MXPA06008159A - Indolylmaleimide derivatives - Google Patents

Abstract

A compound of formula I wherein R, Re, Rb, Rc, Rd and Re are as defined in the, specification, processes for their production, their uses, in particular in transplantation, and pharmaceutical compositions containing them.

Description

DERIVATIVES OF INDOLIL-MALEI IDA The present invention relates to indolyl-maleimide derivatives, to processes for their production and to pharmaceutical compositions containing them. More particularly, the present invention provides a compound of the formula I: where: Ra is H; alkyl of 1 to 4 carbon atoms; or alkyl of 1 to 4 carbon atoms substituted by OH, NH 2, NH-alkyl of 1 to 4 carbon atoms, or N (di-alkyl of 1 to 4 carbon atoms) 2; one of R, Rc, Rd, and Re is halogen; alkoxy of 1 to 4 carbon atoms; or alkyl of 1 to 4 carbon atoms; and the other three substituents are each H; or Rb, Rc, Rd, and Re are all H; and R is a radical of the formula (a): where: R. is - (CH2) n-NR3R4, wherein: each of R3 and R4 is independently H or alkyl of 1 to 4 carbon atoms; or R3 and R4 form, together with the nitrogen atom to which they are bound, a heterocyclic residue; n is 0, 1, or 2; and R2 is H; halogen; alkyl of 1 to 4 carbon atoms; CF3; OH; SH; NH2; N02; alkoxy of 1 to 4 carbon atoms; thioalkyl of 1 to 4 carbon atoms; NH-alkyl of 1 to 4 carbon atoms; N- (di-alkyl of 1 to 4 carbon atoms) 2, CN. The compound of formula I can be in free form or in salt form. Alkyl or alkoxy may be straight or branched chain. Halogen can be F, Cl, Br, or I, preferably F, Cl, or Br. Heterocyclic residue means a heterocyclic ring of 3 to 8, preferably 5 to 8 members, saturated, unsaturated, or aromatic, which comprises one or two heteroatoms, preferably selected from N, O, and S, and is optionally substituted. Suitable examples for R- include, for example, pyridyl, for example 3- or 4-pyridyl, piperidyl, for example piperidin-1-yl, 3- or 4-piperidyl, homo-piperidyl, piperazinyl, homo-piperazinyl, imidazolyl , imidazolidinyl, pyrrolyl, pyrrolidinyl, or morpholin-4-yl, optionally substituted, for example mono- or poly-substituted. When the heterocyclic residue is substituted, it may be substituted on one or more ring carbon atoms, and / or on a ring nitrogen atom when present. Examples of a substituent on a ring carbon atom include, for example, alkyl of 1 to 4 carbon atoms, for example CH3; cycloalkyl of 3 to 6 carbon atoms, for example cyclopropyl, optionally further substituted by alkyl of 1 to 4 carbon atoms; wherein p is 1, 2, or 3, preferably 1; CF3; halogen; NH2; -CH2- NR7R8, wherein each of R7 and R8 is independently H, alkyl of 1 to 4 carbon atoms, or R7 and R8 form, together with the nitrogen atom to which they are attached, a heterocyclic or a heteroaryl residue; -CH2-OH; -CH2-0-alkyl of 1 to 4 carbon atoms, -CH2-halogen, or -CH2-CH2-halogen. Examples of a substituent on a ring nitrogen atom are, for example, alkyl of 1 to 6 carbon atoms; acyl, for example R'x-CO, wherein R'x is H, alkyl of 1 to 6 carbon atoms, or phenyl optionally substituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or amino, for example formyl; cycloalkyl of 3 to 6 carbon atoms; cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms; phenyl; phenyl-alkyl of from 1 to 4 carbon atoms, for example benzyl; a heterocyclic residue, for example as disclosed above, for example an aromatic heterocyclic residue comprising 1 or 2 nitrogen atoms; or a residue of the formula ß: -R5-Y '(ß) wherein R5 is alkylene of 1 to 4 carbon atoms, or alkylene of 2 to 4 carbon atoms interrupted by O, and Y' is OH, NH2, NH- (alkyl of 1 to 4 carbon atoms), or N- (alkyl of 1 to 4 carbon atoms) 2 interrupted by O, can be, for example, -CH2-CH2-0-CH2-CH2-. The compounds of the formula I can exist in free form or in salt form, for example, salts with, for example, organic or inorganic acids, for example, hydrochloric acid, acetic acid, trifluoroacetic acid. It will be appreciated that the compounds of Formula I may exist in the form of optical isomers, racemates, or diastereoisomers. For example, a ring carbon atom carrying a substituent at the 3-position of the piperazinyl residue is asymmetric, and may have the R or S configuration. It is to be understood that the present invention encompasses all enantiomers and mixtures thereof. Enantiomers are preferred over the racemates. Similar considerations apply in relation to starting materials exhibiting asymmetric carbon atoms as mentioned. In the compounds of Formula I, the following meanings are preferred individually or in any sub-combination: 1. Ra is H or methyl; 2. one of Rb, Rc, Rd, and Re is methyl or ethyl, and the other three substituents are each H; or Rb, Rc, Rd, and Re are all H; 3. R2, is H, Cl, N02, CF3, F, or methyl; 4. n is 1; and 5. each of R3 and R4 is independently H, methyl, ethyl, or isopropyl; or R3 and R4 form, together with the nitrogen atom to which they are bound, a heterocyclic residue, for example an optionally substituted piperazinyl or pyrrolidinyl. The present invention also includes a process for the preparation of a compound of Formula I, which process comprises reacting a compound of Formula II: wherein Ra, Rb, Rc, Rd, and Re are as defined above, with a compound of Formula III: R-CH2-CO-NH2 (III) wherein R is as defined above, and, when required , converting the resulting compound of Formula I obtained in free form to a salt form or vice versa, as appropriate. The process can be carried out in a convenient manner in the presence of a strong base, for example t-BuOK, for example as disclosed in International Publications Nos. WO02 / 38561 or WO 03/08259, its contents being incorporated herein as a reference, and as illustrated in the Examples. The compounds of Formula II and III can be prepared according to known methods, for example as disclosed in International Publications Nos. WO02 / 38561 or WO 03/08259, their contents being incorporated herein by reference, and as illustrated in the Examples. As far as the production of the starting materials is not particularly described, the compounds are known or can be prepared in a manner analogous to the methods known in the art, or as described hereinafter. The following examples are illustrative of the invention without limitation. RT = Ambient temperature. THF = Tetrahydrofuran. DMF = Dimethyl formamide. EtOAc = Ethyl acetate. Pd2 (dba) 3 = Pd (0) -bis- (dibenzylidene-acetone). FCC = Column chromatography by instantaneous evaporation.

TLC = Thin layer chromatography.

Example 1: 3- (2-chloro-6-dimethyl-amino-methyl-naphthalen-1-yl) -4- (1-methyl-1 H-indol-3-M) -pyrrole-2,5 -d iona.

An activated 3 Angstrom molecular sieve (50 milligrams) is added to a solution of 2- (2-chloro-6-dimethyl-amino-methyl-naphthalen-1-yl) -acetamide (54.6 milligrams, 0.20 mmol) and methyl- (1- methyl-1 H-indol-3-yl) -oxo-acetic acid ester (55.7 milligrams, 0.26 mmol) in dry tetrahydrofuran (2.5 milliliters) under an argon atmosphere. Then a solution of 1.0 M KOtBu in tetrahydrofuran (0.59 milliliters, 0.59 millimoles) is added in one portion at room temperature. After 30 minutes at room temperature, thin layer chromatography analysis indicates complete conversion of the starting materials. The reaction mixture is diluted with EtOAc, and poured into a saturated aqueous solution of NH 4 Cl. The organic layer is separated, washed with brine, dried over Na 2 SO 4, and the organic solvent is evaporated. The residue is purified by flash column chromatography (EtOAc / AcOH / H20 700: 1 → 0:90), to provide the title compound. 1 H NMR (d6-DMSO, 400 MHz): d 2.12 (s, 6H), 3.46 (s, 2H), 3.82 (s, 3H), 6.16 (d, J = 8.8 Hz, 1 H), 6.45 - 6.51 (m, 1 H), 6.96 - 7.02 (m, 1 H), 7.32 - 7.40 (m, 2H), 7.60 - 7.68 (m, 2H), 7.88 (s, 1 H), 8.06 (d, J = 10 Hz, 1 H), 8.15 (s, 1 H). ES + -MS: 445.5, 446.6 [M + H] +.

Preparation of 2- (2-chloro-6-dimethyl-amino-methyl-naphthalen-1-yl) -acetamide. Dissolve (2-chloro-6-dimethyl-amino-methyl-naphthalen-1-yl) -acetic acid (276 milligrams, 0.99 mmol), under an atmosphere of argon in dimethylformamide (3 milliliters), add 1, 1 -carbonyl-di-imidazole (177 milligrams, 1.09 mmol) and the clear solution is stirred at room temperature for 3 hours. A concentrated aqueous solution of ammonia (25 percent, 6 milliliters) is added, stirring is continued for 10 minutes at room temperature. The thin layer chromatography analysis indicates the complete consumption of the starting material. The reaction mixture is poured into water. The aqueous layer is extracted with EtOAc, which is then washed with brine and dried over Na 2 SO 4. After removing the solvent, it is found that the residue is the pure title compound, without the need for purification. 1 H NMR (d6-DMSO, 400 MHz): d 2.18 (s, 6H), 3.53 (s, 2H), 4.08 (s, 2H), 6.96- 7.08 (br, 2H), 7.48-7.68 (m, 2H). ); 7.78-7.86 (m, 2H), 7.96-8.00 (d, J = 10 Hz, 1 H). ES + -MS: 277.3, 279.2 [M + H] +.

Preparation of the acid (2-chloro-6-dimethyl-amino-methyl-naphthalen-1-yl) -acetic acid. (2-Chloro-6-dimethyl-amino-methyl-naphthalen-1-yl) -acetic acid ethyl ester (223 milligrams, 0.73 mmol) is dissolved in dioxane (2.6 milliliters). Then water (0.96 milliliters), and lithium hydroxide (21 milligrams, 0.88 millimoles) are added, and the reaction mixture is heated at 60 ° C for 4 hours. Analysis by HPLC indicates complete conversion of the starting material. The reaction is diluted with water, the pH adjusted from 6 to 7 by the addition of 1 M NaHS04, and extracted with EtOAc. Then the aqueous layer is concentrated, and the solid residue is extracted repeatedly with MeOH to yield the pure title compound. ES + -MS: 278.3, 280.1 [M + H] +.

Preparation of (2-chloro-6-dimethyl-amino-methyl-naphthalen-1-yl) -acetic acid ethyl ester. Dimethyl amine (5.6M solution in EtOH, 0.28 milliliters, 1.53 millimoles) is added under an argon atmosphere, to a solution of (2-chloro-6-formyl-naphthalene-1-yl) ethyl ester. ) -acetic (284 milligrams, 1.02 millimoles) in tetrahydrofuran (10 milliliters). The mixture is stirred at room temperature for 18 hours, before adding a solution of sodium cyanoborohydride (78 milligrams, 1.23 millimoles) in MeOH (2 milliliters) and glacial acetic acid (0.29 milliliters, 5.13 millimoles). After stirring at room temperature for 1 hour, the thin layer chromatography analysis indicates the complete consumption of the starting material. The reaction mixture is diluted with water, and adjusted to a pH of 8 to 9 by the addition of a concentrated aqueous solution of NaHCO 3. Extraction with EtOAc, washing with brine, drying over Na 2 SO 4, and removal of the solvent provide the crude reaction product. Purification by flash column chromatography (CH2Cl2 / EtOH / NH3 190: 9: 1) gives the title compound. 1 H NMR (CDCIs, 400 MHz): d 1.26 (t, J = 9 Hz, 3H), 2.30 (s, 6H), 3. 59 (s, 2H), 4.18 (q, J = 9 Hz, 2H), 4.30 (s, 2H), 7.49 (d, J = 10 Hz, 1 H), 7.54 - 7.58 (m, 1 H), 7.69 - 7.76 (m, 2H), 7.91 (d, J = 10 Hz, 1 H). ES + -MS: 306.4, 308.3 [M + H] +.

Preparation of (2-chloro-6-formyl-naphthalen-1-yl) -acéf / co-ethyl ester. The ethyl ester of (2-chloro-6-cyano-naphthalen-1-yl) -acetic acid (1.39 grams, 5.07 mmol) is dissolved in a mixture of water (17 milliliters), pyridine (33 milliliters), and glacial acetic acid (17 milliliters). Then sodium hypophosphite (4.30 grams, 40.62 millimoles) and Raney nickel (3.2 grams) are added at room temperature. The reaction mixture is heated at 100 ° C for 1 hour. The thin layer chromatography analysis indicates the complete consumption of the starting material. The reaction mixture is cooled to room temperature, filtered through Celite. After the addition of silica gel, the solvent is stirred on a rotary evaporator. Purification by flash column chromatography (hexane / EtOAc, 5: 1) yields the title compound. 1 H NMR (CDCl 3, 400 MHz): d 1 .17 (t, J = 8 Hz, 3 H), 4.10 (q, J = 8 Hz, 2 H), 4.24 (s, 2 H), 7.52 (d, J = 10 Hz, 1 H), 7.82 (d, J = 10 Hz, 1 H), 7.94 - 7.98 (m, 2 H), 8.26 (s, 1 H), 10.09 (s, 1 H). ES "-MS: 275.2, 277.3 [M-H] -.

Preparation of (2-chloro-6-cyano-naphthalen-1-yl) -acetic acid ethyl ester. The (2-chloro-6-trifluoro-methansulfonyloxy-naphthalen-1-yl) -acetic acid ethyl ester (3.59 grams, 9.04 mmol) is dissolved in dimethylformamide (30 milliliters) under an argon atmosphere. Palladium (0) -tetrakis- (triphenyl-phosphane) (418 milligrams, 0.36 millimoles) and zinc cyanide (11) (2.12 grams, 18.09 millimoles) are added, the reaction mixture is heated to 125 ° C. After 1 hour, the thin layer chromatography analysis indicates the complete consumption of the starting material. The suspension is cooled to room temperature, and poured into water. Extraction is continued with EtOAc by washing the organic layer with aqueous 1 M HCl, saturated aqueous NaHCO 3 solution, and brine. After drying over Na 2 SO and removing the solvent, purification by flash column chromatography (hexane / EtOAc, 3: 1) gives the title compound. 1 H NMR (d 6 -DMSO, 400 MHz): d 1. 06 (t, J = 8 Hz, 3 H), 3.98 (q, J = 8 Hz, 2 H), 4.24 (s, 2 H), 7.66 (d, J = 10 Hz, 1 H), 7.79 (d, J = 10 Hz, 1 H), 7.96 (d, J = 10 Hz, 1 H), 8.13 (d, J = 10 Hz, 1 H), 8.54 (s) , 1 HOUR).

Preparation of (2-chloro-6-trifluoro-methansulfonyloxy-naphthalen-1-yl) -acetic acid ethyl ester. The (2-chloro-6-hydroxy-naphthalen-1-yl) -acetic acid ethyl ester (3.39 grams, 12.80 mmol) is dissolved under an atmosphere of argon in pyridine (35 milliliters). After cooling to 0 ° C, trifluoro-methanesulfonic acid anhydride (2.32 milliliters, 14.08 millimoles) is added dropwise over 15 minutes. After stirring at 0 ° C for 15 minutes, and at room temperature for 1 hour, the thin layer chromatography analysis indicates the complete consumption of the starting material. The reaction mixture is poured into an aqueous solution of 1 M NaHCO 3. After extraction with EtOAc, washing with brine, and drying the organic layer over Na 2 SO 4, the concentration gives the crude reaction product. Purification by flash column chromatography (hexane / EtOAc, 4: 1) gives the title compound. 1 H NMR (CDCl 3, 400 MHz): d 1.48 (t, J = 9 Hz, 3 H), 4.41 (q, J = 9 Hz, 2 H), 4.52 (s, 2 H), 7.68 (d, J = 10 Hz , 1 H), 7.82 (d, J = 10 Hz, 1 H), 7.98 - 8.00 (m, 2 H), 8.27 (d, J = 10 Hz, 1 H).

Preparation of (2-chloro-6-hydroxy-naphthalen-1-yl) -acetic acid ethyl ester. The (2-chloro-6-methoxy-naphthalen-1-yl) -acetic acid ethyl ester (5.43 grams, 19.48 millimoles) and tetrabutylammonium iodide (9.35 grams, 25.32 millimoles) are dissolved under an argon atmosphere in CH2Cl2 (1 10 milliliters). The reaction mixture is cooled to -78 ° C, and a 1 M solution of BBr3 in CH2Cl2 (48.7 milliliters, 48.7 mmol) is added over 15 minutes. After stirring at -78 ° C for 10 minutes, and at room temperature for 10 minutes, thin layer chromatography analysis indicates complete consumption of the starting material. The reaction mixture is poured into an aqueous solution of concentrated NaHCO 3, and the mixture is stirred vigorously for 20 minutes at room temperature. After extraction with CH2Cl2, the organic layer is washed with brine, and dried over Na2SO4. Purification by flash column chromatography (hexane / EtOAc, 2: 1) gives the title compound. 1 H NMR (CDCl 3, 400 MHz): d 1.19 (t, J = 9 Hz, 3 H), 4.12 (q, J = 9 Hz, 2 H), 4.18 (s, 2 H), 5.35 - 5.60 (br, 1 H) , 6.99 (d, J = 10 Hz, 1 H), 7.33 (d, J = 10 Hz, 1 H), 7.42 (d, J = 10 Hz, 1 H), 7.70 (d, J = 10 Hz , 1 HOUR). ES + -MS: 265.2, 266.8 [M + H] +.

Preparation of (2-chloro-6-methoxy-naphthalen-1-yl) -acetic acid ethyl ester. A mixture of (2-chloro-6-methoxy-naphthalen-1-yl) -acetic acid ethyl ester and (2-chloro-6-methoxy-3,4-dihydro-naphthalene-1 - ethyl ester) il) -acetic (4.07 grams, approximately 14.6 millimoles) is dissolved under an argon atmosphere in dioxane (40 milliliters). 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ, 7.30 grams, 32 mmol) is added, and the reaction mixture is refluxed for 4 hours. After cooling to room temperature, the addition of MeOH causes the reaction mixture to become homogeneous. Silica gel is added, and the solvent is removed by rotary evaporation. Purification by flash column chromatography (hexane / EtOAc 980: 20 to 960: 40) gives the title compound. 1 H NMR (CDCl 3, 400 MHz): d 1.32 (t, J = 9 Hz, 3 H), 4.00 (s, 3 H), 4.26 (q, J = 9 Hz, 3 H), 4.34 (s, 2 H) ), 7.21 (s, 1 H), 7.30 (d, J = 10 Hz, 1 H), 7.52 (d, J = 10 Hz, 1 H), 7.71 (d, J = 10 Hz, 1 H), 7.92 (d, J = 10 Hz, 1 H). ES + -MS: 279.1, 280.9 [M + H] +.

Preparation of (2-chloro-6-methoxy-naphthalen-1-yl) -acetic acid ethyl ester and (2-chloro-6-methoxy-3,4-di-hydro-naphthalene-1) ethyl ester -il) -acetic. A mixture of (2-chloro-1-hydroxy-6-methoxy-1, 2,3,4-tetrahydro-naphthalen-1-yl) -acetic acid ethyl ester (5.0 grams, 16.64 mmol), 1 1 -diphenyl-ethene (3.2 milliliters), Lmethyl-naphthalene (3 milliliters) and palladium on charcoal (10 percent, 500 milligrams) is heated under an argon atmosphere at 180 ° C. After 3 hours, the thin layer chromatography analysis indicates the complete consumption of the starting material. The reaction mixture is cooled to room temperature, diluted with EtOAc and filtered. Removal of EtOAc and purification by flash column chromatography (hexane 100 to hexane / EtOAc 980: 20 to 960: 40) yield the mixture of the title compound.

Preparation of (2-chloro-1-hydroxy-6-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl) -acetic acid ethyl ester. A solution of EtOAc (7.2 milliliters, 73.96 mmol) in tetrahydrofuran (20 milliliters) is added slowly, under an argon atmosphere, at -78 ° C, to a solution of lithium diisopropylamine (prepared from 10.5. milliliters of di-isopropyl-amine (73.96 millimoles), and 46.2 milliliters of n-BuLi 1.6M in hexane (73.96 millimoles)) in tetrahydrofuran (20 milliliters). After stirring at -78 ° C for 30 minutes, a solution of 2-chloro-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (7.79 grams, 36.98 mmol) in tetrahydrofuran is slowly added (20 g. milliliters) during minutes. The reaction mixture is stirred at -78 ° C for 24 hours. Thin layer chromatography analysis indicates the complete conversion of the starting material. The reaction mixture is diluted with EtOAc and poured into a saturated solution of NH 4 Cl. The organic layer is separated, and washed with salt. After drying over Na 2 SO 4, the solvent is removed. Purification by flash column chromatography (hexane / EtOAc, 920: 80 to 880: 120) yields the title compound. 1 H NMR (CDCl 3, 400 MHz): d 1.22 (t, J = 9 Hz, 3 H), 2.33-2.41 (m, 2 H), 2.80 - 3.12 (m, 4 H), 3.12 (s, 1 H ), 3.78 (s, 3H), 4.12 (q, J = 9 Hz, 2H), 5.01 - 5.04 (m, 1 H), 6.60 - 6.62 (m, 1 H), 6.78 - 6.82 (m, 1 H) , 7. 52 (d, J = 10 Hz, 1 H).

Preparation of 2-chloro-6-methoxy-3,4-dihydro-2H-naphthalen-1-one. A solution of 6-methoxy-3,4-dihydro-2H-naphthalen-1-one (5.0 grams, 28.37 mmol) in tetrahydrofuran (25 milliliters) is slowly added, under an argon atmosphere, at -78 ° C, to a solution of lithium diisopropylamine in tetrahydrofuran (25 milliliters; prepared from 4.0 milliliters of di-isopropyl-amine (28.37 millimoles) and 17.7 milliliters of n-BuLi 1.6M in hexane (28.27 millimoles)). After 30 minutes at -78 ° C, a solution of para-tolyl-sulfonyl chloride (5.41 grams, 28.37 mmol) in tetrahydrofuran (25 milliliters) is added over 20 minutes. The cooling bath is removed from dry ice, and the reaction mixture is allowed to reach room temperature. After 1 hour, the thin layer chromatography analysis indicates the complete consumption of the starting material. A saturated aqueous solution of NH 4 Cl (100 milliliters) is added, and the mixture is stirred at room temperature for 15 minutes. The organic layer is separated, washed with brine, dried over Na 2 SO 4, and concentrated. Purification by flash column chromatography (hexane / EtOAc, 920: 80-880: 120) gives the title compound. 1 H NMR (CDCl 3, 400 MHz): d 2.54-2.63 (m, 1 H), 2. 68 - 2.75 (m, 1 H), 3.04 - 3.12 (m, 1 H), 3.38 - 3.46 (m, 1 H), 4.02 (s, 3 H); 4.72 - 4.76 (m, 1 H), 6.87 (s, 1 H), 7.00 - 7.04 (m, 1 H), 8.22 (d, J = 10 Hz, 1 H). ES + -MS: 279.1, 280.9 [M + H] +.

Following the procedure of Example 1, but using the appropriate starting materials, the compounds of Formula A can be obtained, wherein Ra, Rb, R2, R3, and R are as indicated in the following Table 1.

Table 1 Compounds of formula I in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, for example they inhibit Protein Kinase C (PKC), for example, Protein Kinase C isoforms such as a, β, d, e,?,?, inhibit the activation and proliferation of T cells, for example, inhibit the production of T cells or cytokines, for example IL-2, inhibit the proliferative response of T cells or cytokines, for example IL-2, by example, as indicated in the in vitro and in vivo tests, and are per patient, indicated for therapy.

A. In vitro 1 . Protein Kinase C Assay The compounds of the invention are tested for their activity on different isoforms of protein kinase C, according to the following method. The assay is carried out in a 384-well microtiter plate with a transparent bottom, with a non-binding surface. The reaction mixture (25 microliters) contains 1.5 μM of a tridecapeptide acceptor substrate that mimics the pseudo-substrate sequence of PKCa with Ala replacement. Ser, 33P-ATP 10 μM, mM Mg (N03) 2, 0.2 mM CaCl2, protein kinase C at a protein concentration ranging from 25 to 400 nanograms / milliliter (depending on the isotype used), lipid vesicles (containing 30 mole percent of phosphatidyl -serine, 5 mole percent DAG, and 65 mole percent phosphatidyl choline), at a final lipid concentration of 0.5 mM, in 20 mM Tris-HCl buffer, pH 7.4 + bovine serum albumin 0.1 percent. Incubation is carried out for 60 minutes at room temperature. The reaction is stopped by the addition of 50 microliters of stop mix (100 mM EDTA, 200 μM ATP, 0.1 percent Triton X-100, 0.375 milligrams / well of SPA beads coated with streptavidin in phosphate-regulated serum without Ca , Mg After 10 minutes of incubation at room temperature, the suspension is centrifuged for 10 minutes at 300 g.The incorporated radioactivity is measured in a Trilux counter for 1 minute.The measurement of I C50 is routinely carried out by means of the incubation of a serial dilution of the inhibitor at concentrations that are in the range of 1 to 1 000 μM The IC50 values are calculated from the graph by adjusting the curve with the VL Fit® software. 2. Protein Ca Kinase Assay Human recombinant PKCa is obtained from Oxford Biomedical Research, and is used under the conditions of the assay as described in Section A.1 above. In this test, the compounds of Formula I, inhibit PKCa with an IC50 < 1 μM. For example, the compound of Example 6 inhibits PKCa with an I CS0 of 1.1 nM and the compound of Example 5 with an IC50 of 0.9 nM. 3. Protein Kinase Cß 1 Assay Recombinant human PKCßl is obtained from Oxford Biomedical Research, and is used under the conditions of the assay, as described in Section A.1 above. In this assay, the compounds of Formula I, inhibit PKCß I with an IC50 < 1 μM. For example, the compound of Example 5 inhibits PKCßl with an IC50 of 2.3 nM and the compound of Example 7 with an IC5 - of 2.8 nM. 4. Cd Protein Kinase Assay Human recombinant PKCd is obtained from Oxford Biomedical Research, and is used under the conditions of the assay, as described in Section A.1 above. In this test, the compounds of Formula I, inhibit PKCd with an IC50 < 1 μM. For example, the compound of Example 4 inhibits PKCd with an IC50 of 9.4 nM and the compound of Example 5 with a C50 I of 4.5 nM.

. Ce Protein Kinase Assay Human recombinant PKCe is obtained from Oxford Biomedical Research, and is used under the conditions of the assay, as described in Section A.1 above. In this test, the compounds of Formula I, inhibit PKCe with an IC5o < 1 μM. For example, the compound of Example 1 inhibits PKCe with a C50 I of 17.6 nM and the compound of Example 6 with a C50 I of 2.3 nM. 6. Cn Protein Kinase Assay The PKC? Human recombinant is obtained in PanVera, and is used under the conditions of the assay, as described in Section A.1 above. In this test, the compounds of Formula I inhibit PKC? with an IC50 < 1 μM. For example, the compound of Example 3 inhibits PKC? with an IC50 of 53.9 nM and the compound of Example 4 with an ICso of 7.2 nM. 7. Kinase C assay? of Protein Recombinant human PKCT is used under the conditions of the assay as described above. In this assay, the compounds of Formula I, inhibit PKCT with an IC50 < 1 μM. For example, the compound of Example 1 inhibits PKCT with a C50 I of 19.2 nM and the compound of Example 7 with an IC50 of 6.4 nM. 8. CD28 Co-stimulation Assay The assay is carried out with Jurkat cells transfected with a human interleukin-2 promoter / reporter gene construct, as described by Baumann G. et al in Transplant. Proc. 1992; 24: 43-8, the reporter gene of β-galactosidase being replaced by the luciferase gene (de Wet J. et al., Mol. Cell Biol. 1987, 7 (2), 725-737). The cells are stimulated by antibodies coupled with solid phase or phorbol myristate acetate (PMA) and the onymoin Ca ++ ionophore as follows. For antibody mediated stimulation, Microlite ™ 1 microtiter plates (Dynatech) are coated with 3 micrograms / milliliter of goat anti-mouse IgG (Jackson) Fe antibodies in 55 microliters of phosphate-buffered serum (PBS) per well for 3 hours at room temperature. The plates are blocked after removing the antibodies by incubation with 2 percent bovine serum albumin (BSA) in phosphate buffered serum (300 microliters per well) for 2 hours at room temperature. After washing three times with 300 microliters of phosphate-buffered serum per well, 1.0 nanograms / milliliter of anti-T cell receptor antibodies (WT31, Bacton &; Dickinson), and 300 nanograms / m illiliter of anti-CD28 (1 5E8) antibodies in 50 microliters of 2% bovine serum albumin / phosphate-regulated serum, such as stimulating antibodies, and incubated overnight at 4 ° C. ° C. Finally, the plates are washed three times with 300 microliters of phosphate-regulated serum per well. Seven serial triple dilutions of test compounds are prepared in separate plates in duplicate in the test medium (RPM I 1640/10 percent calf fetal serum (FCS) containing 50 μM 2-mercaptoethanol, 100 units / milliliter of penicillin, and 100 micrograms / milliliter of streptomycin), mixed with the transfected Jurkat cells (clone K22 290_H23), and. they are incubated for 30 minutes at 37 ° C in 5 percent C02. Then 100 microliters of this mixture containing 1 x 10 5 cells are transferred to the antibody coated assay plates. In parallel, 100 microliters are incubated with 40 nanograms / milliliter of PMA and 2 μM onomycin. After incubation for 5.5 hours at 37 ° C in 5 percent C02, the luciferase level is determined by measuring the I bioluminescence. The plates are centrifuged for 10 minutes at 500 g, and the supernatant is removed by wicking. The lysis buffer containing 25 mM Tris-Phosphate, pH of 7.8, 2 mM DTT, 1, 2-diamino-cyclohexane-N, N, N ', N-tetra-acetic acid, 10 percent glycerol is added ( volume / volume), and Triton X-100 at 1 percent (volume / volume) (20 5 microliters per well). The plates are incubated at room temperature for 10 minutes under constant agitation. The luciferase activity is evaluated with a bioluminescence reader (Labsystem, Helsinki, Finland) after the automatic addition of 50 microliters per well of luciferase reaction regulator containing 20 mM tricine, (MgC03) 4Mg (OH) 2 x 0 5H20 1.07 μM, MgSO4 2.67 μM, EDTA 0.1 μM, DTT 33.3 μM, Coenzyme A 270 μM, luciferin 470 μM (Chem ie Brunschwig AG), ATP 530 μM, pH 7.8. The delay time is 0.5 seconds, the total measurement time is 1 or 2 seconds. The low control values are units of light from the cells stimulated with the anti-T-cell receptor or with 5 PMA; the high controls are from cells stimulated with anti-T cell receptor / anti-CD28 or PMA / ionomycin without any test sample. Low controls are subtracted from all values. The inhibition obtained in the presence of a test compound is calculated as the percentage of inhibition of! high control. The concentration of the test compounds that results in 50 percent inhibition (IC50) is determined from the dose response curves. In this assay, the compounds of Formula I inhibit Jurkat cells stimulated with anti-T cell / anti-CD28 receptor and PMA / ionomycin, with an IC50 < 1 μM. For example, the compound of Example 5 inhibits the cells Jurkat stimulated by anti-T-cell / anti-CD25 receptor and PMA / ionomycin with a 1C50 of 1 1 .5 nM, and the compound of Example 7 with an IC50 of 27.5 nM 9. Mixed Lymphocyte Reaction Aloqeneica (M LR) The two-way MLR assay is carried out according to conventional procedures (J. Immunol. Methods, 1973, 2, 279, and Meo T. et al., Immunological Methods, New York , Academic Press, 1979, 227-39). Briefly stated, spleen cells from CBA and BALB / c mice (1.6 x 105 cells from each strain per well in microtitre plates of flat bottom tissue culture, 3.2x105 in total) are incubated in an RPMI medium containing 10 percent fetal calf serum, 100 units / milliliter of penicillin, 100 micrograms / milliliter streptomycin (Gibco BRL, Basel, Switzerland), 50 μM 2-mercaptoethanol (Fluka, Buchs, Switzerland) , and the compounds diluted in series. Seven steps of triple dilution are carried out in duplicate per test compound. After 4 days of incubation, 1 μCi of 3H-thymidine is added. Cells are harvested after an additional incubation period of 5 hours, and incorporated 3 H-thymidine is determined according to conventional procedures. The background values (low control) of the MLR assay are the proliferation of BALB / c cells only. Low controls are subtracted from all values. High controls without any sample are taken as 100 percent proliferation. The percent inhibition by the samples is calculated, and the concentrations required for 50 percent inhibition (1C50 values) are determined. For example, the compound of Example 5 inhibits with an IC 50 of 1 83 nM and the compound of Example 7 with an IC 50 of 528 nM.

B. In Vivo Rat Heart Transplant The combination of strains used: male Lewis (haplotype RT1) and BN (haplotype RT1). The animals are anesthetized using isoflurane by inhalation. Following the heparinization of the donor rat through the inferior abdominal vena cava with simultaneous exsanguination through the aorta, the chest is opened, and the heart rapidly cools. The aorta is ligated and divided distal to the first branch, and the brachiocephalic trunk is divided into the first bifurcation. The left pulmonary artery is ligated and divided, and the right side is divided but left open. All other vessels are dissected to free, ligate and divide, and the donor's heart is removed to become frozen. The receiver is prepared by dissecting and cross-attaching the infra-renal abdominal aorta and the vena cava. The graft is implanted with end-to-side anastomosis, using a 10/0 monofilament suture, between the brachiocephalic trunk of the donor and the recipient's aorta, and from the right pulmonary artery of the donor to the vena cava of the recipient. The fasteners are removed, the retroabdom graft is attached inally, the abdominal contents are washed with warm serum, and the animal is closed and allowed to recover under a heating lamp. Survival of the graft is monitored by daily palpation of the donor heart beating through the abdominal wall. Rejection is considered complete when the heart stops beating. Increases in graft survival are obtained in animals treated with a compound of Formula I administered orally in a daily dose of 1 to 100 milligrams / kilogram twice a day, preferably 1 to 30 milligrams / kilogram twice a day .

Irrigation Model Against the Host Spleen cells (2x107) of Wistar / F rats are injected subcutaneously into the cushion of the right hind paw of the hybrid rats (Wistar / F x Fischer 344) F- | . The cushion of the left leg is left untreated. The animals are treated with the test compounds for 4 consecutive days (0-3). The poplipeal lymph nodes are removed on day 7, and the weight differences between two corresponding lymph nodes are determined. The results are expressed as the inhibition of lymph node enlargement (given as a percentage), comparing the weight differences of the lymph node in the experimental groups with the weight difference between the corresponding lymph nodes of a group of animals that were left untreated with a test compound. The effects of enlargement of the lymphatic node are obtained in animals treated with a compound of Formula I administered orally in a daily dose of 1 to 100 milligrams / kilogram twice a day. The compounds of Formula I, therefore, are useful in the treatment and / or prevention of diseases or disorders mediated by T-lymphocytes and / or protein kinase C, for example acute or chronic rejection of allo-and xenografts of organs or tissues, diseases of the graft against the host, atherosclerosis, vascular occlusion due to vascular injury such as angioplasty, restenosis, obesity, syndrome X, impaired glucose tolerance, polycystic ovary syndrome, hypertension, heart failure, chronic obstructive pulmonary disease, diseases of the central nervous system, such as Alzheimer's disease or amyotrophic lateral sclerosis, cancer, infectious diseases such as SI DA, septic shock or adult respiratory distress syndrome, ischemia / reperfusion injury, for example, infarction of myocardium, embolism, ischemia of the intestine, renal failure or hemorrhagic shock, or traumatic shock for example, traumatic brain injury. The compounds of Formula I are also useful in the treatment or prevention of acute or chronic inflammatory diseases or disorders mediated by T-cells, or autoimmune diseases, for example rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis. , myasthenia gravis, type I or II diabetes and the disorders associated therewith, respiratory diseases such as asthma or inflammatory lesion of the lung, inflammatory lesion of the liver, inflammatory glomerular lesion, cutaneous manifestations of disorders or immunologically mediated diseases, inflammatory diseases and hyperproliferative skin (such as psoriasis, atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis, and other eczematous dermatitis, seborrheic dermatitis), inflammatory diseases of the eyes, for example Sjoegren's syndrome, keratoconjunctivitis or uveitis, inflammatory disease intestine disease, Crohn's disease, or ulcerative colitis. For the above uses, the required dosage, of course, will vary depending on the mode of administration, the particular condition to be treated, and the desired effect. In general, it is indicated that satisfactory results are obtained systemically at daily dosages of from about 0.1 to about 100 milligrams / kilogram of body weight. An indicated daily dosage in the higher mammal, for example in humans, is in the range of about 0.5 milligrams to about 2,000 milligrams, conveniently administered, for example, in divided doses up to four times a day, or in a delayed form. The compounds of Formula I can be administered by any conventional route, in particular enterally, for example orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions., topically, for example in the form of lotions, gels, ointments or creams, or in a nasal or suppository form. Pharmaceutical compositions comprising a compound of Formula 5 I, in free form or in pharmaceutically acceptable salt form, in association with at least one pharmaceutically acceptable carrier or diluent, can be manufactured in a conventional manner, by mixing with a carrier or diluent pharmaceutically acceptable. Unit dosage forms for oral administration contain, for example, from about 0.1 milligrams to about 500 milligrams of active substance. Topical administration is, for example, to the skin. An additional form of topical administration is to the eye. The compounds of Formula I can be administered in free form or in a pharmaceutically acceptable salt form, for example as indicated above. These salts can be prepared in a conventional manner, and exhibit the same order of activity as the free compounds. In accordance with the foregoing, the present invention also provides: 1. A method for preventing or treating disorders or diseases mediated by T-lymphocytes and / or protein kinase C, eg, as indicated above, in a subject in need of such treatment, which method comprises administering to this subject an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. 1.2 A method for preventing or treating acute or chronic rejection of transplantation, or inflammatory or autoimmune diseases mediated by T cells, for example, as indicated above, in a subject in need of such treatment, which method comprises administering to this subject an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. 2. A compound of Formula I, in free form or in the form of a pharmaceutically acceptable salt, for use as a pharmaceutical product, for example, in any of the methods indicated under 1.1 and 1.2 above. 3. A pharmaceutical composition, for example, for use in any of the methods as in 1 .1 and 1 .2 above, which comprises a compound of Formula I in free form or in pharmaceutically acceptable salt form, in association with a pharmaceutically acceptable diluent or vehicle for the same. 4. A compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the preparation of a pharmaceutical composition for use in any of the methods as in 1.1 and 1.2 above.

The compounds of Formula I can be administered as the sole active ingredient, or in conjunction with other drugs in immunomodulatory regimens or with other anti-inflammatory agents, for example for the treatment or prevention of acute or chronic allograft rejection. or xenograft, or inflammatory or autoimmune disorders. For example, they can be used in combination with cyclosporins, or with ascomycins or their analogues or immunosuppressive derivatives, for example cyclosporin A, ISA Tx247, FK-506, ABT-281, ASM 981; an mTOR inhibitor, for example rapamycin, 40-O- (2-hydroxy-ethyl) -rapamycin, CCI779, ABT578, or a rapalog, for example AP23573, AP23464, AP23675, AP23841, TAFA-93, biolimus 7, or biolimus 9, etcetera; corticosteroids; cyclophosphamide; azathioprene; methotrexate; an EDG receptor agonist having accelerating properties of lymphocyte onset, for example FTY 720 or an analogue thereof; leflunomide or analogues thereof; mizoribin; mycophenolic acid or a salt thereof, for example the sodium salt; mycophenolate-mofetil; 15-deoxy-spergualin or analogues thereof; immunosuppressive monoclonal antibodies, for example monoclonal antibodies to the leukocyte receptors, for example MHC, CD2, CD3, CD4, CD 1 1 a / CD 18, CD7, CD25, CD 27, B7, CD40, CD45, CD58, CD 137, ICOS, CD 150 (SLAM), OX40, 4-1 BB or its ligands, for example CD154; or other immunomodulatory compounds, for example a recombinant binding molecule having at least a portion of the extracellular domain of CLTA4 or a mutant thereof, for example at least an extracellular portion of CTLA4 or a mutant thereof, attached to a sequence which is not of CTLA4 protein, for example CTLA4lg (for example, designated as ATCC 68629) or a mutant thereof, for example LEA29Y, or other inhibitors of adhesion molecules, for example monoclonal antibodies or low molecular weight inhibitors, including LFA-1 antagonists, selectin antagonists, and VLA-4 antagonists. The compounds of Formula I can also be administered in conjunction with an anti-proliferative drug, for example a chemotherapeutic drug, for example as used in the treatment of cancer, including, but not limited to, aromatase inhibitors, anti -estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-active agents, alkylating agents, histone deacetylase inhibitors, farnesyl transferase inhibitors, COX-2 inhibitors, MMP inhibitors, mTOR inhibitors, antigestabolites antineoplastic, platinum compounds, compounds that reduce the activity of protein kinase and other anti-angiogenic compounds, gonadorelin agonists, anti-androgens, bengamides, bisphosphonates, anti-proliferative antibodies and temozolomide, or with an anti-diabetic drug, an insulin secretagogue, or an insulin secretion enhancer, for example a sulfonyl urea, for example tolbut amide, chlorpropamide, tolazamide, acetohexamide, 4-chloro-N - [(1-pyrrolidinyl-amino) -carbonyl] -benzenesulfonamide (glycopyramide), glibenclamide (glyburide), gliclazide, 1-butyl-3-methanylyl-urea, carbutamide, glibonuride, glipizide, gliquidone, glisozepide, glibutiazole, glybuzole, glihexamide, glimidine, glipinamide, fenbutamide, or tolyl cyclamide, a derivative of an oral insulinotropic agent, for example a short-acting insulin enhancer, for example meglitinide, repaglinide , a phenyl-acetic acid derivative, for example nateglinide, a DPP-IV inhibitor, for example 1 - dihydrochloride. { 2 - [(5-Cyano-pyridin-2-yl) -amino] -ethyl-amino} -acetyl- (2S) -cyano-pyrrolidine, LAF237, GLP-1 or an analogue of a GLP-1 agonist, or an insulin sensitizer, for example a peroxisome proliferator-activated receptor agonist? (PPAR?), For example a glitazone, a type that is not glitazone, such as an analogue of N- (2-benzoyl-phenyl) -L-tyrosine, for example GI-262570, or an oxolidinadione, for example JTT501, a double agonist of PPARα / PPARα, for example DRF-554158, NC-2100 or NN-622, a retinoid X receptor agonist or a rexinoid, for example 2- [1-] (3, 5.5, 8, 8-pentamethyl-5, 6,7, 8-tetrahydro-2-naphthyl) -cyclopropyl] -pyridine-5-carboxylic acid, 4 - [(3, 5.5, 8, 8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl) -2-carbonyl] -benzoic acid, 9-c / s-retinoic acid or an analog, derivative, or pharmaceutically acceptable salt thereof , in diabetes therapy.

In accordance with the foregoing, the present invention provides, in a still further aspect: A method as defined above, which comprises the co-administration, for example in a concomitant or sequential manner, of a therapeutically effective amount of a protein kinase C inhibitor, or T-cell activation and proliferation, for example a compound of Formula I, in free form or in a pharmaceutically acceptable salt form, and a second drug substance, this second substance being drug an immunosuppressive, immunomodulatory, anti-inflammatory, anti-prolifferative, or anti-diabetic drug, for example as indicated above. 6. A therapeutic combination, for example a therapeutic kit, which comprises: a) an inhibitor of protein kinase C, or of the activation and proliferation of T-cells, for example a compound of Formula I, in the form free or in pharmaceutically acceptable salt form; and b) at least one second agent selected from at least one immunosuppressive, immunomodulatory, anti-inflammatory, anti-proliferative, and anti-diabetic drug. Component a) and component b) can be used concomitantly or in sequence. The therapeutic kit may comprise instructions for its administration. When a protein kinase C inhibitor is administered, or the activation and proliferation of T cells, for example a compound of Formula I, in conjunction with another immunosuppressive / immunomodulatory, anti-inflammatory, anti-proliferative therapy, or anti-diabetic, for example to prevent or treat acute or chronic graft rejection or inflammatory or autoimmune disorders as specified hereinabove, dosages of the immunosuppressive, immunomodulatory, anti-inflammatory, anti-proliferative, or coadministered anti-diabetic compound , of course, will vary depending on the type of co-drug used, for example if it is a spheroid or a cyclosporin, of the specific drug used, of the condition being treated, etc. The compounds of Formula I have an interesting pharmacokinetic profile, and interesting in vitro and in vivo activities.

Claims (9)

REIVIN DICAC I ONE S

1 . A compound of the formula I: where: Ra is H; alkyl of 1 to 4 carbon atoms; or alkyl of 1 to 4 carbon atoms substituted by OH, NH2, NH-alkyl of 1 to 4 carbon atoms, or N (di-alkyl of 1 to 4 carbon atoms) 2; one of Rb, Rc, Rd, and Re is halogen; alkoxy of 1 to 4 carbon atoms; or alkyl of 1 to 4 carbon atoms; and the other three substituents are each H; or Rb, Rc, Rd, and Re are all H; and R is a radical of the formula (a): wherein: Rn is - (CH2) n-NR3R4, wherein: each of R3 and R4 is independently H or alkyl of 1 to 4 carbon atoms; or R3 and R4 form, together with the nitrogen atom with which they are bound, a heterocyclic residue; n is 0, 1, or 2; and R2 is H; halogen; alkyl of 1 to 4 carbon atoms; CF3; OH; SH; NH2; N02; alkoxy of 1 to 4 carbon atoms; thioalkyl of 1 to 4 carbon atoms; NH-alkyl of 1 to 4 carbon atoms; N- (di-alkyl of 1 to 4 carbon atoms) 2, CN; or a salt of them.

2. A compound according to claim 1, wherein Ra is H or methyl; one of Rb, Rc, Rd, and Re is methyl or ethyl, and the other three substituents are H; or Rb, Rc, Rd, and Re are all H; R2 is H; Cl, methyl, or N02; n is 1; and each of R3 and R4 is independently H, methyl, ethyl, or isopropyl; or R3 and R4 form, together with the nitrogen atom to which they are bound, a heterocyclic residue or a salt thereof.

3. A compound according to claim 1 or 2, which is selected from: 3- (2-chloro-6-dimethylamino-methylene-naphthalene-1-yl) -4- (1 - methyl-1 H-indol-3-yl) -pyrrole-2,5-dione; 3- (2-Chloro-6-methyl-amino-methyl-naphthalen-1 -yl) -4- (1 H -indol-3-yl) -pyrrole-2,5-dione; 3- (6-am i non-methyl-naphthalen-1-yl) -4- (1-methyl-1 H-indol-3-yl) -pyrrole-2,5-dione; 3- (2-Chloro-6-dimethyl-arnino-methyl-naphthalen-1 -yl) -4- (1 H -indol-3-yl) -pyrrole-2,5-dione; 3- (2-Chloro-6-dimethyl-amino-methyl-naphthalen-1-yl) -4- (7-methyl-1 H -indol-3-yl) -pyrrole-2,5-dione; 3- (2-Chloro-6-methyl-amino-methyl-naphthalen-1-yl) -4- (7-methyl-1 H -indol-3-yl) -pyrrole-2,5-dione; 3- (6-amino-methyl-naphthalen-1-yl) -4- (1 H -indol-3-yl) -pyrrole-2,5-dione; 3- (6-Amino-methyl-naphthalen-1-yl) -4- (7-methyl-1 H-indol-3-yl) -pyrrole-2,5-dione; or a salt of them.

4. A compound according to any of claims 1 to 3, in free form or in pharmaceutically acceptable salt form, for use as a pharmaceutical product.

5. A pharmaceutical composition, which comprises a compound according to any of claims 1 to 3, in free form or in pharmaceutically acceptable salt form, in association with a pharmaceutically acceptable diluent or carrier therefor.

6. The use of a compound according to any of claims 1 to 3, in free form or in pharmaceutically acceptable salt form, or a pharmaceutical composition according to claim 5, in the manufacture of a medicament for the treatment or the prevention of diseases or disorders mediated by T lymphocytes and / or protein kinase C.

7. The use of a compound according to any one of claims 1 to 3, in free form or in pharmaceutically acceptable salt form, or a pharmaceutical composition according to claim 5, in the manufacture of a medicament for the treatment and / or prevention of acute or chronic inflammatory diseases or disorders, autoimmune diseases, graft rejection, cancer or infectious diseases mediated by T-cells.

8. A pharmaceutical combination, which comprises a compound according to any of claims 1 to 3, in free form or in pharmaceutically acceptable salt form, and an additional agent selected from the immunosuppressive agents, immunomodulatory agents, anti- inflammatory, chemotherapeutic, anti-proliferative, and anti-diabetic.

9. A process for the production of a compound of Formula I, according to claim 1 or claim 2, which process comprises reacting a compound of Formula I I: wherein Ra, R, Rc, Rd and e are as defined in claim 1 and claim 2, with a compound of Formula III: R-CH2-CO-NH2 (III) wherein R is as defined in claim 1 and claim 2, and, when required, convert the resulting compound of the Formula I obtained in free form or in salt form, or cease, as appropriate. 1 0. A method for the treatment or prevention of disorders or diseases mediated by T-lymphocytes and / or by protein kinase C, in a subject in need of such treatment, whose method comprises administering to this subject a effective amount of a compound according to any of claims 1 to 3, or a pharmaceutically acceptable salt thereof.