carboxylic acid 6.36 g (0.0242 mol) of acid were dissolved. -Boc-indolin-2- (R, S) -carboxylic acid and 8.0 g (24.2 mmol) of NeZ-lisinmethyl ester x HCl in 70 ml of CH2C12 and added dropwise at room temperature in the course of 30 min to a suspension of 9.27 g (36.3 mmol) of 2-chloro-l-methylpyridinium iodide and 8.41 ml (60.4 mmol) of triethylamine in 60 ml of CH2C12. It was then boiled for 8 hours at reflux. The solvent was removed under vacuum in the rotary evaporator, the residue was added to 200 ml of EE and the organic phase was washed once with water, twice with half-saturated solution of KHS04, twice with saturated 2N NaOH solution and one once with saturated NaCl solution. The solvent was removed under vacuum in the rotary evaporator and the residue was purified by chromatography on 400 g of silica gel with CH2Cl2 / MeOH 95: 5. After removing the solvent under vacuum in the rotary evaporator and drying under vacuum by an oil pump, 10.91 g (84%) of light brown powder was obtained. Thin layer chromatography: CH2Cl2 / MeOH 95: 5 Rf = 0.74 4 -.- NMR (DMSO-d6, 270 MHz): 1.3-1.75 (m, 15, 9 Boc + 6 CH2-Lys); 2.8-3.0 (m, 3, CH2-Lys + H-C3-Ind); 3.4-3.55 (m, 1, H-C3'-Ind); 3.65 (s, 3, C00CH3); 4.2 (m, 1, H a-C-Lys); 4.8 (m, 1, H-C2-Ind); 5.0 (s, 2, CH2-Z); 6.85 (m, 1, Ar-Ind); 7.15 (t, 2, Ar-Ind); 7.2-7.4 (m, 5 Ph-Z); 7.7 (m, 1, NHCO); 8.4 (m, 1, Ar-Ind) EA: calculated for C29H37N307 (539.4) C 64.56; H 6.86; N 7.79 found: C 64.61; H 7.06, N 7.67; MS: (ESI +) calculated: 539.4, found: 540.3 Example 7: Synthesis of: Ester (S-phenylalanine methyl) amide of l-Boc-indolin-2- (R, S) -carboxylic acid Step 1: S-phenylalanine methyl ester x HCl In a 100 ml balloon from a mouth were added dropwise at room temperature in the course of 30 min 5.3 ml (72.6 mmoles) of thionyl chloride to a suspension of 8.0 g (48.4 mmoles) S-phenylalanine in 50 ml of MeOH. It was then heated to reflux for 3 h. The methanol and excess thionyl chloride were first distilled under vacuum by water jet and then in the rotary evaporator. The residue was dissolved in 50 ml of MeOH and 800 ml of diethyl ether was added. A white precipitate occurred. The solvent was removed by sussing through a frit, 7.93 g (75%) of a white powder was obtained. -NR (DMSO-d6, 270 MHz): 3.0-3.2 (m, 2, CH2); 3.65 (s, 3, COOMe); 4.35 (m, 1, H a-C); 7.2-7.4 (m, 5, Ph); 8.5-8.7 (m, 3, NH3 +) Step 2: N- [1-Boc-indoline-2- (R, S) -carbonyl ester (S-phenylalanine) ester amide. 3.5 g (16.2 mmol) of S-phenylalanine methyl ester hydrochloride was dissolved. and 4.27 g (16.2 mmol) in 70 ml of CH2C12 and were added dropwise at room temperature over the course of 30 min to a suspension of 6.21 g (24.3 mmol) of 2-chloro-1-methylpyridinium iodide and 5.32 ml ( 40.5 mmole) of triethylamine in 60 ml of CH2C12. The reaction mixture was then heated to reflux for 8 h. The solvent was removed under vacuum in the rotary evaporator, the residue was added to 200 ml of EE and the organic phase was washed once with water, twice with half-saturated solution of KHS04, twice with 2N NaOH solution and once with saturated NaCl solution. The solvent was removed under vacuum in the rotary evaporator and the residue was purified by chromatography in 400 g of silisagel are CH2Cl2 / MeOH 95: 5. After again removing the solvent under vacuum in. the rotary evaporator and drying under vacuum by an oil pump gave 7.71 g (62%) of light yellow powder. Thin layer chromatography: CH2Cl2 / MeOH 95: 5 Rf = 0.87 XH-NMR (DMSO-d6, 270 MHz): 1.2-1.5 (m, 9, Bos); 2.3-2.45 (m, 0.5, H-C3-Ind); 2.8-3.5 (m, 3.5, C3-Ind + CH2); 3.65 (d, 3, COOMe); 4.4-4.65 (m, 1, C2-Ind); 4.8 (m, 1, H -C); 6.8-7.3 (m, 8, 5Ph + 3 Ar-Ind); 7.7 (m, 1, Ar-Ind); 8.55 (m, 1, NH) EA: calculated for C24H28N205 (424.3) C 67.92; H 6, 6; N 6.6 found: C 67.94; H 6.79; N 6.59 MS: (ESI +): calculated: 424.4, found: 425.2 Example 8: Synthesis of: N- [N * - (4-methoxyphenylacetyl) -piperidyl-4-carbonyl] -indolin-2- (R, S) -carboxylic acid methyl ester (This compound can be used as a previous step for the preparation of an amide of general formula I) 1.2 g (3.0 mmol) of N- [1-Boc-piperidyl-4-carbonyl] -indolin-2- (R, S) -carboxylic acid methyl ester were dissolved at room temperature At room temperature in 30 ml of CH2C12, 1.14 g (10 mmol) of TFA were added and the mixture was left stirring for 24 h. The reaction mixture was concentrated to the vessel in the rotary evaporator, added to 100 ml of ethyl acetate and washed three times with saturated aqueous solution of NaHCO 3 and once with saturated aqueous NaCl solution. The organic phase was dried over MgSO4 and the solvent was removed under vacuum in the rotary evaporator. The residue was dissolved in 30 ml of CH2C12, and 1.01 g (10 mmol) of triethylamine of 366 mg was added. (3.0 mmol) of 4-dimethylaminopyridine was cooled to 0 ° C and a solution of 606 mg (3.3 mmol) of 4-methoxyphenylacetyl chloride in 10 ml of CH2C12 was provided. After shaking during After 24 hours, the reaction mixture was freed from the solvent under vacuum on a rotary evaporator, added to 100 ml of ethyl acetate and washed twice with 1N HCl solution, 2 times with saturated aqueous solution of NaHCO 3 and 1 time with saturated aqueous NaCl solution. After removing the solvent by vacuum distillation on the rotary evaporator, the residue was chromatographed on 80 g flashgel with n-hexane / AcOEt. The corresponding fractions were collected and released from the solvent under vacuum in the rotary evaporator and dried under vacuum by an oil pump. 1.1 g of product was obtained as white foam. Thin layer chromatography: AcOEt, Rf = 0.22 XH-NMR (DMS0-d6 270 MHz): 1.35-1.85 (m, 13, Boc, 4 Pip); 2.7-2.8 (m, 4, H-'C (3), H-C (5)); 3.25 (m, 1, H-C (3) -Ind); 3.65 (m, 1, H-C (3 ') - Ind); 3.8 (s, 3, C00CH3); 3.95 (m, 1, H-C (4) -Pip); 5.45 (d, 1, H-C (2) -Ind); 7.05 (m, 1, Ar); 7.1-7.3 (m, 2, Ar); 8.1 (d, 1, Ar). EA: calculated for C25H28N205 (436.51) C 68.70; H 6.47; N 6.42 found: C 69.97; H 6.98; N 5.27.

Example 9; Synthesis of: Methyl ester of N- (4-methoxyphenylacetyl) -indolin-2- (R, S) -carboxylyl acid (This compound can be used as a preliminary step for the preparation of an amide of general formula I) In a 100 ml of a mouth with septum was placed 1 g of (R, S) -indolin-2-carboxylic acid methyl ester x HCl and 1.14 g (9.36 mmol) of DMAP in 25 ml of dry CH2C12. TO At 0 ° C, 1.04 g (856 1) of 4-methoxyphenylacetyl chloride was added dropwise with a syringe over the course of 30 min. It was then left stirring for 3 h at room temperature. The solvent was removed under vacuum in the rotary evaporator and the residue was purified by flash chromatography on 150 g flash silica gel (CH2Cl2 / MeOH 9: 1). After removing the solvent in vacuo from the rotary evaporator, 830 mg (59%) of a light gray powder was obtained. Thin layer chromatography: CH2C12; Rf = 0.31 X H-NMR (DMSO-d 6, 270 MHz): 3.15-3.3 (m, 1, H-C (3) -Ind); 3.5-3.7 (m, 3, CH2 + H-C (3 ') -Ind); 5.0 (m, 1, H-C (2) -Ind); 6.85 (m, 2, Ar-Ind); 7.0 (m, 1, Ar-Ind); 7.1-7.3 (m, 4, phenyl); 8.25 (d, 1, Ar-Ind) EA: calculated for C19H19N104 (325.3): C 70.15; H 5.85; N 4.31 found: C 70.34; H, 5.78; N 4.22 MS: (ESI +) calculated: 325.3, found: 326.1 Example 10; Synthesis of: N-Boc-inolin-2- (R, S) -sarboxylyl 4-piperidylamide In a 100-ml bead balloon, 2.63 g (10.0 mmoles) of 1-Bos- (R, S) acid were solved. -indolin-2-sarboxíliso with 1.13 g (12.0 mmoles) of 4-aminopyridine, 1.47 g (12.0 mmoles) of 4-dimethylaminopyridine in 30 ml of CH2C12 at 0 ° C and a solution of 2.48 g (12.0 mmoles) of dicyclohexylcarbodiimide in 5 ml was added. of CH2Cl2. After 48 h the reaction mixture was filtered through Celite, the solvent was removed in vacuo from the rotary evaporator, the residue was taken up in 100 ml of ethyl acetate, washed twice with 10% asuous solution of HCl, 2 times with saturated aqueous solution of NaHCO 3 and once with saturated aqueous NaCl solution. After the solvent was removed by vacuum distillation in a rotary evaporator, the residue was chromatographed on 50 g of flashgel with n-hexane / AcOEt. After removing the solvent under vacuum in the rotary evaporator, the residue was crystallized in AcOEt / ether, whereby 2.4 g of the product were obtained. Thin layer chromatography: CH2Cl2 / MeOH = 95/5; Rf = 0.19 -NMR (CDC13 270 MHz): 1.58 (s, 9H, Boc); 3.43-3.54 (m, 2H, H-C (3) -Ind); 5.0 (m, 1, H-C2-Ind); 7.02 (m, ÍH, H-C (7) -Ind); 7.17-7.26 (m, 3H, H-C (6), H-C (5), H-C (4) -Ind); 7.45 (q, 2H, H-C (3), H-C (5) -Py); 7.57 (NH); 8.47 (q, 2H, H-C (2); H-C (6)-Py) • EA: calcined for C ^ H ^ N ^ (339.40): C 67.84; H 6.29; N 12.49; Found: C 67.75; H 6.33; N, 12.53 Example 11: Synthesis of: [Piperazine-acetic acid-morpholide] -N-Boc-indoline-2- (R, S) -carboxylic acid amide In a 100 ml balloon from a mouth were placed 2.63 g (10.0 mmol) of 1-Boc- (R, S) -indolin-2-carboxylic acid with 2.56g (12.0 mmol) of piperazine-acetic acid morpholide, 1.47 g (12.0 mmol) of 4-dimethylaminopyridine in 30 ml of CH2C12 at 0 ° C and a solution of 2.48 g (12.0 mmoles) of dicyclohexylcarbodiimide in 5 ml of CH2C12 was added. After 48 hours the reaction mixture was filtered through Celite, the solvent was removed under vacuum in the rotary evaporator, the residue was taken up in 100 ml of ethyl acetate, washed twice with 10% aqueous solution. of HCl, 2 times with saturated aqueous solution of NaHCO 3 and 1 time with saturated aqueous NaCl solution. After the solvent was removed by vacuum distillation in a rotary evaporator, the residue was chromatographed on 50 g of flashgel with n-hexane / AcOEt. After removing the solvent under vacuum in a rotary evaporator, the residue was crystallized from AcOEt / ether, whereby 2.4 g of the product were obtained. Thin layer chromatography: CH2Cl2 / Me0H = 95/5; Rf = 0.19 ^ - MR (CDC13 27 Q Hz): 1.48-1.58 (d, 9H, Boc); 3.21 (s, 2H, HC (2")), 3.42-3.69 (m, 16 H), 5.1 (br, 2H, HC (3) -Ind), 6.48 (q , HH), 6.90 (q, HH), 7.14 (m, HH), 8.22 (q, HH), EA: calculated for C24H34N4Og (458.56): C 62.86, H7. 47; N 12, 21; found: C 63, 21; H, 7, 48; N, 13, 61.

Example 12; Synthesis of: [Piperazineacetic acid-morpholide] -N- [l-Boc-piperidyl-4-carbonyl] -indolin-2- (R, S) -carboxylic acid amide 458.56 mg (1.0 mmol) of [piperazine acetic acid] -morpholide] -l-Boc-indolin-2- (R, S) -carboxylic acid amide in 20 ml of CH2C12, added 1.14 g (10 mmol) of TFA and left stirring for 24 h. The reaction mixture was evaporated in vacuo under a rotary evaporator, added to 10 ml of ethyl acetate and washed twice with saturated aqueous solution of NaHCOs and once with saturated aqueous NaCl solution. The organic phase was dried over MgSO4 and the solvent was removed under vacuum in the rotary evaporator. The residue was dissolved in 10 ml of CH2C12, 505 mg (5 mmol) of triethylamine, 320.7 mg (1.4 mmol) of 4-Boc-piperidinesarboxylic acid and 357.7 mg (1.4 mmol) of 2-slorohydrochloride were added. -l-methylpyridinium, was heated to reflux for 8 h. The reaction mixture was freed from the solvent under vacuum on the rotary evaporator, added to 100 ml of ethyl acetate and washed twice with water, once with 10% aqueous HCl solution, 2 times with saturated aqueous solution NaHC03 and 1 time with saturated aqueous NaCl solution and dried over MgSO4. After removing the solvent by vacuum distillation in the rotary evaporator, the residue was crystallized from ethyl acetate / isopropanol. EA: calculated for C ^ H ^ N, - ^ (557.70): C 62.46; H 7.77; N 12.56 found: C 61.56; H 7.62; N 11.96.

Example 13 i Synthesis of: [N- [N '- (4-methoxy-f-enylacetyl) -piperidyl-4-carbonyl] -indolin-2- (R, S) -amino acid ester [S- (NeZ) -lysinmethyl] - sarboxíliso Step 1: N-[l-Boc-piperidyl-4-carbonyl] -indolin-2- (R, S) -carboxylic acid ester [S- (NeZ) -lysinmethyl] 3.74 g (10 mmol) was dissolved of N- [1-Boc-piperidyl-4-carbonyl] -indolin-2- (R, S) -carboxylic acid and 3.31 g (10 mmol) of NeZ-lysine methyl ester x HCl in 20 ml of CH2C12 and were added by dripping at room temperature over the course of 30 min to a suspension of 5.11 g (20 mmol) of 2-chloro-1-methylpyridinium iodide and 4.04 g (40 mmol) of triethylamine in 30 ml of CH2C12. After heating to reflux for 8 hours the reaction mixture was freed from the solvent under vacuum in the rotary evaporator. The residue was taken up in 200 ml of ethyl acetate and the organic phase was washed once with water, twice with half-saturated aqueous KHS04 solution, twice with 2N aqueous NaOH solution and once with saturated aqueous NaCl solution. After drying over MgSO4, the solvent was removed under vacuum in a rotary evaporator and the residue was purified by chromatography on 400 g of silica gel with CH2Cl2 / MeOH 95: 5. The corresponding fractions were combined and the solvent was removed under vacuum in the evaporator. rotary. After vacuum drying by an oil pump, 4.2 g of a light brown powder were obtained. Thin layer chromatography: CH 2 Cl 2 / MeOH 95: 5 Rf 0 0.41 EA: (calculated for C 32 H 48 N 408: 650.78): C 64.60; H 7.13; N 8.61; Found: C 64.73; H 7.01; N 8.64 Step 2: Amide of the N- [N '- (4-methoxyphenylacetyl) -piperidyl-4-carbonyl] -indoline-2- (R, S) -carboxylic acid ester [3- (NZ) -lysinmethyl] 3.25 g (5.0 mmol) of amide of the N- [1-Boc-piperidyl-4-carbonyl] -indolin-2- (R, S) -carboxylic acid ester [S- (NeZ) -lysinmethyl] at room temperature in 50 g. ml of CH2C12, 2.28 g (20 mmol) of TFA was added and stirred for 4 h. The reaction mixture was concentrated under vacuum in a rotary evaporator, added to 100 ml of ethyl acetate and washed 3 times with saturated aqueous solution of NaHCO 3 and 1 time with saturated aqueous NaCl solution. The organic phase was dried over MgSO4 and the solvent was removed under vacuum in the rotary evaporator. The residue was dissolved in 30 ml of CH2C12, 1.01 g (10 mmol) of triethylamine, 366 mg (3.0 mmol) of 4-dimethylaminopyridine was added, cooled to 0 ° C and a solution of 1.01 g was provided. (5.5 mmol) of 4-methoxyphenylacetyl chloride in 10 ml of CH2C12. After stirring for 24 hours, the mixture of the solvent reaction was freed under vacuum in a rotary evaporator.was added to 100 ml of ethyl acetate and washed 2 times with IN aqueous HCl solution, 2 times with saturated aqueous solution of NaHCO 3 and 1 time with saturated aqueous NaCl solution. After distilling off the solvent in vacuo on a rotary evaporator, the residue was chromatographed on 80 g flash gel with n-hexane / AcOEt. The corresponding fractions were collected and the solvent was removed under vacuum in a rotary evaporator, dried under vacuum by an oil pump, resulting in the product in the form of a white foam. EA: calibrated for C39H46N408 x H20 (716.84): C 65.35; H 6.75; N 7.82; Found: C 65.47; H 6.89; N 7.81. The examples 1-7 and 10-13 presented surprisingly showed to be strongly binding immunofolin modulators that in fixed form are suitable and are capable of binding immunophilins with pathogenic effect in liquids, especially in body fluids. To detect strong binders of Cyp B or, where appropriate, of FKBP of formula I, the immobilized binders were subjected to an SDS-PAGE (Figure 1) with cell homogenate. Binders fixed to a support that have a special affinity for immunophilins bind specifically to them with an affinity that is greater than that of CsA or, where appropriate, FK 506. The high affinity of the binders fixed to a support, represented by formula I, against immunophilins, by an SDS-PAGE. See sheet 1/1.

Explanation of the SDS-PAGE a) Homogenized cells b) Eluate of homogenized cells after equilibrating with binders of general formula I fixed to a support c) Separation of cyclophilin B with SDS from the matrix mentioned in b), at 25 ° C d) Control of SDS e) Separation of cyclophilin B with SDS from the matrix mentioned in b), at 95 ° C f) Protein standard (sigma: 12 kDa, 18 kDa, 25 kDa, 45 kDa, 66 kDa) g) Cell homogenate eluate after equilibration with immobilized CsA h) Separation of cislofilin B from the CsA matrix mentioned in g), with SDS at 25 ° C i) Separation of cyclophilin B from the CsA matrix mentioned in g), with SDS at 95 ° C k) Control of SDS The compounds according to the invention according to formula (I) are surprisingly distinguished by the binding to immunophilins and inhibit their astivity of peptidylprolyl-cis-trans-isomerase (PPlase). For the input selection (1 μmol / l substance) inhibition of human cyclophilin B is determined in the PPlase assay. This activity of PPlase is evaluated according to a worldwide enzymatic assay: G. Fischer, H. Bang, C. Mech, Biomed. Biochim. Acta, 43, 1101-1111; G, Fischer, H, Bang, A. Schellenberger, Biochim. Biophys. Acta, 791, 87-97, 1984; D. H. Rich et al, J. Med. Chem.38, 4164-4170, 1995). The compounds according to the invention of general formula I are pre-incubated together with 10 nmol of Cyp B for 15 min at 4 ° C. The enzymatic reaction is started after adding chymotrypsin and HEPES buffer with the Suc-Ala-Ala-Pro-Phe-Nan assay peptide. At sontinuation, changes in extinction at 390 nm are observed and evaluated. The extinction change determined photometrically results from two partial reactions: a) the rapid chemitrotic cleavage of the trans peptide; b) non-enzymatic cis-trans isomerization, which is catalyzed by cyclophilins. The corresponding PPlase activity of the compounds according to the invention of general formula I is shown in Table 1: Table 1: The formation of the molecule composed of CsA-CypB-Salcineurin (Ca2 + -dependent phosphatase) appears to be responsible for the known immunosuppressive effects of CsA. For the analysis of the interaction between the compounds according to the invention of general formula I and this molecule composed of CsA-Cyp B or, where appropriate, CsA-Cyp B-calcineurin, the invention-containing compounds were incubated with homogenates of cells of a strain of human T cells with 3H-CsA (100 nmol). After the gel filtration in Superose 12, the radioactivity of the eluted fractions was measured and compared with the untreated control. The corresponding displacement of 3H-CsA of the compound molecule Cyp B-CsA and Cyp-CsA-calcineurin by the compounds according to the invention of general formula I is shown in table 2: Table 2: The proliferation assay of IL-2 consists in the introduction of 3H-thymidine in T cells stimulated with OKT-3 (human anti-CD-3 antibodies) and is carried out in the following manner: 100000 T cells are seeded in 150 μl of culture medium per well in microtitre plates, stimulated by the addition of OKT-3 (1 μg / ml) and incubated with respective compounds according to the invention of general formula I hs. After this incubation time, 10 1 of the 3H-thymidine solution (0.5 μCi) are pipetted into each well. It is then incubated for 6 hours at 37 ° C in a 5% C02 atmosphere. After hardening the cells, the radioassay is quantified in the β-counter. The strong sorption inhibition of the indusid proliferation by CD3 of the compounds according to the invention of general formula I is shown in Table 3: Table 3: The compounds according to the invention of general formula I show as CsA, FK 506 or, where appropriate, Rapamycin in the animal experiment blocking cytokines such as IL-2, IL-4 and IL-5, which in case of disease provoke allergen-induced inflammation. To determine the inhibition of cell division of the compounds according to the invention of general formula I, 4800 human tumor cells were cultured for 48 hours in the presence of the compounds according to the invention of general formula I, they were supplied with 10 μl of yellow tetrazolium salt solution (MTT) and incubated for a further 4 h at 37 ° C in an atmosphere of C02. The resulting violet coloration was analyzed photometrically at 570 nm. After adding 100 μl of SDS solution each, the coloration was photometrically quantified after insubating overnight. No general cytotoxicity of the compounds according to the invention of general formula I was detected.

Claims (6)

R E I V T N D I C? P T O N S New specific immunophilin binders of formula I where Rx, R2, R3, R4, X, Y, A, B and D have the following meaning: Rx hydrogen, (C ^ C ^) -alkyl or (C2-C6) -alkyloxy groups, where the alkyl group is straight or branched chain and can be substituted by a mono or bicyclic heteroaryl with 1-4 heteroatoms, preferably N, S, 0, such as morpholine, piperazine, piperidine, indole, indazole, phthalazine, thiophene, furan, imidazole, or one or more times by a phenyl ring, where this phenyl ring in turn can be substituted one or more times by halogen, (Cx-C6) -alkyl, (C3-C7) -cycloalkyl, by carboxyl groups, carboxyl groups esterified with (C-) C8) -stranched or branched chain alkanols, carbamoyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, benzyloxy, amino groups, which in turn are substituted by benzyl, benzoyl, acetyl, RL can also be the amino moiety of the following methyl esters of amino acids: histidine, leucine, valine, serine (Bzl), threonine, pipecolinic acid, acid 4- p ip eri di nc arboxí 1 i co, 3- piperidincarboxílico acid, e-NH2-lysine, eZ-NH-lysine, e- (2C1-Z) -NH-lysine ,, 2-pyridylalanine, phenylalanine, tryptophan , glutamic acid, arginine (Cough), asparagine, citrulline, himocitrulin, ornithine, proline, acid 2-indole alcohol, octahydroindolinecarboxylic acid, tetrahydroisoquinolinecarboxylic acid, 5-aminovaleric acid, 8-aminooctanoic acid; R2 hydrogen, (C- ^ C ^) -alkyl or (C2-C6) -alkyloxy groups, where the alkyl group is straight or branched chain and can be substituted by a mono- or bicyclic heteroalkyl with 1-4 heteroatoms, preferably N , S, 0, such as morpholine, piperazine, piperidine, indole, indazole, phthalazine, thiophene, furan, imidazole, or one or more times by a phenyl ring, where this phenyl ring in turn may be substituted one or more times by halogen , (C?-C6) -alkyl, (C3-C7) -cycloalkyl, by carboxyl groups, by carboxyl groups esterified with straight or branched chain (CL-Cg) alkanes, carbamoyl groups, trifluoromethyl, 5-hydroxyl, methoxy, ethoxy, benzyloxy, amino, which in turn are substituted by benzyl, benzoyl, acetyl; R3 hydrogen, butyloxycarbonyl, carboxybenzyl, carbonylaril or carbonyl-heteroaryl with 1-4 10 heteroatoms, preferably N, S, 0, mono, bi or tricyclics, wherein the aryl or, where appropriate, the heteroaryl in turn may be substituted one or more times by halogen, (Ci-Cg) -alkyl, (C3) -C7) -cycloalkyl, by carboxyl groups, 15 carboxyl groups esterified with straight or branched chain (Ci-Cg) alkanols, carbamoyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, benzyloxy, amino groups, which in turn are substituted by benzyl, benzoyl, acetyl,
1. In addition, R3 can be carboxy (C-L-Cg) -alkyl, where the alkyl group can be straight or branched chain and can be substituted by a mono or bicyclic heteroaryl with 1-4 heteroatoms, preferably N, S, 0, as 25 morpholine, piperazine, piperidine, indole, indazole, phthalazine, thiophene, furan, imidazole or, where appropriate, may be substituted one or more times by a phenyl ring, where this phenyl ring in turn may be substituted one or more times by halogen, (Ci-Cg) -alkyl, (C -) 7- 5 cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight or branched chain alkanes, carbamoyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, benzyloxy, amino groups , which in turn are replaced 10 for benoyl, benzoyl, acetyl, R3 can also be the acidic residue of the following amino acids: histidine, leucine, valine, serine (Bzl), threonine, pipecoliniso acid, 4-piperidinesarboxílico acid, 3-piperidinecarboxylic acid, e-NH2-lysine, e- Z-NH-lysine, e- (2C1-Z) -NH-lysine, 2-pyridylalanine, phenylalanine, tryptophan, glutamic acid, arginine (Cough), asparagine, citrulline, homociulin, ornithine, proline,
2. 2-indole incarboxylic acid, tetrahydroisoquinoline-carboxylic acid, 5- aminovaleric acid, 8-aminooctanoic acid, where the N-terminus of the amino acids may be 25 substituted by butyloxycarbonyl, carboxybenzyl or by the acid moiety of aryl or heteroarylcarboxylic acids with 1-4 heteroatoms, preferably N, S, O, mono, bi or tricyclic, such as methoxyphenylacetic acid, naphthylacetic, pyridylacetic, quinazolinonylacetic acid, indazolylacetic acid, acid indolilglioxíliso, fenilglioxíliso acid, isobutylglyoxylic, 2-aminotiazol-4-glyoxylic acid or, in its saso, by sarboxi- (CLC- ^) -alkyl, sarboxisislopentano, sarboxiciclohexane, benzoílo, which can be substituted one or more times by halogen, groups methoxy, amino, carbamoyl, trifluoromethyl, carboxyl, carboxyl groups esterified with straight or branched chain (CL-Cg) -alkanols; R4 H, F, 0R5; R5 = hydrogen, (C
3. 3-C7) -cisloalkyl, (Ci-Cg) -alkyl or carboxy- (Cx-Cg) -alkyl, where the alkyl group may be straight or branched chain and may be substituted by a carbonylaryl or carbonyl -heteroaryl with 1-4 heteroatoms, preferably N, S, 0, mono, bi or tricyclics, where the aryl or, where appropriate, heteroaryl in turn may be substituted by halogen, (Cx-C6) -alkyl, (C3) -C7) -cycloalkyl, by carboxyl groups, carboxyl groups esterified with (CL-Cg) -stranched or branched chain alkanes, carbamoyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, benzyloxy, amino groups, which in turn are replaced by benzyl , benzoyl, acetyl; A = aromatic, non-aromatic, aromatic heterocyclic with 1-2 heteroatoms, preferably N, S, O, non-aromatic heterocyclic with 1-2 heteroatoms, preferably N, S, O; B = CH2; D = CH; B-D = CH = C; 'X = O, S, H; Y = C, simple link. 2. - Specific binder according to claim 1, sarasterized because it is the amide of the ester [S- (Ne-Boc) -lysinmethyl] of N- [l-Boc-piperidyl-
4. 4-carbonyl] -indolin-2- acid (R, S) -carboxylic. 3, - Specific binding agent according to claim 1, characterized in that it is the amide of the ester [S- (e-NH2) -lysinmethyl] of N- [piperidyl-4-carbonyl] -indolin-2- (R, S -carboxylic. 4. Specific binding agent according to claim 1, characterized in that it is the amide of the ester [S- (N-e-Boc) -lysinmethyl] of N- [l-Boc-indolin-2- (R, S) -sarbonyl] -indolin-2- (R, S) -carboxylic acid. 5.- Amide of the ester [S- (e-NH2) -lysinmethyl] of the acid N- [indolin-2- (R, S) -carbonyl] -indolin-2- (R, S) -carboxylic acid. 6. Amide of the ester (S- (N-e-Z) -lisinmethyl) of N- [1-Boc-indolin-2- (R, S) -carbonyl] -indolin-2- (R, S) -carboxylic acid, 1. - Amide of the ester (S- (N-e-Z) -lisinmethyl) of l-Boc-indolin-2- (R, S) -carboxylic acid. 8.- Amide of the ester (S-phenylalanine methyl) of l-Boc-indolin-2- (R, S) -carboxylic acid. 9. N-Boc-indolin-2- (R, S) -carboxylic acid 4-piperidylamide. 10. [Piperazineacetic acid-morpholide] -amide of N-Boc-indolin-2- (R, S) -carboxylic acid. 11. [Piperazineacetic acid-morpholide] -N- [1-Boc-piperidyl-4-sarbonyl] -indolin-2- (R, S) -carboxylic acid amide. 12.- [S- (N-e-Z) -lisinmethyl] ester amide of N- [N '- (4-methoxyphenylacetyl) -piperidyl-4-carbonyl] -indolin-2- (R, S) -carboxylic acid. 13. Use of the compounds according to one of claims 1 to 12 for the preparation of a finished drug. 14. Use of the compounds according to claim 13 for the preparation of a drug with anti-asthmatic and immunosuppressive effect or in combination with antiasthmatics or, where appropriate, immunosuppressants, therapeutically conosides. 15. Forms fixed to a support containing compounds according to one of claims 1 to 12 to be applied to bind immunophilins of pathogenic effect in liquids, especially body fluids. 16. Medicament containing at least one compound according to one of claims 1 to 12 in addition to the carrier substances or vehicles and / or diluents or, where appropriate, usual auxiliary substances. 17. Process for the preparation of a medicament, characterized in that one works with a compound according to one of the claims from 1 to 12 together with the support substances or vehicles or diluents or, where appropriate, other auxiliary substances, usual, for transform them into pharmaceutical preparations or, in their saso, a therapeutically aplisable form. 18. Medicament according to claims 1 to 14, 16 and 17 in the form of somprimidos or dragees, capsules, solutions or, where appropriate, ampoules, suppositories, patches or powder preparations can be placed in inhalers. 19. Process for the preparation of new specific immunofilin binders of formula I according to claim 1, wherein R.sub.2 R.sub.3, R.sub.3, R.sub.1, Y, A, B and D have the meaning set forth in claim 1, characterized in that an indole derivative of formula II is transformed, where R4, A, B, D, X and Y have the stated meaning II with an alkanol III of chain length C1-C1 A10H III to obtain an alkyl ester of indole derivative IV, where R4, A, B, D, X and Y have the stated meaning IV the ester IV is transformed with a compound V, where R3, X and Y have the stated meaning OH i to obtain a compound VI, where R3, R4 / A, B, D, X and Y have the stated meaning, VI then this compound VI is saponified to obtain a compound VII, where R3, R4, A, B, D, X and Y have the stated meaning VII and then compound VII is transformed with a compound VIII, where Rx and R2 have the stated meaning, VIII to obtain the target compound of formula I R E fl TT V. N The new specific immunofilin binders of the general formula (I) have an anti-asthmatic and immunosuppressive effect and are suitable for the preparation of medicaments.