MXPA98009345A - Indolyl-pyrrolydenemethylpyrrole derivatives and process for their preparation - Google Patents

Abstract

A compound which is a 2-(1H-indol-2-yl)-5[(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole of formula (I), wherein each of R1, R2, R3 and R4 independently represents hydrogen, C1-C6 alkyl, halogen, cyano, nitro, hydroxy, C1-C6 alkoxy unsubstituted or substituted by phenyl, C1-C6 alkyl-carbonyloxy or amino;R5 represents halogen, hydroxy or C1-C11 alkoxy unsubstituted or substituted by phenyl;and R6 represents hydrogen, C2-C20 alkanoyl, C3-C20 alkenoyl, phenyl, C1-C20 alkyl or C2-C20 alkenyl, wherein the alkanoyl, alkenoyl and alkyl groups are unsubstituted or substituted;or a pharmaceutically acceptable salt thereof, is useful as immunomodulating agent and for treating adult-T-cell leukemia-lymphoma.

Description

DERIVATIVES OF INDILILPIRROLIDENO ETILPIRROL AND PROCEDURE FOR PREPARATION Field of the Invention The present invention relates to novel indolylpyrrolidenemethylpyrrole derivatives and their use as therapeutic agents, for example, as immunomodulatory agents, in particular, as immunosuppressive agents, to a process for their preparation and to the pharmaceutical compositions comprising them.

Brief Description of the Invention At present, cyclosporin A, an immunosuppressive agent, used in combination with other complementary therapies such as, for example, azathioprine and corticosteroids, constitutes the treatment chosen for the prevention of rejection of organ transplantation. The use of other inmnosuppressive agents such as FK506, mycophenolate, have been used or suggested.

REF .: 28833 of mofetil and rapamycin as useful agents for the treatment and / or prevention of rejection to organ transplantation. The use of any of these known immunosuppressive compounds is associated, either individually or in combination with a high incidence of side effects such as nephrotoxicity and / or hepatotoxicity. Thus, there is currently a need for improved therapies that replace or be used together with cyclosporine or other immunosuppressive drugs currently known for the treatment and / or prevention of rejection of organ transplantation, the graft reaction. anti-host, autoimmune diseases and chronic inflammatory diseases that include but are not limited to psoriasis and rheumatoid arthritis.

Description of the invention The indolylpyrrolidenemethylpyrrole compounds of the present invention are useful as simple therapy agents as well as in combination with other compounds currently used in these clinical regimens, for example, cyclosporin. In view of their biological properties, the compounds of the present invention should be useful to allow the administration of reduced doses of other immunosuppressive agents used together with them, thereby reducing the adverse effects caused by these agents. The novel compounds of 2- (1H-indol-2-yl) -5 [(2H-pyrrol-2-ylidene) methyl] -lH-pyrrole having the formula (I) which is indicated are an object of the present invention. then (I) wherein each of R 1, R 2, R 3 and R 4, which may be the same or different, independently represent hydrogen, C 1 -C 6 alkyl, halogen, cyano, nitro, hydroxy, C 1 -C 6 alkoxy unsubstituted or substituted by phenyl, C 1 -C 2 alkylcarbonyloxy, -NraRb wherein each of R a and R b are independently hydrogen or C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonylamino, carboxy, C 6 -C 6 alkoxycarbonyl , aralkylcarbamoyl, arylcarbamoyl or -CONRcRd where each of Rc and Rd are, independently, hydrogen or Ci-Cβ alkyl or, Rc and Rd, taken together with the nitrogen atom to which they are bound, form a ring of morpholino or piperidino; R5 represents halogen, hydroxy or Ci-Cn alkoxy substituted or substituted by phenyl; and R6 represents hydrogen, C2-C2o alkanoyl, or C3-C20 alkenoyl, phenyl, C?-C20 alkyl or C2-C2or alkenyl wherein the alkanoyl, alkenoyl, alkyl and alkenyl groups are unsubstituted or substituted by 1 to 3 substituents are independently selected from halogen, Ci-Cß alkoxy, hydroxy, aryl, aryloxy, cyano, carboxy, (C?-C6 alkoxy) carbonyl, (C3-C4 alkenyl) carbamoyl, aralkylcarbamoyl, arylcarbamoyl and -CONRcRd where Rc and Rd are as defined before; and the pharmaceutically acceptable salts thereof.

Within its scope, the present invention includes all possible isomers, stereoisomers and optical isomers and also mixtures thereof, as well as the metabolites and metabolic precursors or bioprecursors of the compounds of the formula (I). The compounds of the invention can also be represented by the tautomeric formula (la) which is presented below where R1, R2, R3, R4, R5 and R6 are as defined above.

Accordingly, during the course of the description of the invention, the chemical compounds provided by the present invention are named according to the chemical nomenclature established for the compounds of the formula (I) or (a), based on the the structural evidence validated by the people qualified in the technique. A halogen atom is preferably chlorine or fluorine.

The alkyl, alkoxy, alkenyl, alkanoyl, alkenoyl, alkadienoyl and alkylidene groups can be straight or branched chain groups. An aryl group as a substituent and as a moiety in an aryloxy, aralkyl or arylcarbamoyl group is, for example, an aromatic mono- or poly-nuclear C6-C2o moiety, typically phenyl, unsubstituted or substituted with one or two substituents that are they select, independently, between halogen, hydroxy, C? -C6 alkyl and C? -C6 alkoxy. Accordingly, an aralkyl group is, for example, benzyl or phenethyl, wherein the phenyl ring is optionally substituted by one or two substituents which are independently selected from halogen, hydroxy, Ci-Cß alkyl and C? -C alkoxy? .

A C3-C4 or C3-C6 alkenyl group is preferably an allyl group. A C? -C6 alkyl group is preferably a C1-C4 alkyl group, in particular, a methyl or ethyl group. An unsubstituted Ci-Cu alkoxy group is preferably a C 1 -C 4 alkoxy or C 8 -C 8 alkoxy group, usually methoxy, ethoxy, propoxy, butoxy and undecyloxy. A C? -Cß alkoxy group substituted by phenyl is preferably a C?-C 4 -alkoxy phenyl group, usually benzyloxy or phenylethoxy. The acyl moiety in a Ci-Ce-carbonyloxy alkyl group and in a Cj-C6-carbonyl anino group is, for example, C2-Cs alkanoyl, typically acetyl. A C.sub.1 -C.sub.12 alkyl group is preferably a C.sub.1 -C.sub.3 alkyl group, in particular, an undecyl group. A C2-C20 alkenyl group is preferably a C5-C14 alkenyl group, in particular, an undecenyl group. A C2-C2o alkanoyl group is, preferably, a C5-C14 alkanoyl group, in particular, an undecanoyl group. An alkenoyl group C3-C20 is preferably a C5-C14 alkenoyl group, in particular, an undecenoyl group.

A group (C 1 -C 6 alkoxy) carbonyl is preferably a (C 1 -C 4) alkoxycarbonyl group, usually methoxycarbonyl or ethoxycarbonyl. A C6-C6-carbonylamino group is, for example, a C-C4-carbonylamino alkyl group, usually acetylamino or propionylamino. Some examples of the pharmaceutically acceptable salts of the compounds of the invention are, either, those having inorganic bases, such as the hydroxides of sodium, potassium, calcium and aluminum or those having organic bases, such as lysine, arginine, N -methyl-glucamine, triethylamine, triethanolamine, dibenzylamine, methylbenzylamine, di- (2-ethyl-hexyl) -amine, piperidine, N-ethylpiperidine, N, N-diethyl-aminoethylamine, N-ethylmorpholine, β-phenethylamine, N-benzyl -β-phenethylamine, N-benzyl-N, N-dimethylamine and other acceptable organic amines as well as salts with inorganic acids, for example, hydrochloric, hydrobromic and sulfuric acids and also with organic acids, for example, citric acids , tartaric, maleic, malic, fumaric, methanesulfonic and ethanesulfonic.

As stated above, the present invention also includes within its scope the pharmaceutically acceptable bio-precursors (which are also known as pro-drugs) of the compounds of the formula (I), i.e., the compounds that possess a formula other than formula (I) above, but which, independently of it, when administered in a human being are converted in vivo, directly or indirectly, into a compound of formula (I). Preferred compounds of the invention are those in which, in formula (I), each of R 1, R 2, R 3 and R 4 independently represent hydrogen, C 1 -C 4 alkyl, halogen, cyano, nitro, hydroxy, C1-C4 alkoxy unsubstituted or substituted by phenyl, amino, carboxy, (C1-C4 alkoxy) carbonyl or CONRcRd in which each of Rc and Rd are, independently, hydrogen or C1-C4 alkyl or, Rc and Rd, taken together with the nitrogen atom to which they are attached, form a ring of morpholino or piperidino; R5 represents hydroxy or Ci-Cu alkoxy unsubstituted or substituted by phenyl; and R6 represents hydrogen, C1-C1 alkyl or C3-C14 alkenyl, wherein the alkyl and alkenyl groups are unsubstituted or substituted by a substituent selected from halogen, C3-C4 alkoxy, hydroxy, aryl, aryloxy, cyano, carboxy , (C1-C4 alkoxy) carbonyl, aralkylcarbamoyl, arylcarbamoyl and -CONRcRd wherein each of Rc and Rd are, independently, hydrogen or C1-C4 alkyl or, Rc and Rd, taken together with the nitrogen to which they are attached, form a ring of morpholino or piperidino. Some examples of the specific compounds of the invention that are preferred are: 2- (1H-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH -pyrrole; 2- (1H-indol-2-yl) -4-methoxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-methoxy-5- [(5-pentyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-benzyloxy-5-t (5-pentyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-methoxy-5- [(5-ethyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-methoxy-5- [(5-propyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-methoxy-5- [(5-isopropyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-methoxy-5- [(5-butyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-benzyloxy-5 - [(5-ethyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-benzyloxy-5- [(5-propyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-benzyloxy-5- [(5-isopropyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-benzyloxy-5- [(5-butyl-2H-pyrrol-2-ylidene) methyl] -IH-pyrrole; 2- (5-methoxy-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-methoxy-lH-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-chloro-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-chloro-lH-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-Cyano-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-Cyano-lH-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-hydroxy-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-hydroxy-lH-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -IH-pyrrole; 2- (5-amino-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-amino-lH-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-methyl-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-benzyloxy-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-Fluoro-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-carboxy-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-carbamoyl-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (6-carboxy-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (6-carbamoyl-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (6-Nitro-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (7-ethyl-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -iH-pyrrole, and the esters C alquilo-alkyl C6 thereof, in particular, the methyl and ethyl esters as well as the pharmaceutically acceptable salts thereof, in particular the hydrochlorides, hydrobromides and methanesulfonates. It is another object of the present invention to provide a compound of the formula (I), as defined above, for use in a method of treating the human or animal body by means of therapy, in particular, as an immunomodulatory agent and , especially, as an immunosuppressive agent. It is also an object of the present invention to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier and / or diluent and as an active ingredient, a compound of the formula (I), as defined herein, or a salt pharmaceutically acceptable thereof. Additionally, the present invention provides the use of a compound of the formula (I), as defined above, for the preparation of a medicament with immunomodulatory activity and, in particular, with immunosuppressive activity. Also, the present invention provides a method of treatment for mammals, including humans, in need of an immunomodulatory agent, said method comprising administering to said mammal an effective amount of a compound of the formula (I), as defined in present, or a pharmaceutically acceptable salt thereof. The compounds of the formula (I) and the pharmaceutically acceptable salts thereof can be obtained by an analogy procedure. According to a preferred embodiment of the invention, a compound of the formula (I) and salts thereof can be prepared by means of a process, it comprises treating a compound of the formula (II), where R5 and R6 are as defined above and X is a leaving group, with a compound of the formula (III) (lll) where R1, R2, R3 and R4 are as defined above and R7 is hydrogen or a lower alkyl chain; and, if desired, converting a compound of the formula (I) to another compound of the formula (I) and / or, if desired, salifying a compound of the formula (I) and / or, if it is desired to convert a salt of a compound of the formula (I) into a free compound and / or, if desired, to remove a mixture of isomers of a compound of the formula (I) in the simple isomers. When R7 is a lower alkyl chain, it is preferably a C1-C4 alkyl chain, for example methyl, ethyl or isopropyl. In a compound of the general formula (II), the leaving group X can be, for example, a trifluoromethanesulfonate group or a halogen such as chlorine, bromine or iodine. The reaction between a compound of the formula (II) and a compound of the formula (III) can be carried out in a suitable organic solvent such as, for example, tetrahydrofuran, dioxane, dimethoxyethane, DMF, toluene, methanol, ethanol, water or mixtures thereof, in the presence of a suitable palladium catalyst (0), in the presence of a basic agent such as, for example, K2CO3, Na2CO3, NaHCO3, K3P04, NaOAc, KOH, NaOH, Ba (OH) 2, EtOAc , BU4NF, Et3N, at a temperature ranging between 60 ° C and 120 ° C approximately, for a period ranging from 1 hour to 3 days approximately. A wide range of palladium (0) catalysts can be used such as, for example, Pd (PPh3) 4, PdCl2 (PPh3) 2, Pd (0Ac) 2 plus PPh3 or other ligands as described, for example, in Chem. Rev. 95, 2457 (1995). Optionally, a salt such as, for example, LiCl, LiBr, KCl, KBr can be introduced in order to stabilize the catalyst.

According to a preferred embodiment of the invention, in the chaos in which in a compound of the formula (II) the leaving group X is trifluoromethanesulfonate, a catalyst which is preferred is Pd (PPh3) 4 in the presence of sodium carbonate or potassium carbonate and the reaction can be carried out in dioxane or toluene, at a temperature between 65 ° C and 90 ° C approximately, for a period ranging from about 5 to 24 hours.

According to what was expressed above, a compound of the formula (I) can be converted into another compound of the formula (I) following known methods. By way of example, in a compound of the formula (I) a carboxy group can be converted to the corresponding (Ci-Cß alkyl) or arylcarbamoyl group by means of the reaction with the appropriate Ci-Cβ alkylamine or arylamine, respectively, in the presence of a suitable carbodiimide, such as, for example, dicyclohexylcarbodiimide or 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide, in an inert solvent such as, for example, dichloromethane or tetrahydrofuran, at a temperature comprised between 0 ° C and 30 ° C approximately.

In addition, the optional salification of a compound of the formula (I) can be carried out as well as the conversion of a salt into a free compound and the separation of a mixture of isomers in its simple isomers resorting to the use of conventional methods . By way of example, the separation of the optical isomers can be carried out by salification with an optically active base or acid and by subsequent fractional crystallization of the diastereomeric salts, followed by recovery of the optically active isomeric acids or bases, respectively .

The compounds of the formula (II) are novel compounds and constitute an object of the invention. A compound of the formula (II) can be obtained from a compound of the formula (IV) where R5 and R6 are as defined above, by means of a suitable reagent such as, for example, anhydridetrifluoromethane sulfonic acid or a halogenating agent such as, for example, P0C13, P0Br3, POCl (OEt) 2 / TMSI in an inert organic solvent as, for example, dichloromethane, dichloroethane, acetonitrile and, optionally, in the presence of an organic base such as Et3N or pyridine, at a temperature ranging from -20 ° C to about 50 ° C. The compounds of the formula (III) are novel compounds and constitute another object of this invention. They can be prepared from an appropriate substituted indole as described in published procedures as, for example, in J. Org. Chem. 46, 157 (1981) and Synthesis, 613 (1991). The compounds of the formula (IV) are novel compounds and constitute another object of the present invention. They can be prepared by reacting a compound of the formula (V) (V) OHC JÍ N R6 H where R6 is as defined above, with a compound of the formula (VI) where R5 is as defined above. The condensation between a compound of the formula (V) and a compound of the formula (VI) can be carried out by acidic or basic catalysis, in a solvent such as, for example, water, methanol, ethanol, dioxane, THF, DMF. , DMSO or the mixtures thereof, at a temperature comprised between 25 ° C and 120 ° C approximately, during a period ranging from 1 to 24 hours approximately. An acidic catalyst can be, for example, an inorganic acid such as, for example, HCl, HBr, H2SO4, H2N03 or an organic acid such as, for example, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid or trifluoroacetic acid.

Also, a basic catalyst may be, for example, an inorganic base such as NaOH, KOH. K2Co3, Ba (OH) 2, NaH or an organic base such as, for example, t-BuOk, MeLi, Buli, LDA. In addition, a compound of the formula (IV) can be converted into another compound of the formula (IV) having a different alkoxy group R3 by means of the use of well-known chemical processes conventionally used for the transesterification of organic esters.

By way of example, the compounds of the formula (V) can be prepared by means of the Vilsmeier formulation of the compounds of the formula (VII) where R6 is as defined above, according to well-known chemical procedures. The compounds of the formula (VII) are known compounds or they can be prepared using mere variations of the published methods, for example, those reported in the chemical literature indicated below: Tetrahedron 32, 1851 (1976); J. Org. Chem 53, 1410 (1988); J. Org. Chem 28, 857 (1963); J. Am. Chem. Soc. 84, 4655 (1962); Ann. 450, 181 (1926); Ber. 99, 1414 (1966). The compound of the formula (VI) is commercially available or it can be synthesized according to what is described, for example, in Synthesis, 391 (1992) and Tetrahedron Letters 25, 1871 (1984). A compound of the formula (VI) can be converted into another compound of the formula (VI) having a different alkoxy group R 3, resorting to the use of well-known chemical processes conventionally used for the transesterification of organic esters. When groups such as COOH and / or OH, which need to be protected before being subjected to the above-illustrated reactions, are present in the compounds of the formula (I) and in their intermediates, they can be protected before that the reactions take place and later be unprotected, according to methods well known in organic chemistry.

The compounds of the formula are defined herein (I) and the pharmaceutically acceptable salts thereof as the "compounds of the present invention", the "compounds of the invention" and / or the "active ingredients of the pharmaceutical compositions of the invention". Pharmacology The compounds of the invention have an immunomodulatory activity and, in particular, an immunosuppressive activity, as observed in the various biological tests. By way of example, the compounds of the present invention have been evaluated on the basis of the tests detailed below: 1. Proliferation of murine splenocytes induced by the mitogen Concanavalin A; 2. Proliferation of murine splenocytes induced by irradiated splenic splenic splenic cells (MLR); 3. Proliferation of tumor cell lines (human erythroleukemia K562, murine melanoma B16); 4. "Delayed type hypersensitivity" test; . Bioavailability after oral administration; and they have been found to be very active and specific immunosuppressive agents. The tests 1 2 allow the study of the compounds on models of "proliferation mediated by T cell growth factors (for example IL-2) and are considered immunologically specific." Test 3 allows to investigate the inhibitory effect of the present compounds on a generic proliferation pathway, regardless of the specific growth factors of the immune system .. Test 4 shows the activity mediated by T lymphocytes. Tests have been carried out as shown: Test No. 1 The spleens of C57B1 / 6 mice were removed aseptically and a cell suspension was prepared in a complete medium. The viability of the cells was evaluated by exclusion with trypan blue. Spleen cells (4 x 105) were cultured in triplicate in a volume of 0.15 ml, in flat-bottomed microculture plates, in the absence or in the presence of an optimal concentration of ConA (1.7 microcrops / ml) and of different concentrations of the test compound. The cultures were incubated for 72 h at 37 ° C in a humidified 5% CO 2 incubator. 18 h before the cultures were terminated, 0.2 microCi of [methyl-3 H] thymidine was introduced into each well. The cells were harvested on glass fiber filters and the uptake of [3 H] TdR (cpm) was quantified in a liquid scintillation counter. Test No. 2 The spleens of C57B1 / 6 mice were removed aseptically (response) and Balb / c mice (stimulation), and cell suspensions were prepared in a complete medium. The response cells (1 x 106) were co-cultured in triplicate with irradiated stimulator cells (1500R) (5 x 105) in a volume of 0.15 'ml, in the presence or absence of different concentrations of the test compound, in Microculture plates with flat bottom. The cultures were incubated for 96 h at 37 ° C in a humidified 5% CO 2 incubator and, in the last 18 h, in the presence of 0.2 microCi of 3 H-TdR.

Cells were harvested on a glass fiber filter and 3 H-tdR (cpm) uptake was quantified in a liquid scintillation counter. Test No. 3 Tumor cells were harvested in the logarithmic growth phase and seeded in triplicate in flat-bottomed microculture plates at a concentration of 1 x 104, in the presence or absence of different concentrations of the test compound. After 48 h of incubation at 37 ° C in 5% C02, evaluation of cell viability was carried out using the MTT colorimetric method according to what Ferrari and his colleagues, J. Immunol. Methods (1990) 131, 165-72. Test No. 4 Comparative evaluation of in vivo activity by H R analysis The immunosuppressive activity of the compounds of the invention was evaluated in vivo by an HTR (Hypersensitivity of Retardation Type) analysis. According to the test, red blood cells of sheep (GRO) (1 x 105 cells) suspended in 500 mcL of saline were injected into the tail vein of C57 Bl / 6 female mice (8-9 weeks old) in vivo. age) . After five days, the red blood cells of sheep were injected at 1 x 108 suspended in 50 mcL of saline solution in the left hind paw. The increase in the thickness of the leg was measured with a dial micrometer 24 h after the provocation. The test compounds were administered daily for a period of six days at different doses that began on the day of the first administration. The activity was expressed as ED30 (the dose capable of reducing the increase in thickness by 30% as opposed to controls). Test No. 5 Evaluation of bioavailability in vivo The purpose of the study is to determine the pharmacokinetics and oral bioavailability of the compounds present in rats. Species / strain / sex: rat / Lewis / male. Number of formulations: 1 oral; 1 intravenous Amount of animals / formulation: 3 + 2 controls (+ one rat subsequently treated with the formulation (V), 9 in total) Dosage: iv: 1 mg of salt / kg, oral: 10 mg of salt / kg.

Vehicles: iv: a solution was prepared at a concentration of 5 mg / ml in PEG 400 / Tween 80 (6: 1 v: v), then it was diluted with dextrose to a final concentration of 0.5 mg / ml; oral: a solution was prepared at a concentration of 5 mg / ml in Cremophor ELP / EtOH abs (6.5: 3.5 v: v), then diluted with saline to a final concentration of 1 mg / ml. . Experimental: Three cannulated rats / formulation were treated. Only one rat / formulation was treated with the vehicle, as a basal sample. Intravenous administration in the flow vein was provided as a bolus; oral administration by gastric gavage as a solution. Blood was extracted from the superior vena cava of each rat and collected in heparinized tubes at the intervals detailed below: 2 '(only for IV), 5', 15 ', 30'; 1, 2, 4, 6, 8, 24 and 32 h after dosing. The plasma was obtained immediately afterwards by centrifugation (10,000 rpm for 3 min) and then stored in tubes labeled at -30 ° C until the analysis was performed. Analytical assay: extraction of the compounds was carried out by protein precipitation by the addition of 100 mcl of acetonitrile to 25 mcl of plasma. The concentrations of the compounds (as free bases) in plasma were determined by the LC-MS method. Column: APEX CN RP 5 me, 10x4 mn (Jones chromatography); mobile phase: 70% acetonitrile / 30% lmM ammonium formate + 0.01% triethylamine adjusted to pH 2.0 with formic acid; flow rate: 1 ml / min; injection volume: 10 mcL; Oven temperature: 45 ° C; MS detection by APCI using MRM positive ion; MRM transition: 330 m / z > 239 m / z, retention time: 1.4 min; LLOQ: 5.03 ng / ml; ULOQ: 10,060 ng / ml. In the table below, bioavailability is expressed as F%. Table 1 below shows, by way of example, the results for the four representative compounds of the invention obtained in Tests Nos. 4 and 5.

Table 1 In Table 1: PNU _ 190364 means 2- (1H-indol-2-yl) -4-methoxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; PNU 190192 means 2- (1H-indol-2-yl) -4-methoxy-5- [(5-pentyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; PNU 190537 means 2- (lH-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; Y PNU 166823 means 2- (lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride. In view of their valuable biological properties, the compounds of the invention can therefore be useful in mammals, including humans, as immunosuppressive agents for the prevention and treatment of the rejection phenomena associated with the transplantation of organs and tissues. , graft-versus-host reactions and autoimmune diseases. Accordingly, a mammal, and even humans, that need an immunomodulatory agent and, in particular, an immunosuppressive agent, can be treated with a method comprising administering a therapeutically effective amount of a compound of the invention or a pharmaceutically salt. acceptable the same. In this way, the condition of the patient can be improved, be it a human being or an animal. Preferred cases of organ and tissue transplants which can be successfully treated with the compounds of the invention, which were previously described are, for example, the cases of heart, kidney, bone marrow, lung, liver and blood transplants. Transplants of multiple organs. Preferred cases of autoimmune diseases that can be successfully treated with the compounds of the invention that were previously described are, for example, the cases of rheumatoid arthritis, systemic lupus erythematosus, juvenile diabetes, autoimmune hemolytic anemia, myasthenia gravis, multiple sclerosis. , psoriasis, ulcerative colitis, idiopathic thrombocytopenic purpura, chronic active hepatitis, glomerulonephritis, idiopathic leukopenia, primary biliary cirrhosis, thyroiditis, thyrotoxicosis, dermatomyositis, discoid lupus erythematosus, psoriatic arthritis, regional enteritis, nephrotic syndrome, lupus nephritis, lupoid hepatitis, Sjdgren, Goodpasture syndrome, Wegener's granulomatosis, scleroderma, Sezari's disease, uveitis and mumps orchitis. Usually, rheumatoid arthritis, systemic lupus erythematosus, juvenile diabetes, myasthenia gravis, multiple sclerosis and psoriasis. The therapeutic regimen for the different clinical syndromes should be adapted to the type of pathology taking into account also, as usual, the route of administration, the way in which the compound is administered as well as the age, weight and conditions of the subject involved. . In general, the oral route is used for all the tables that require said compounds. Preference is given to injection or intravenous infusion for acute treatments.

For maintenance regimens, oral or parenteral, intramuscular or subcutaneous route is preferred. For these purposes, the compounds of the invention, for example, the compound PNU 190364, can be administered orally at dosages comprised, for example, between 0.5 and 10 mg / kg approximately of body weight per day in adult humans. Dose may be used for the active compounds comprised between, for example, 0.25 and 5 mg / kg approximately of the body weight per day for parenteral administration and for intravenous injection or infusion in adult humans. Of course, these dosing regimens may be adjusted in order to provide an optimal therapeutic response. The nature of the pharmaceutical compositions containing the compounds of this invention together with pharmaceutically acceptable carriers or diluents will, of course, depend on the route of administration desired. The compositions can be formulated in a conventional manner using the usual ingredients. As an example, the compounds of the invention, can be administered in the form of aqueous or oily solutions or suspensions, tablets, pills, gelatin capsules, syrups, drops or suppositories. Thus, for oral administration, the pharmaceutical compositions containing the compounds of this invention are preferably tablets, pills or gelatin capsules containing the active substance together with diluents, such as lactose, dextrose, sucrose, mannitol , sorbitol and cellulose; lubricants, for example, silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; or they may also contain binders such as starches, gelatin, methylcellulose, carboxymethylcellulose, gum arabic, tragacanth, polyvinylpyrrolidone; disaggregation agents such as, for example, starches, alginic acid, alginates, sodium starch glycolate; effervescent mixtures; colorants; sweeteners; wetting agents such as, for example, lecithin, polysorbates, lauryl sulfates and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations can be prepared in a known manner, for example, by resorting to the use of mixing, granulating, tabletting, sugar coating or film coating processes. Liquid dispersions for oral administration can be, for example, syrups, emulsions and suspensions. The syrups may contain as a carrier, for example, sucrose or sucrose with glycerin and / or mannitol and / or sorbitol. The suspensions and the emulsions may contain, as a carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, eg, sterile water, olive oil, ethyl oleate, glycols, for example propylene glycol and, if desired, an appropriate amount of lidocaine hydrochloride. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or, preferably, they may be in the form of sterile aqueous isotonic saline solutions.

The suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, for example, cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. Additionally, the present invention provides products containing a compound of the formula (I) or a pharmaceutically acceptable salt thereof and an additional drug as a combined preparation for simultaneous, individual or sequential use in immunosuppressive therapy in mammals. Said additional drug may be, for example, a corticosteroid, an immunosuppressant or antitumor agent or mixtures of two or more thereof. The term "antitumor agent" is intended to comprise both a simple antitumor drug and also "cocktails", ie, a mixture of said drugs according to clinical practice. Some examples of antitumor agents that can be formulated with a compound of the formula (I) include methotrexate and cyclophosphamide as well as mixtures thereof.

The term "immunosuppressive agent" is intended to comprise both a simple immunosuppressant drug and also "cocktails", ie, a mixture of said drugs according to clinical practice. Some examples of the immunosuppressive agents that can be formulated with a compound of the formula (I) include, for example, one of those listed below: cyclosporin A or cyclosporin C, a non-polar cyclic oligopeptide; FK506, a fungal macrolide immunosuppressant; azathioprine, or 6- [(l-Methyl-4-nitro-lH-imidazol-5-yl) -thio] 1 H-purine; methotrexate; rapamycin, a fungal macrolide immunosuppressant, mycophenolate mofetil, or 6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-l, 3-dihydroisobenzofuran-5-yl) -4-methyl-4- ( E) 2- (4-morpholinyl) -ethyl esterhexenoic ester; an immunosuppressive glucocorticoid such as prednisone or dexamethasone; and / or a polyclonal such as, for example, an anti-human thymocyte antibody, or a monoclonal such as, for example, an anti-human CD3 antibody; or a mixture of two or more thereof. It should be noted that the co-administration of an immunosuppressive agent, as defined above and, at least one compound of the formula (I) or, a pharmaceutically acceptable salt thereof, as defined herein, produces an activity Enhanced immunosuppressant in a synergistic manner and, thus, provides a superaditive immunosuppressive effect, that is, an effect greater than the sum of the actions of the components individually. A person skilled in the art will appreciate that said superaditive immunosuppressive effect makes it possible to administer lower levels of dosage of immunosuppressive agents and, in this way, the side effects caused by the immunosuppressive agents usually used are reduced. Accordingly, the present invention also provides a pharmaceutical composition for use in immunosuppressive therapy in mammals, and even in humans, comprising: (a) an immunosuppressive agent in a pharmaceutically acceptable carrier and / or excipient, and ( b) at least one compound of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier and / or excipient, in the amounts necessary to produce the superadditive immunosuppressive effect. Another aspect of the present invention is a method of immunosuppressive therapy to be used in mammals, and even in humans, that need it, said method comprises the administration to said mammal of (a) an immunosuppressive agent and (b) at least a compound of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, in effective amounts to produce a superadditive immunosuppressive effect. In this way, in view of the combined therapeutic effect that can be obtained by means of said combined preparation, lower doses of immunosuppressive agents may be used. Accordingly, the invention also provides a combination preparation comprising (a) an immunosuppressant agent and (b) at least one compound of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, in an effective amount to produce a superadditive immunosuppressive effect for the use of a method for decreasing the side effects caused by immunosuppressive therapy in mammals, including humans in need thereof. In the combined preparations, the pharmaceutical compositions and the method of treatment according to the present invention is preferably used only a compound of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof. The combination preparation according to the invention can also include packages or compositions in combination in which the constituents are placed side by side and can therefore be administered simultaneously, separately or sequentially to one and the same mammal, including humans . The compounds of the formula (I) and pharmaceutically acceptable salts thereof have been found to also be active in the treatment of T-cell-adult leukemia-lymphoma, in particular caused by infection with HTLV-I in mammals. , including humans. Such therapeutic activity of the compounds of the invention is proven, for example, by the fact that they have been found to be active to selectively inhibit IL-2 induced activation and the expansion of human murine T cells, thus showing a profile pharmacological therapy consistent with IL-2-dependent ATL therapy.

Inhibition of the activity induced by IL-2 proliferation The murine Th2 cells of D10-G4.1 (ATCC TIB 224) are dependent on IL-2 for their development. These are cultured in complete RPMI 1640 medium enriched with rhIL-2 (6 ng / ml) and ConA (6 ng / ml).

To test the inhibitory effects of the compounds of the invention on the activity of IL-2, the DIO cells are washed twice with complete medium, resuspended at 10 5 cells / ml in the same medium, and distributed in triplicate (104 cells / well ) in 96-well flat bottom plates. 50 ml of rhIL-2 and 50 ml of the test compound at different concentrations are simultaneously added to the cells. The cultures are then incubated at 37 ° C in a humidified incubator with 5% C02, for 48 h, the last 18 h in the presence of 0.2 μCi of 3 H-TdR.

The uptake of 3H-TdR in cells (cpm) is taken as a measure of cell proliferation.

For example for the representative compound of the invention 2- (lH-indol-2-yl) -4-methoxy-5- [(5-pentyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole (internal code) PNU 190192) the following activity data were obtained. cpm mean from triplicate wells (SE) In the treatment of a leukemia and an adult T cell lymphoma one or more compounds of the formula (I) can be administered as defined above, alone or in association with an agent antitumor. Preferably, a compound of the formula (I) is used. Accordingly, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof for use in the treatment of adult T-cell leukemia-lymphoma. A further objective of the present invention is a method of treating mammals, including humans, suffering from adult T-cell leukemia-lymphoma, said method comprising administering to them a therapeutically effective amount of a compound of the formula (I) , as defined herein, or a pharmaceutically acceptable salt thereof. The object of the present invention is also to provide a pharmaceutical composition having activity against adult T-cell leukemia-lymphoma, comprising a compound of the formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, as an active ingredient, and a pharmaceutically acceptable carrier or diluent. A further objective of the present invention is to provide a combined method of treating adult T-cell leukemia-lymphoma in mammals, including humans, in need thereof, said method comprising administering a compound of the formula (I) thereto, or a pharmaceutically acceptable salt thereof, and an antitumor agent in amounts and close enough in time, to produce a therapeutically useful effect. The present invention also provides a product containing a compound of the formula (I), or a pharmaceutically acceptable salt thereof, and an antitumor agent as a combined preparation for simultaneous, separate or sequential use in therapy against leukemia-cell lymphoma. Adult T The term "antitumor agent" is understood to comprise a simple antineoplastic agent and "cocktails", for example a mixture of such drugs according to clinical practice. An antineoplastic agent in the treatment of adult T-cell leukemia-lymphoma can be for example an agent selected from the group consisting of a vinca antineoplastic alkaloid, an antineoplastic antibiotic, an antineoplastic antimetabolite, an antineoplastic platinum coordination complex, a compound of antineoplastic taxane, an antineoplastic ceramide compound, an antineoplastic distamycin compound, an antineoplastic epidofilotoxin compound and an antineoplastic inhibitor of topoisomerase I. Examples of specific antineoplastic agents, according to the invention, which are administered with a compound of the formula (I) are: vincristine, vinblastine, etoposide, talimustine-amidoxime, 3- (l-methyl-4- (l-methyl-4- ( l-methyl-4- (4, N, N-bis (2-chloroethyl) aminobenzene-l-carboxamido)? irol-2-carboxamido) pyrrole-2-carboxamido) pyrrole-2-carboxamido) proprionamidoxime, (2S-RR -4E) -1,3-dihydroxy-2-tetradecanoylamido-4-octadecene, paclitaxel, docetaxel, 7-epitaxol, 7-epitaxtero, epirubicin, doxorubicin, cyclophosphamide, idarubicin 4 '-yodoxorubicin, daunorubicin, actinomycin D, bleomycin plicamycin, mitomycin, canpothecin, 9-aminocanfothecin, canfotecin 11 (CPT 11), topotecan, methotrexate, cytarabine, azaudirine, azarabine, fluorodeoxyuridine, deoxicoformycin, mercaptopurine, cisplatin and carboplatin. In particular, these are epirubicin doxorubicin, cyclophosphamide, 9-aminocamptothecin and camptothecin 11. The dose of a compound of the invention to be administered to a patient suffering from adult T-cell leukemia-lymphoma, in particular caused by infection with HTLV -I, will vary with the precise nature of the conditions being treated and the treatment recipient. A therapeutically effective dose of the compounds of the formula (I), for example the hydrochloride compound of 2- (lH-indol-2-yl) -4-methoxy-5- [(5-pentyl-2H-pyrrole-2- ylidene) methyl] -lH-pyrrole (PNU 190192), is in the range of about 0.03 to about 1.5 mg / kg, preferably about 0.06 mg / kg to about 0.7 mg / kg when administered intravenously, while the dose of The same compound for oral administration in adult humans is generally from about 0.3 mg / kg / day to about 15 mg / kg / day. The dose of a compound of the formula (I) and of an antitumor agent, in the case of combination therapy, to be used is, of course, dependent on various factors such as the organism to be treated (e.g. , human or animal, age, weight, general condition, health), the severity of symptoms, the disorder to the accompanying treatment with other pharmaceutical agents, or the frequency of treatment. The doses are generally administered several times a day and preferably one to three times a day. The effective amounts of an antitumor agent are generally those commonly used in therapy, as is known to those of skill in the art. However, the amounts of the individual active compounds must be within the range given above, for example within the effective dose and tolerable for the organism to be treated. The oral route is used, in general, for all the conditions required by the compounds of the invention. Preference is given to intravenous injection or infusion for acute treatments. For maintenance regimens, the oral or parenteral route is preferred, for example, intramuscular or subcutaneous.

The nature of the pharmaceutical preparations and the compositions according to the invention will of course depend on the desired route of administration. The compositions can be formulated in the conventional manner with the usual ingredients, for example as described above. The following examples illustrate, but do not limit the invention.

Example 1: Compound (IV) To a solution of 2-formyl-5-undecyl pyrrole (4 g, 16.03 mmol) and 4-methoxy-3-pyrrolin-2-one (3.63 g, 32.06 mmol) in DMSO (53 ml) 2N sodium hydroxide (45 ml) is added under a nitrogen atmosphere and the mixture is stirred at 60 ° C for 8 hours. After dilution with water (200 ml) the yellow suspension is extracted with dichloromethane (600 ml). The organic phase is stirred with water and brine, anhydrified over anhydrous sodium sulfate and evaporated to dryness. The crude material is taken up in hexane and filtered to give 4-methoxy-5- (5-undecyl-lH-pyrrol-2-yl-methylene) -1,5-dihydro-pyrrol-2-one (4.86 g; 14.11 mmol) as a yellow crystalline solids. 88% yield.

LNMR (400 mhz, CDCI3), ppm: 0.87 (3H, m), 1.2-1.5 (16H, m), 1.72 (2H, m), 2.73 (2H,), 3.89 (3H, s), 5.08 (1H, d, J = l .7 Hz), 5.97 (ÍH, dd, J = 2.4 and 3.2 HZ), 6.31 (ÍH, s), 6.36 (ÍH, t, J = 3.2 Hz), 10.25 (ÍH, bs), 10.74 (ÍH, bs).

Example 2: Compound (II) To a solution of 4-methoxy-5- (5-undecyl-lH-pyrrol-2-yl-methylene) -1,5-dihydro-pyrrol-2-one (1 g, 2.90 mmol) ) in dichloromethane (50 ml) at 0-5 ° C add trifluoromethanesulfonic anhydride (0.586 ml, 3.48 mmol) dropwise under nitrogen atmosphere. After stirring at this temperature for 30 minutes, the reaction mixture is poured into a 2% sodium hydrogen carbonate solution and extracted with ethyl acetate (2 x 50 ml). The collected organic extracts are stirred with brine, anhydrified on anhydrous sodium sulfate and evaporated to dryness. The crude material is subjected to chromatography on a short column of silica gel eluting with hexane / ethyl acetate 85/15 to give the 2-trifluoromethanesulfonyloxy-4-methoxy-5- [(5-undecyl-2H-pyrrole-2- ilidene) methyl] -lH-pyrrole (980 mg, 2.06 immoles) as a yellow solid. Performance: 71%.

XNMR (400 mhz, CDCl 3), ppm: 0.88 (3H, m), 1.1-1.6 (16H, m), 1.68 (2H, m), 2.70 (2H, m), 3:88 (3H, s), 5.45 (HH, s), 6.08 (1H, d, J = 4.0 Hz), 6.70 (HH, d, J = 4.0 Hz), 7.05 (HH, s), 10.9 (HH, bs).

Example 3: Interconversion between compounds (VI) A solution of 4-methoxy-3-pyrrolin-2-one (3g, 26.52 mmoles) in absolute ethanol (60 ml) is treated with sodium ethoxide (2.17 g, 31.82 mmoles) under nitrogen atmosphere. The solution is refluxed for 2 hours and then emptied into a 30% NaH2P0 solution (200 ml). The resulting mixture is extracted with ethyl acetate (3x150 ml) and the organic phase is stirred with brine, dried over sodium sulphate and evaporated to dryness to obtain 4-ethoxy-3-pyrrolin-2-one ( 2.19 g, 17.24 mmoles). Performance: 65%. 1NMR (400 mhz, CDC13), ppm: 1.38 (3H, t), 3.89 (2H, s), 4.01 (2H, q), 5.03 (1H, s), 6.15 ( ÍH, bs).

Example 4: Interconversion between compounds (IV) A solution of 4-methoxy-5- (5-undecyl-lH-pyrrol-2-yl-methylene) -1,5-dihydro-pyrrol-2-one (190 mg 1 mmol) in amyl alcohol (4.75 ml) and dioxane (4.75 ml) with 0.25 N methanesulfonic acid in dioxane (1 ml) and stirred at room temperature under a nitrogen atmosphere for 6 hours. hours. Subsequently, the mixture was poured into water (50 ml) and extracted with ethyl acetate (3 x 30 ml). The organic phase was stirred with brine, dried with sodium sulfate and evaporated to dryness. The crude material was purified on silica gel with elution of ethyl acetate / methanol 98/2 to obtain 4-amyloxy-5- (5-undecyl-lH-pyrrol-2-yl-methylene) -1,5-dihydro-pyrrole -2-one (110 mg, 0.45 mmol). Performance: 45%. XNMR (400 mhz, CDC13), ppm: 0.91 (6H, m), 1.2-1.5 (20H, m), 1.72 (2H, m), 1.82 (2H, m), 2.73 (2H,), 4.01 (2H, t), 5.08 (IH, d, J = I, 7 Hz), 5.99 (IH, dd, J = 2.4 and 3.2 HZ), 6.30 (HH, s), 6.36 (HH, t, J = 3.2 Hz), 10.30 (HH, bs), 10.75 (HH bs). Example 5: Compound (III) To a solution of 2, 2, 6,6-tetramethylpiperidine (11.0 g, 78 mmol) in THF (170 ml), at -78 ° C and under nitrogen, a solution was added slowly 1.6M of BuLi (56.1 ml; 89.7 mmol) in hexane to maintain the temperature below -65 ° C. The mixture was stirred at -75 ° C for 10 minutes and then tempered at 0 ° C for 30 minutes. After cooling again to -78 ° C, a solution of 1-tert-butoxycarbonylindole (15.6 g, 72 mmol) in THF (300 ml) was added, keeping the temperature below -65 ° C. The mixture was stirred for 1 hour at -75 ° C and then a solution of trimethyl borate (7.5 g, 72 mmol) in THF (200 ml) was added in the form of drops. The reaction was allowed to warm to room temperature during the course of the night. A 0.25 N solution of HCl (200 ml) was introduced and the THF was removed in vacuo. The residue was extracted with ethyl ether (3 x 150 ml) and the combined organic phases were washed with water (2 x 100 ml) and, thereafter, dried with sodium sulfate. Subsequently, the solution was concentrated, cooled to 0 ° C and filtered to obtain crystalline (1-tert-butoxycarbonyl-indol-2-yl) boronic acid (6.95 g, 26.6 mol). Yield: 37%. 1NMR (400 mhz, CDC13), ppm: 1.73 (9H, s), 7.31 (2H, m), 7.56 (2H, m), 7.57 (2H, bs), 8.01 ( ÍH, bd, J = 8.2 Hz).

Example 6: Compound (I) An oxygen-free solution of 2-trifluoro-methanesulfonyloxy-4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole ( 418 mg, 0.877 mmol) in dioxane (30 ml) sequentially, under an argon atmosphere, with (lt-butoxycarbonyl-indol-2-yl) boronic acid (916 mg, 3.51 mmol), potassium carbonate ( 969 mg, 7.02 mmol), tetrakis (triphenylphosphamine) palladium (0) (50 mg, 0.044 mmol) and it was heated at 90 ° C, with stirring, for 6 hours. After proceeding with cooling, the reaction mixture was poured into ice-water (100 ml) and extracted with ethyl acetate (3 x 50 ml). The organic phase was stirred with water and brine, anhydrified with anhydrous sodium sulfate and then filtered and evaporated to dryness in vacuo. The residue was purified on a short Al203 column (activity II-III) using hexane / ethyl acetate 4/1 as eluent. The fractions collected were concentrated, treated with a solution of hydrochloric acid in isopropyl ether and then evaporated to dryness, under vacuum and at room temperature, to obtain 2- (lH-indol-2-yl) -4- hydrochloride. methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -iH-pyrrole (295 mg, 0.612 mmol), m.p., 92-95 ° C. Yield: 70%. XNMR (400 mhz, CDC13), ppm: 0.87 (3H, m), 1.1-1.9 (18 H, m), 3.00 (2H, m), 4.06 (3H, s) , 6.29 (HH, dd, J = 1, 7 and 4.1 Hz), 6.32 (1H, d, J = 2 Hz), 6.95 (HH, dd, J = 2.4 and 4) , 1 Hz), 7.0-7.4 (3H, m), 7.13 (HH, s), 7.61 (2H, m), 12.4 (HH, bs), 13.2 (HH) , bs), 13.3 (1H, bs) The following compounds can be synthesized by an analogous procedure: 2- (5-methoxy-lH-indol-2-yl) -4-methoxy-5-hydrochloride - [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole XNMR (400 mhz, CDC13), ppm: 0.85 (3H, m), 1.1-1.9 (18H, m), 2.97 (2H, m), 3.82 (3H, s), 4.03 (3H, s), 6.26 (2H, m), 6.91 (1H, dd, J = 2 , 4 and 4.0 Hz), 6.97 (2H, m), 7.07 (2H, m), 7.47 (IH,) 12.3 (IH, bs), 13.1 (IH, bs ), 13.2 (ÍH, bs). 2- (lH-Indol-2-yl) -4-methoxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride (PNU 190364) XNMR (400 mhz, CDCI3 ), ppm: 2.65 (3H, s), 4.04 (3H, s), 6.23 (1H, dd, J = 1, 5, 4.0 Hz), 6.28 (1H, d, J = 1, 8 Hz), 6,91 (1 H, dd, J = 4, 2,5), 7,04 (H, s), 7,10 (H, m), 7,16 (H, d , 1.5 Hz), 7.31 (HH, m), 7.58 (2H, m), 12.33 (HH, bs), 13.05 (HH, bs), 13.15 (HH, bs ). 2- (lH-Indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride, (PNU 190537) XNMR (400 mhz, CDC13), ppm: 2.66 (HH, s), 5.25 (2H, s), 6.25 (HH, dd, J = 1.7, 3.9 Hz), 6.37 (HH, d , J = 2, l Hz), 6.94 (lH, dd, J = 3.9, 2.5), 7.11 (lH, m), 7.16 (lH, s), 7.19 ( ÍH, d, 1.7 Hz), 7.31 (HH, m), 7.4-7.5 (5H, m), 7.60 (2H, m). 2- (lH-indol-2-yl) -4-methoxy-5- [(5-pentyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride, (PNU 190192) 1NMR. (400 mhz, CDC13), ppm: 0.91 (3H, t, J = 7.2 Hz), 1.40 (4H, m), 1.81 (2H, m), 3.00 (2H, t , J = 7.7 Hz), 4.05 (3H, s), 6.29 (ΔH, dd, J = 1, 8, 4.0 Hz), 6.30 (ΔH, d, J = 1, 8 Hz), 6.95 (ΔH, dd, J = 2.6, 4.0 Hz), 7.11 (2H, m), 7.19 (ΔI, d, J = 1, 8 Hz), 7 , 31 (HH, m), 7.60 (2H, d, J = 8.8 Hz), 12.39 (HH, bs), 13.14 (HH, bs), 13.22 (HH, bs) . 2- (lH-indol-2-yl) -4-benzyloxy-5- [(5-pentyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride, (PNU 169819) .NMR (400 mhz , CDC13), ppm: 0.91 (3H, t, J = 7.2 Hz), 1.40 (4H, m), 1.81 (2H, m), 3.00 (2H, t, J = 7.7 Hz), 5.26 (2H, s), 6.29 (1H, dd, J = 1, 8, 4.0 Hz), 6.37 (1H, d, J = 1, 8 Hz) , 6.96 (HH, dd, J = 2.5, 4.0 Hz), 7.11 (HH, m), 7.18 (2H, s), 7.31 (HH,), 7.4 -7.5 (5H, m), 7.60 (2H,), 12.41 (ÍH, bs), 13.19 (1H, bs), 13.27 (1H, bs). 2- (lH-indol-2-yl) -4-methoxy-5- [(5-ethyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; 2- (lH-Indol-2-yl) -4-methoxy-5- [(5-propyl-2H-? Irrol-2-ylidene) ethyl] -lH-pyrrole hydrochloride; 2- (1H-Indol-2-yl) -4-methoxy-5- [(5-isopropyl-2H-pyrrol-2-ylidene) methyl] -IH-pyrrole hydrochloride; 2- (1H-Indol-2-yl) -4-methoxy-5- [(5-butyl-2H-pyrrol-2-ylidene) methyl] -iH-pyrrole hydrochloride; 2- (lH-Indol-2-yl) -4-benzyloxy-5- [(5-ethyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; 2- (1H-Indol-2-yl) -4-benzyloxy-5- [(5-propyl-2H-pyrrol-2-ylidene) methyl] -IH-pyrrole hydrochloride; 2- (lH-Indol-2-yl) -4-benzyloxy-5- [(5-isopropyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; 2- (lH-indol-2-yl) -4-benzyloxy-5- [(5-butyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; 2- (5-Methoxy-lH-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; 2- (5-Chloro-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride, (PNU 169683) XNMR (400 mhz, CDC13), ppm: 0.87 (3H, t, J = 7 Hz), 1.2-1.5 (16H, m), 1.8 (2H, m), 3.00 (2H , t, J = 7.7 Hz), 4.05 (3H, s), 6.31 (2H, m), 6.98 (IH, dd, J = 2.6, 4.0 Hz), 7 , 09 (ÍH, d, J = 1, 5 Hz), 7,13 (1H, s), 7,25 (1H, dd, J = 2,2, 8,8 Hz), 7,51 (ÍH, d, J = 8.8 Hz), 7.55 (1H, d, J = 2.2 Hz), 12.50 (HH, bs), 13.14 (1H, bs), 13.21 (HH, bs). 2- (5-Chloro-lH-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; 2- (5-Cyano-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; 2- (5-Cyano-lH-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -IH-pyrrole hydrochloride; 2- (5-Hydroxy-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; 2- (5-Hydroxy-lH-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -IH-pyrrole hydrochloride; 2- (5-Amino-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -IH-pyrrole Dihydrochloride 2- (5 -amino-lH-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -IH-pyrrole; 2- (5-Methyl-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; 2- (5-Benzyloxy-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; 2- (5-Fluoro-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; 2- (5-carboxy-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; 2- (5-carboxy-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -IH-pyrrole hydrochloride, methyl ester; 2- (5-Carbamoyl-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; 2- (6-carboxy-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; 2- (6-carboxy-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride, methyl ester; 2- (6-Carbamoyl-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; 2- (6-Nitro-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride; and 2- (7-Ethyl-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole hydrochloride. Example 7 Formulation: capsules (150 mg). The capsules, each weighing 400 mg and containing 150 mg of the active substance, were prepared in accordance with what is detailed below.

Composition: 2- (lH-indol-2-yl) -4-methoxy-5- [(5-150mg undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole lactose 198mg hydrochloride Corn Starch 5Omg Magnesium Stearate 2mg Total 400mg It was encapsulated in two-piece hard gelatin capsules.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (20)

RE I V I ND I C AC I ONE S

1. A compound which is a derivative of (lH-indol-2-yl) 5 [(2H-pyrrol-2-ylidene) methyl] -lH-pyrrole of the formula (I) characterized in that each of R 1, R 2, R 3 and R 4, which may be the same or different, independently represents hydrogen, C 1 -C 6 alkyl, halogen, cyano nitro, hydroxy, C 1 -C 6 alkoxy unsubstituted or substituted by phenyl, Ci-Cβ-carbonyloxy alkyl, -NRaRb wherein each of Ra and Rb are, independently, hydrogen or Ci-Cß alkyl, Cj-Cβ-carbonylamino, carboxy, (C?-C6 alkoxy) carbonyl, aralkylcarbamoyl , arylcarbamoyl, or -CONRcRd where each of Rc and Rd are, independently, hydrogen or C? -C6 alkyl or, Rc and Rd, taken together with the nitrogen atom to which they are bound, form a ring of morpholino or piperidino; R 5 represents halogen, hydroxy or Ci-Cn alkoxy unsubstituted or substituted by phenyl; and R6 represents hydrogen, C2-C2o alkanoyl, C3-C20 alkenoyl phenyl, C?-C20 alkyl or C2-C2o alkenyl wherein the alkanoyl, alkenoyl, alkyl and alkenyl groups are unsubstituted or substituted by 1 to 3 substituents which are selected , independently, between halogen, Ci-Cd alkoxy, hydroxy, aryl, aryloxy, cyano, carboxy, (Ci-Cβ alkoxy) carbonyl, (C3-C4 alkenyl) carbamoyl, aralkylcarbamoyl, arylcarbamoyl and -CONRcRd where Rc and Rd are as defined before; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, characterized in that each of R1, R2, R3 and R4 independently represent hydrogen, C1-C4 alkyl, halogen, cyano, nitro, hydroxy, unsubstituted C1-C4 alkoxy or substituted by phenyl, amino, carboxy, (C1-C4 alkoxy) carbonyl or -CONRcRd wherein each of Rc and Rd are, independently, hydrogen or C3-C4 alkyl or, Rc and Rd, taken together with the nitrogen atom to which they are bound, form a ring of morpholino or piperidino; R5 represents hydroxy or Ci-C alkoxy unsubstituted or substituted by phenyl; and R6 represents hydrogen, C1-C14 alkyl or C3-C14 alkenyl, in which the alkyl and alkenyl groups are unsubstituted or substituted by a substituent selected independently from halogen, C1-C14 alkoxy, hydroxy, aryl, aryloxy, cyano , carboxy, (C1-C4 alkoxy) carbonyl, aralkylcarbamoyl, arylcarbamoyl and -CONRcRd where Rc and Rd are, independently, hydrogen or C1-C4 alkyl or, Rc and Rd, taken together with the nitrogen atom to which they are united, they form a ring of morpholino or piperidino.

3. A compound selected from: 2- (1H-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-methoxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -IH-pyrrole; 2- (1H-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-methoxy-5- [(5-pentyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-benzyloxy-5- [(5-pentyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-methoxy-5- [(5-ethyl-2H-pyrrol-2-ylidene) methyl] -iH-pyrrole; 2- (1H-indol-2-yl) -4-methoxy-5- [(5-propyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-methoxy-5- [(5-isopropyl-2H-pyrrol-2-ylidene) methyl] -IH-pyrrole; 2- (1H-indol-2-yl) -4-methoxy-5- [(5-butyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-benzyloxy-5- [(5-ethyl-2H-pyrrol-2-ylidene) methyl] -iH-pyrrole; 2- (1H-indol-2-yl) -4-benzyloxy-5- [(5-propyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (1H-indol-2-yl) -4-benzyloxy-5- [(5-isopropyl-2H-pyrrol-2-ylidene) methyl] -IH-pyrrole; 2- (1H-indol-2-yl) -4-benzyloxy-5- [(5-butyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-methoxy-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) ethyl] -IH-pyrrole; 2- (5-methoxy-lH-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-chloro-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-chloro-lH-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-Cyano-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-Cyano-lH-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-hydroxy-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-hydroxy-lH-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -IH-pyrrole; 2- (5-amino-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-amino-lH-indol-2-yl) -4-benzyloxy-5- [(5-methyl-2H-pyrrol-2-ylidene) methyl] -IH-pyrrole; 2- (5-methyl-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-benzyloxy-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) ethyl] -lH-pyrrole; 2- (5-Fluoro-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-carboxy-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (5-carbamoyl-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (6-carboxy-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (6-carbamoyl-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (6-Nitro-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; 2- (7-ethyl-lH-indol-2-yl) -4-methoxy-5- [(5-undecyl-2H-pyrrol-2-ylidene) methyl] -lH-pyrrole; and the Ci-Cß alkyl esters as well as the pharmaceutically acceptable salts thereof.

4. A compound, according to claim 3, in the form of a hydrochloride, hydrobromide or methanesulfonate salt.

5. A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and / or diluent and, as an active ingredient, a compound according to claim 1.

6. A compound, according to claim 1, for use in a method of treatment of the human or animal body by means of therapy.

7. A compound, according to claim 1, for use as an immunomodulatory agent or for the treatment of leukemia-lymphoma in adult T cells.

8. The use of a compound, according to claim 1, for the preparation of a medicament having an immunomodulatory activity and for its use in the treatment of leukemia-lymphoma in adult T cells.

9. A product containing a compound of the formula (I), according to claim 1, and an additional drug as a combined preparation for simultaneous, individual or sequential use in immunosuppressive therapy in mammals.

10. A product, according to claim 9, characterized in that the additional drug is an immunosuppressive agent selected from: cyclosporin A or cyclosporin C, a non-polar cyclic oligopeptide; FK506, a fungal macrolide immunosuppressant; azathioprine, or 6- [(1-methyl-4-nitro-1H-imidazol-5-yl) -thio] 1H-purine; methotrexate; rapamycin, a fungal macrolide immunosuppressant; mycophenolate mofetil, or 6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-l, 3-dihydroisobenzofuran-5-yl) -4-methyl-4- (E) -hexenoic ester 2- (4-morpholinyl) -ethyl; an immunosuppressive glucocorticoid such as, for example, prednisone or dexamethasone; and / or a polyclonal such as, for example, an anti-human thymocyte antibody or a monoclonal antibody, such as, for example, an anti-human CD3 antibody; or a mixture of two or more thereof.

11. A pharmaceutical composition for use in immunosuppressive therapy in a mammal, including a human being, characterized in that it comprises: (a) an immunosuppressive agent in a pharmaceutically acceptable carrier and / or excipient, and (b) at least one compound, according to claim 1, in a pharmaceutically acceptable carrier and / or excipient, in amounts sufficient to produce a superadditive immunosuppressive effect.

12. A combination preparation, characterized in that it comprises (a) an immunosuppressant agent and (b) at least one compound of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, in an amount effective to produce a superadditive immunosuppressive effect for use in a method that reduces the side effects caused by immunosuppressive therapy in mammals, including humans, that need it.

13. A product containing a compound according to claim 1, and an antitumor agent as a combined preparation for use simultaneously, individually or sequentially in immunosuppressive therapy for adult T-cell leukemia-lymphoma.

14. A method of treatment for a mammal, including a human being, that needs an immunomodulatory agent, said method is characterized in that it comprises administering to said mammal an effective amount of a compound according to claim 1.

15. A method of treatment for a mammal, including a human being, suffering from adult T-cell leukemia-lymphoma, said method is characterized in that it comprises administering to said mammal a therapeutically effective amount of a compound according to claim 1.

16. A method of immunosuppressive therapy for use in a mammal, including a human being, that needs it, said method is characterized in that it comprises the administration to said mammal of: (a) an immunosuppressive agent and, (b) minus a compound according to claim 1, in effective amounts such as to produce a superadditive immunosuppressive effect.

17. A method, according to claim 16, characterized in that the immunosuppressive agent (a) is selected from: cyclosporin A or cyclosporin C, a non-polar cyclic oligopeptide; FK506, a fungal macrolide immunosuppressant; azathioprine, or 6- [(l-Methyl-4-nitro-lH-imidazol-5-yl) -thio] 1 H-purine; methotrexate; rapamycin, a fungal macrolide immunosuppressant; mycophenolate mofetil, or 6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-l, 3-dihydroisobenzofuran-5-yl) -4-methyl-4- (E) -hexenoic ester 2- (4-morpholinyl) -ethyl; an immunosuppressive glucocorticoid such as, for example, prednisone or dexamethasone; and / or a polyclonal such as, for example, an anti-human thymocyte antibody or a monoclonal antibody, such as, for example, an anti-human CD3 antibody; or a mixture of two or more thereof.

18. A method of combined treatment for adult T-cell leukemia-lymphoma in a mammal, including humans, that needs it, said method is characterized in that it comprises administration of a compound, according to claim 1, and antitumor agent, in amounts and at close and sufficient intervals to produce a therapeutically useful effect.

19. A process for the production of a compound, according to claim 1, characterized in that said method comprises the treatment with a compound of the formula (II) (ll) wherein R5 and R6 are as defined in claim 1 and X is a leaving group, with a compound of the formula (III) where R1, R2, R3 and R4 are as defined in claim 1 and R7 is hydrogen or a lower alkyl chain and, if desired, a compound of the formula (I) is converted to another compound of the formula (I) and / or, if desired, a compound of the formula (I) is salified and / or, if desired, converted into a salt of a compound of the formula (I) in a free compound and / o, if desired, a mixture of isomers of a compound of the formula (I) is separated into the simple isomers.

20. A compound of the formula (III) where R1, R2, R3 and R4 are as defined in claim 1 and R7 is hydrogen or a lower alkyl chain, and Boc is a 1-tert-butoxycarbonyl group.