MXPA99010183A - Substituted 3,3-diamino-2-propenenitriles, their preparation and use - Google Patents

Abstract

Substituted cyanoenamines of general formula (I) wherein Z, R1, R2 and R3 are defined in the description, compositions thereof and methods for preparing the compounds are described. The compounds are useful in the treatment of diseases of the central nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system.

Description

3.3-D ___ t ^ NO-2-PROPENTMI - 0S REPLACED, ITS PREPARATION AND USE FIELD OF THE INVENTION The present invention relates to 3, 3-diamino-2-propennitriles substituted, in the following also referred to as cyanoenamines, with the methods for their preparation, with the compositions comprising the compounds, with the use of those compounds as medicines and their use in therapy, for example, in the treatment of diseases of the central nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system.

BACKGROUND OF THE INVENTION Potassium channels play an important role in the potential of the membrane. Among the different types of potassium channels are the ATP-sensitive channels (KATp-) which are regulated by changes in the intracellular concentration of adenosine triphosphate. The KATp- channels have been found in cells of various tissues such as cardiac cells, pancreatic cells, skeletal muscle cells, smooth muscle, central neurons and the anterior pituitary. The channels have been associated with various cellular functions, for example the secretion of hormones (insulin from pancreatic beta cells, hormone REF: 32005 growth and prolactin of adenohypophysial cells), vasodilation (smooth muscle cells), duration of cardiac action potential, release of neurotransmitters in the central nervous system. It has been found that modulators of KATp- channels are of importance for the treatment of various diseases. Certain sulfonylureas, which have been used for the treatment of non-insulin-dependent diabetes mellitus, act by stimulating the release of insulin through an inhibition of KATp ~ channels on pancreatic beta cells. It has been found that potassium channel openers, which comprise a heterogeneous group of compounds, are capable of relaxing vascular smooth muscle and therefore have been used for the treatment of hypertension. In addition, potassium channel openers can be used as bronchodilators in the treatment of asthma and several other diseases. In addition, it has been found that potassium channel openers promote hair growth and have been used for the treatment of baldness. The potassium channel openers are also able to relax the smooth muscle of the urinary bladder and therefore, they can be used for the treatment of urinary incontinence. The potassium channel openers that relax the smooth muscle of the uterus can be used for the treatment of preterm labor. Since some KATP-channel openers are capable of antagonizing vasospasms in the basilar or cerebral arteries, the compounds of the present invention can be used for the treatment of vasospatic disorders such as subarachnoid hemorrhage and migraine. Potassium channel openers hyperpolarize neurons and inhibit the release of neurotransmitters and it is expected that the compounds of the present may be used for the treatment of various diseases of the central nervous system, for example epilepsy, ischemia and neurodegenerative diseases, and for the management of pain. Recently, it has been demonstrated that 1,1-dioxide diazoxide (7-chloro-3-methyl-2H-1, 2,4-benzothiadiazine) and certain derivatives of 3- (alkylamino) 1,1-dioxide - 4H-pyrido [4, 3-e] -1, 2,4-thiadiazine inhibits insulin release through activation of KATP-channels on pancreatic beta cells (Pirotte B. et al., Biochem. Pharmacol, 47 , 1381-1386 (1994); Pirotte B. et al., J. Med. Chem. , 36, 3211-3213 (1993). Diazoxide has also been shown to delay the onset of diabetes in BB rats (Vlahos WS et al., Metabolism 40, 39-46 (1991).) In diabetic rats, diazoxide has been shown to increase insulin secretion and increase receptor binding. insulin and consequently improve glucose tolerance and decrease weight gain (Alemzadeh R. et al., Endocrinol, 133, 705-712, 1993) It is expected that such potassium channel openers can be used for the treatment of diseases characterized by an overproduction of insulin and for the treatment and prevention of diabetes.

DESCRIPTION OF THE INVENTION The present invention relates to substituted 3,3-diamino-2-propennitriles, in the following also referred to as cyanoenamines, of the general formula I: where R1 is alkyl optionally substituted with halogen, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, dialkylamino, arylalkylamino or diarylamino; aralkyl, aryl optionally substituted with alkyl, trifluoromethyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkyl-sulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; heteroaryl optionally substituted by alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, nitro, alkyl-sulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; R2 and R3 are independently hydrogen, alkyl optionally substituted by aryl, heteroaryl, a 5-, 6- or 7-membered heterocyclic system, halogen, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, dialkylamino, arylalkylamino or diarylamino; aryl, optionally substituted by alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkyl-sulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; heteroaryl optionally substituted by alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, nitro, alkyl-sulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; or R2 and R3 are linked together by (CH2) n-, where n provided that R2 and R3 can not be hydrogen at the same time; Z is hydrogen, cyano, alkoxycarbonyl, optionally substituted by aminocarbonyl, alkylsulfonyl or arylsulfonyl optionally substituted by alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, nitro, alkyl-sulfonyl, arylsulfonyl, cyano , < alkoxycarbonyl or aminocarbonyl; and the pharmaceutically acceptable salts thereof. Within the scope of the invention are included all diastereomers and enantiomers of the compounds of formula I, some of which are optically active, and also mixtures including racemic mixtures thereof. The scope of the invention also includes all tautomeric forms of the communication of formula I. The salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts or optionally alkylated ammonium salts, such as those of hydrochloric acids, hydrobromic, hydriodic, phosphoric, sulfuric, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, tartaric, fumaric, mandelic, benzoic, cinnamic, methanesulfonic, ethanesulfonic, picric and the like, and include the acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2, (1977) and incorporated herein by reference or lithium, sodium , potassium, magnesium and the like. The term "5, 6 or 7 membered heterocyclic system" as used herein refers to: an unsaturated or saturated monocyclic system containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur and having 5 members, for example , pyrrole, furan, thiophene, pyrroline, dihydrofuran, dihydrothiophene, imidazole, imidazoline, pyrazole, pyrazoline,. oxazole, thiazole, isoxazole, isothiazole, 1, 2, 3-oxadiazole, furazan, 1,2,3-triazole, 1,2,3-thiadiazole or 2,3,1-thiadiazole; an aromatic monocyclic system containing two or more nitrogen atoms having six members, for example pyrazine, pyrimidine, pyridazine, 1,2,4-triazine, 1,2,3-triazine or tetrazine; a non-aromatic monocyclic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur having 6 or 7 members, for example pyran, thiopyran, piperidine, dioxane, oxacin, isoxacin, dithiane, oxathine, thiazine, piperazine, thiadiazine, dithiazine , oxadiacin or oxoacepane. "Alkyl" refers to a branched, fused, linear, cyclic, bicyclic, lower alkyl, which has l to 15 carbon atoms, preferably from 1 to 6 carbon atoms. Aryl refers to phenyl or phenyl substituted with alkyl or phenyl, or phenyl fused with cycloalkyl, or polycyclic aromatic systems such as naphthyl, anthracenyl, phenanthrenyl, fluorenyl, etc. "Alkylene" refers to branched or fused alkylene, linear, cyclic, lower, having from 1 to 15 carbon atoms, preferably from 1 to 6 carbon atoms. "Heteroaryl" refers to any of pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl unsubstituted or substituted by isomeric alkyl possible, as well as benzo derivatives and corresponding dibenzo or other ring systems fused therewith. Heteroaryl is also meant to mean the partially or completely hydrogenated derivatives of the heterocyclic systems recited above. "Alkoxy" refers to -O-alkyl and aryloxy refers to -O-aryl. Cyan refers to -CN, hydroxy refers to -OH, amino refers to -NH2 and nitro refers to -N02. "Dialkylamino" refers to -N (alkyl) 2. "Alkylarylamino" refers to - (alkyl) (aryl) and "diamino" refers to -N (aryl) 2. Halogen refers to -F, -Cl, -Br and -I. Aralkyl refers to -alkylene-aryl. Alkylthio refers to -S-alkyl and arylthio refers to -S-aryl. Alkoxycarbonyl refers to -CO-O-alkyl and aminocarbonyl refers to -CO-N (alkyl) 2 -CO-N (alkyl) (aryl) or -CO-N (aryl) 2. Acylamino refers to -N (alkyl) -CO-alkyl or (alkyl) -CO-aryl. A leaving group refers to a group or atom capable of existing in solution as a negatively charged species, or a positively charged group or atom. The compounds of the present invention interact with the potassium channels, and consequently act as openers or blockers of the potassium channels regulated by ATP-, which makes them useful in the treatment of various diseases of the cardiovascular system, for example, ischemia. cerebral, hypertension, ischemic heart disease, angina pectoris and coronary heart disease; the pulmonary system; the gastrointestinal system; the central nervous system and the endocrinological system. The compounds of the present invention can also be used for the treatment of diseases associated with decreased skeletal muscle blood flow, such as Reynauds disease and intermittent claudication. In addition, the compounds of the invention can be used for the treatment of chronic diseases of the airways, including asthma, and for the treatment of detrusor muscle instability secondary to obstruction by outflow of bladder and therefore for kidney stones, helping its passage along the ureter. The potassium channel openers also relax the smooth muscle of the urinary bladder, in this way, the compounds of the present invention can be used for the treatment of urinary incontinence. The compounds of the present invention may also be used for the treatment of conditions associated with disturbances in gastrointestinal mobility, such as irritable bowel syndrome. Additionally, these compounds can be used for the treatment of preterm labor and dysmenorrhea. In addition, potassium channel openers promote hair growth, therefore, the compounds of the present invention can be used for the treatment of baldness. In diseases such as nesidioblastosis and insulinoma, in which an insulin hypersecretion causes severe hypoglycemia, the compounds of the present invention can be used to reduce insulin secretion. In obesity it is very frequent to find hyperinsulinemia and insulin resistance. This condition could lead to the development of non-insulin-dependent diabetes (NIDDM). It is expected that the potassium channel openers and consequently the compounds of the present invention can be used to counteract the hyperinsulinemia, and therefore prevent diabetes and reduce obesity. In the treatment of reported NIDDM hyperinsulinemia with potassium channel openers, and consequently the compounds of the present invention, it may be beneficial to restore sensitivity to glucose and normal insulin secretions. In the initial cases of insulin-dependent diabetes (IDDM) or in problematic cases, the potassium channel openers, and consequently the compounds of the present invention, can be used to induce the rest of the beta cells, which can prevent the progress of autoimmune disease. The compounds of the present invention which act as blockers of the KATP_ channels can be used for the treatment of NIDDM. Preferably, the compounds of the present invention can be used for the treatment or prevention of diseases of the endocrinological system, such as hyperinsulinemia and diabetes. Accordingly, in another aspect, the invention relates to a compound of the general formula I or a pharmaceutically acceptable acid addition salt thereof for use as a therapeutically acceptable substance, preferably to be used as a therapeutically acceptable substance in the treatment of hyperinsulinemia and the treatment or prevention of diabetes. In addition, the invention also relates to the use of the compounds of the invention of formula I as useful medicaments for treating hyperinsulinemia and for I treat or prevent diabetes. In still another aspect, the present invention relates to methods for preparing the aforementioned compounds. The methods comprise the synthesis in solid and combined phase of organic compounds, more particularly, a therapeutically important class of compounds, namely, cyanoenamines, substituted in different ways, useful as potassium channel openers. The new synthetic sequence described in this invention gives access to a new class of cyanoenamines, useful as potassium channel openers. The following terms are intended to have the following general meanings: 1. Substrate: refers to any insoluble or partially insoluble material, to which the compounds can be covalently bound. The substrates can be selected from the group consisting of any type of organic or inorganic polymeric or oligomeric compounds, for example polystyrene with different degrees of crosslinking, polyethylene glycol (PEG), polyethylene glycol bonded to polystyrene (for example TentaGel), polyacrylamides, polyamides, polysaccharides or silicates. Optionally, a given portion of the substrate can be attached to a tag, i.e., a material or device which allows unambiguous identification of this portion of the substrate within a plurality of portions of the substrate. 2. Linker: a molecule with at least two reactive sites, which allow its covalent attachment to other molecules or a substrate. Either the binding of the binder to the substrate or the binding of the binder to the molecules bound thereto or the binder itself may be cleavable after selective exposure to an activator such as a selected chemical activator or other specific conditions, for example, by treatment with a strong acid or by exposure to electromagnetic radiation or by metal catalysis. 3. Arrangement: a collection of N simple compounds or N mixtures of compounds with a common structural element, synthesized simultaneously in parallel using the same synthetic reaction sequence. The precise structure of a single compound with an array of compounds or the components of a mixture within an array of mixtures is determined by the sequence of reagents that give rise to this compound or mixture and can inferred from the recorded reaction protocol. The spatial arrangement of the arrangement is irrelevant. 4. Cyanoenamine: Organic compound containing the structural element RR'N-CR "= CR" '-CN. 5. Protective group: A material which is chemically bound to a molecule or a substrate and which can be removed after selective exposure to an activator such as a selected chemical activator or other specific conditions, for example, by treatment with a strong acid or by exposure to electromagnetic radiation or by metal catalysis. 6. Combined synthesis: An ordered strategy of parallel synthesis of arrays of simple compounds or mixtures, by the sequential addition of reagents. 7. Abbreviations: The following frequently used abbreviations are intended to have the following meanings: AcOH: glacial acetic acid DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene DCM dichloromethane, methylene chloride DIC diisopropylcarbodiimide DMF N, N-dimethyl formamide EDC N-ethyl-N '- (3-dimethyl-aminopropyl) carbodiimide hydrochloride, "water-soluble carbodiimide" FMoc: fluorenylmethyloxycarbonyl NMP: N-Methylpyrrolidone R: organic radical TFA: trifluoroacetic acid THF: tetrahydrofuran. The method for the synthesis of therapeutically useful compounds is also provided by virtue of the present invention. The invention also provides a rapid method for the combined synthesis and selection of cyanoenamine derivative arrays as a therapeutically important class of compounds. The invention also provides a solid phase synthesis of cyanoenamines, which eliminates the steps of purification and isolation, and thus greatly increases the efficiency of the synthesis. The specification also describes an important extension of the methods of synthesis in solid phase to non-oligomeric organic compounds. A further understanding of the nature and advantages of the invention can be realized by reference to the remaining portions of the specification. The application of the present invention also includes the rapid preparation and selection, preferably in parallel and simultaneous form, of a large number of cyanoenamines substituted differently from the general formula I where Z, R1, R2 and R3 are as defined above or of general formula II II where Su is a substrate, L is a chemical bond or a linker, R1, R2 and R3 are as defined above. A total illustration of the solid phase synthesis of the cyanoenamines is shown in Reaction Scheme 1.

Scheme 1 I (trifluoroacetate) In this synthesis, the substrate Su can be any insoluble or partially insoluble material, to which the compounds can be covalently bound. Preferably, the substrate can be selected from the group consisting of polystyrene, polyethylene glycol (PEG), polyethylene glycol bonded to polystyrene (for example TentaGel), polyamides, polysaccharides and silicates. Depending on the type of substrate chosen, different types of solvents or protective groups can be used. The alcohol bound to the substrate 1 can be acylated with an appropriate cyanoacetic acid derivative of the general structure NC-CH2-COX, X being a leaving group, preferably with the symmetrical anhydride generated in si tu (Zaragoza, F. Tetrahedron Lett, 1995, 36, 8677-8678). Alternatively, other cyanoacetic acid derivatives generated or isolated therein may be used as acylating reagents, such as the derivatives of mixed anhydrides of alkyl chloroformates and cyanoacetic acid, or the imidazolide or other types of activated esters, such as N-hydroxybenzotriazolyl ester or N-hydroxysuccinyl ester or other activated esters, obvious to those skilled in the art. The esterification reaction can optionally be carried out in the presence of a catalyst, for example 4-dimethylaminopyridine, to give a derivative of the general formula. { substrate} -. { Binding } -0-CO-CH2-CN. The cyanoacetic acid derivative bound to the resulting resin 2 can then be treated with an excess of an aromatic or aliphatic isothiocyanate of the general structure R1-NCS in an appropriate solvent such as NMP, DMF or THF, in the presence of a base, preferably diisopropylethylamine or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). The resulting intermediate product 3 can then be treated with EDC and a primary or secondary aliphatic or aromatic amine of the general structure R2R3NH in a suitable solvent, such as NMP, DMF, acetonitrile, DCM, 1,2-dichloroethane, toluene, ethyl acetate, etc., preferably in DMF. Alternatively, other condensing agents (for example, benzotriazol-1-yl-oxy-tris- (dimethylamino) phosphonium hexafluorophosphate ("BOP"), carbonyldiimidazole, N-ethyl-N '- (3-trimethylammoniumpropyl) - can be used. carbodiimide, diisopropylcarbo-diimide, dicyclohexylcarbodiimide, etc.), alone or in the presence of a catalyst such as pyridinium tosylate or salts of tertiary amines. This reaction is closely related to a published procedure for the conversion of thioureas to cyanoguanidines (K.S.A., S. Z. Ahmed, B. C. O'Reilly, Tetrahedron Lett. 1989, 30, 7313-7316). Cleavage of the cyanoenamine binder bound to the substrate II can release the cyanoenamine derivative I to the solution. The cleavage conditions will depend on the type of substrate and binder chosen. For example, in the case of a polystyrene resin with a Wang binder or a Rink binder, the treatment of cyanoenamine bound to the support II with TFA or pure or mixtures of TFA / DCM can lead to cleavage of the binder. Therefore cyanoenamine I can turn out to be its tautomer of cyanoamidin-trifluoroacetate, which can tautomerize in a reversible in cyanoenamine when treated with bases or a buffer. Alternatively, additional chemical transformations can be carried out with the cyanoenamine II derivatives. These cyanoenamines II, which contain an NH group, can be acylated in the nitrogen by treatment with an excess of an activated carboxylic acid derivative or with an isocyanate or with an isothiocyanate with a sulfonyl chloride, to give the carboxamides, ureas, thioureas or corresponding sulfonamides, respectively. Each of these reactions can be effected by conventional means, readily apparent to those skilled in the art. Alternatively, additional chemical transformations can be carried out with the cyanoenamine I derivatives, which give high yields and pure crude products, so that no further purification of these derivatives will be required for their selection. For example, those cyanoenamine derivatives containing an NH group can be acylated in the nitrogen by treatment with an excess of an activated carboxylic acid derivative or with an isocyanate or with an isothiocyanate or with a sulfonyl chloride, to give the carboxamides, corresponding ureas, thioureas or sulfonamides, respectively. Each one of those Reactions can be carried out by conventional means, readily apparent to those skilled in the art. Using this synthetic method, arrangements of cyanoenamine derivatives II or I can be constructed with the aid of a device for solid phase synthesis in parallel. This can be any of the bolt method developed by Geysen et al (J. Immunol. Meth, 1987, 102, 259-274) or a device with several reactors for solid phase synthesis (containers with a permeable wall), which they allow the automated or manual addition of reagents and solvents, as well as the removal of solvents from the reactors through the simultaneous or individual application of a pressure difference between the inside and the outside of the permeable wall of the reactors. Such an arrangement can be prepared in a multiple organic synthesizer (for example "ACT 496" of "Advanced ChemTech") by reacting individually under the conditions specified below a cyanoacetylated substrate located in individual containers, with different isothiocyanates of the general structure R1- NCS in the presence of a base. The resulting intermediates 3 can then be reacted with different amines of the general structure R2R3NH in DMF in the presence of EDC to give an array of different cyanoenamine II derivatives. The Cleavage of the support will provide an array of the corresponding cyanoenamines I. The present invention also provides the synthesis of arrangements of mixtures of cyanoenamine derivatives. This can be achieved either by the "separate and mix" method (Sepetov, NF, Krchnák, V., Stankova, M., Wade, S., Lam, KS, and Lebl Proc. Na ti. Acad. Sci. USA 1995 , 92, 5426-5430) or using mixtures of the corresponding reagents. By virtue of the present invention, basically two different types of cyanoenamine I or II arrays can be constructed: completely combined arrangements (FCA) and non-combined combinations (NFCA). FCA refers to arrangements of substituted cyanoenamines, in which all possible combinations of a set of selected building blocks (R groups) are made. As an example, an FCA of N-cyanoenamines can be prepared by selecting n-isothiocyanates and m-amines, so that n x m = N, and synthesizing all possible combinations of isothiocyanate / amine. The selection of the building blocks can be made with respect to the properties expected of the members of the arrangement. NFCA refers to cyanoenamine arrangements, in which only a selection of all possible combinations of a set of blocks of selected construction. As an example, an NFCA of N-cyanoenamines can be prepared by first selecting n-isothiocyanates and m amines, so that n x m >; N. A selection of N cyanoenamines is then made for all theoretically possible n x m cyanoenamines by grouping all possible n x m cyanoenamines in N groups of cyanoenamines with similar expected properties and selecting from each of these groups a cyanoenamine, which is then synthesized. The selection of building blocks and cyanoenamines can be made with respect to the properties expected of the members of the arrangement. For the preparation of such arrangements of compounds, the exact positions of the substrate, per se, give no structural information about the compound prepared in this particular batch of the substrate. For this reason, the spatial arrangement of the substrate is irrelevant. The structural information will be accessible from the records of the reagent sequences added to each batch of the substrate. At each step of the preparation of an FCA or an NFCA, the exact location of a container with substrate is recorded within a container array and the structure of the different reagents added to this container, so that the precise structure can always be deduced. of the cyanoenamine resulting from a given container.

The resulting arrangements of cyanoenamines can then be selected by comparing individual cyanoenamines in terms of their ability to bind to a particular receptor or to induce a particular biological process or to catalyze a biochemical or chemical reaction. This can be achieved basically in two different ways. One possibility may be the selection of cyanoenamines bound to the substrate II, for example against a soluble receptor. This could be, for example, a peptide or radioactively labeled enzyme, which would easily allow to determine the binding strength of a cyanoenamine bound to the substrate II given to this peptide by washing the excess radioligand used and determining the remaining radioactivity of each cyanoenamine complex bound to the substrate II-peptide. Alternatively, as another example, the catalytic activity of the cyanoenamines bound to the substrate II different for a synthetic process or a given chemical reaction can be measured by comparing the rate at which this biological process or biochemical reaction takes place in the presence and absence of a cyanoenamine bound to the given substrate II. The second option for the selection may be to select the cyanoenamines I, after having cleaved the binder of the cyanoenamines bound to the substrate II and using microtiter plates loaded with suitably indexed from similar multiple well arrays, in solution against a receptor or enzyme attached to a substrate optionally. The selection of small soluble molecules is conventional and well known. Typically, radioassays are used, in which the competitive binding of the radioactively labeled natural ligand of a given receptor and a compound to be tested to determine the binding of this receptor is investigated. As an example, cyanoenamines can be selected for potassium channel opening activity. This can be achieved by first treating the rat aorta with 86Rb *, and then with the cyanoenamines I. The ratio of radioactive 86Rb * released to the solution and the remaining radioactivity in the tissue can be proportional to the opening activity of potassium channels of the cyanoenamine I tested. This type of assay has been described in the literature (see for example T. Nakajima, T. Iza a, T. Kashiwabara, S. Nakajima, Y. Munezuka, Chem. Pharm. Bull., 1994, 42, 2475-2490). Cyanoenamines like I can also be prepared in solution. The method used is outlined below: Acceptor-substituted acetonitriles were reacted with isothiocyanates in the presence of a base. The resulting thioamides were treated with primary or secondary amines in the presence of a desulfurizing agent, such as for example mercury (II) oxide or EDC, to give cyanoenamines as I. Unsubstituted cyanoacetamidines could be prepared from cyanoenamines I with Z = tert-butyloxycarbonyl by treatment with trifluoroacetic acid in dichloromethane. Hydrolyzing therefore the ester group, followed by the occurrence of decarboxylation, to give the corresponding cyanoacetamidine trifluoroacetates.

PREVIOUS TECHNIQUE It has been claimed that some derivatives of 2-cyano-3- (dimethylamino) -3-arylamino-2-propennitriles are antagonists of angiotensin II (EP 591891, Chem. Abstr. 1995, 122, 81364; Chem. Abstr. 1994, 121, 300890). Example: It has been claimed that other compounds that have this structural element with antithrombotic (EP 547517, Chem. Abstr. 1993, 119, 249845; Chem. Abstr. 1993, 119, 180666), for example: It has been claimed that several 3- (arylamino) -3- (alkylamino) -2-cyano-2-propennitriles and 2-acrylamides are fungicides and herbicides (EP 10396, Chem. Abstr 1982, 57, 140276; Chem. Abstr. 1980, 93, 144701), some examples are: The reaction of the amines RR'NH with mono-imidates of malononitrile of the general formula NC-CH2-C (OR) = NH gives the compounds of the type RR'NC (NH2) = CH-CN, where one of the two groups amino is limited to NH2 (Coceo, MT; Congiu, C; Maccioni, A .; Plumitallo, A., J. Heterocycl. Chem. , 1989, 26, 1859-1862; Klerrun, K.; Pruesse, W.; Baron, L .; Daltrozzo, E., Chem. Ber, 1981, 114, 2001-2018; Coceo, M. T .; Onnis, V., Synthesis, 1993, 2, 199-201; Fanshawe, W. J. et al., J. Org. Chem. , 1964, 29, 308-311; Troschuetz, R .; Dennstedt, T. Arch. Pharm. (Weinheim Germany), 1994, 327, 85-90). One more method consists of the reaction of O-alkylated cyanoacetamides with aliphatic amines (GJ Durant et al., Patent, CH 606026, Chem. Abstr, 1979, 90, 87449. GJ Durant, patent, US 4024260, Chem. Abstr, 1977, 87, 135327). Also the reaction of 3, 3-dimethoxyacrylonitrile with amines, which can be carried out in steps to prepare the compounds of the general formula RR'N- C (NR "R" ') = CH-CN, has been reported (G. J Durant, patent, US 4277485, Chem. Abstr., 1981, 95, 156591) and used for the preparation of ranitidine analogues. In addition, it has been reported that the reaction of 3,3-dichloroacrylonitrile with amines gives cyanoenamines of the general structure (RR'N) 2C = CH-CN, with two identical amine portions RR'N- (Hashimoto et al., J. Org. Chem., 1970, 35, 828-831, Takeda Chem. Ind. Ltd., JP 7022328, 1970, Chem. Abstr., 73, 98434z). In addition to those, some special methods have been described for the synthesis of these compounds (for example Sasaki, T., Kojima, AJ Chem. Soc. Sec. C, 1970, 476-80; Clark, J., Parvizi, B. , Southon, IW, J. Chem. Soc., Perkin Trans., 1, 1976, 125-130, Smith, Kline and French Lab. Lim, FR 2229417, DE 2423813, Chem. Abstr., 82, 170943; Meyer; K ., Justus Liebigs Ann. Chem., 1978, 1491; Elagamey, AGA; EI-Taeel, FMA, J. Prakt. Chem., 1991, 333, 333-338). Several different synthetic methods have been described for the preparation of 3, 3-bis (alkyl / arylamino) -2-propennitriles substituted with acceptor or receptor at position 2 (Elvidge, JA et al., J. Chem. Soc, Perkin Trans. I, 1983, 1741-1744, Yatsishin, AA, et al., Zh. Org. Khim 1979, 15, 1381-1384; Hartke, K., Angew, Chem. 1964, 76, 781).

References 1. Gallop, M. A .; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A .; Gordon, E. M. J. Med. Chem. 1994, 37, 1233-1251. 2. Gordon, E. M .; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A .; Gallop, M.A. J. Med. Chem. 1994, 37, 1385-1401. 3. Terrett, N. K.; Gardner, M.; Gordon, D. W .; Kobylecki, R. J.; Steele, J. Tetrahedron. 1995, 51, 8135-8173. 4. Lebl, M .; Krchnák, V .; Sepetov, N. F.; Kocis, P .; Patek, M .; Flegelova, Z .; Ferguson, R.; Lam, K. S. Journal Of Protein Chemistry. 1994, 13, 484-486. 5. Sepetov, N. F.; Krchnák, V .; Stankova, M.; Wade, S .; Lam, K. S .; Lebl, M. Proc. Na ti. Acad. Sci. USA 1995, 92, 5426-5430. 6. Liskamp, R. M. J. Angew. Chem. Int. Ed. Engl. 1994 ,. 33, 633-636. 7. Houghten, R. A .; Kay, B. K.; Madden, D .; Krchnák, V .; Lebl, M .; Chabala, J. C; Kauffman, S.

Perspectives in Drug Discovery and Design 1994, 2, 249-325. 8. Seligmann, B .; Abdul-Latif, F.; Al-Obeidi, F.; Flegelova, Z. European Journal of Medicinal Chemistry 1995, 30, 319-335. 9. Baldwin, J. J .; Burbaum, J. J.; Henderson, I .; Ohlmeyer, M. H. J. J. Am. Chem. Soc. 1995, 117, 5588-5589. 10. Jung et al., "Multiple Peptide Synthesis Methods and their Applications", Angew. Chem. Int. Ed. Engl. 1992, 31, 367-383. 11. J. A. Eliman, Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support, U.S. Patent 5,288,514; Feb. 22, 1994.

PHARMACOLOGICAL METHODS The ability of compounds to interact with potassium channels can be determined by several methods. When patching techniques are used (Hamill O.P., Marty A., Nefer E., Sakman B. and Sigworth F.J., Plügers Arch. 1981, 391, 85-100) the ionic current can be recorded through a single channel. The activity of the compounds as potassium channel openers can also be measured as the relaxation of the rat aortic rings according to the following procedure: A section of rat thoracic aorta was dissected between the aortic arch and the diaphragm and mounted as • ring preparations as described by Taylor PD et al. , Brit. J. Pharmacol. , 1994, 111, 42-48.

After an equilibrium period of 45 minutes under a tension of 2 g, the preparations were contracted to achieve 80% of the maximum response using the required concentration of phenylephrine. When the response to phenylephrine reached a constant level, potential vasodilatory agents were cumulatively added to the bath in small volumes using semilogarithmic molar increments at 2 minute intervals. Relaxation was expressed as the percentage of tension contracted. The potency of the compound was expressed as the concentration required to evoke a 50% relaxation of the tissue. In pancreatic b cells the opening of KATP-channels can be determined by measuring the subsequent change to free cytoplasmic Ca2 + concentration according to the method of Arkhammer P. et al., J. Biol. Chem. 1987, 262, 5448-5454.

Efflu of 86Rb'1 'of a cell line ß The RIN 5F cell line was grown in RPMI 1640 with Glutamax I, supplemented with 10% fetal sheep serum (from GibcoBRL, Scotland, UK) and kept in an atmosphere of 5% C02 / 95% air at 37 ° C. The cells were detached with a solution of Trypsin-EDTA (from GibcoBRL, Scotland, UK), resuspended in medium, adding 1 Ci / mL 86Rb + and growing again in microtiter plates (3596 96-well, sterile pools, from Costar Corporation, MA, USA) at a density of 50000 cells / well in 100 μl / well, and growing 24 hours before being used in the trial. The plates were washed 4 times with a Ringer buffer (150 mM NaCl, 10 mM Hepes, 3.0 mM KC1, 1.0 mM CaCl2, 20 mM sucrose, pH 7.1). Eighty μl of Ringer's buffer and 1 μL of control or test compound dissolved in DMSO were added. After 1 hour of incubation at room temperature with a lid, 50 μL of the supernatant was transferred to PicoPlates plates (Packard Instrument Company, CT, USA) and 100 μL MicroScint 40 (Packard Instrument Company, CT, USA) was added. Plates were counted in a TopCount (Packard Instrument Company, CT, USA) for 1 min / well in the program for 32P. The calculation of the EC50 and the Emax was carried out by SlideWrite (Advanced Graphics Software, Inc., CA. USA) using a logistic curve with four parameters: y = (ad) / (1+ (x / c) b) + d , where a = the estimated activation at the zero concentration, b = a slope or slope factor, c = concentration at the middle of the curve and d = the activity estimated at infinite concentration. CE5o = c and Emax = d, when the curve turns into infinite concentrations. The compounds according to the invention are effective over a wide range of doses. In general satisfactory results are obtained with doses of about 0.05 mg to about 1000 mg, preferably about 0.1 mg to about 500 mg, per day. A more preferable dose is from about 5 mg to about 200 mg per day. The exact dose will depend on the mode of administration, the manner in which it is administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the attending physician or veterinarian. The route of administration can be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral, for example, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal, with the oral route being preferred . Typical compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which can be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier. which can be in the form of a capsule, sachet, paper or other container. In the manufacture of the compositions, conventional techniques for the preparation of the pharmaceutical compositions can be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a vial, capsule, sachet, paper or other container. When the carrier serves as a diluent, it can be a solid, semi-solid or liquid material that acts as a carrier, excipient or medium for the active compound. The active compound can be absorbed onto a solid granular container, for example in a pouch. Examples of suitable carriers are water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, monoglycerides and diglycerides of fatty acid, fatty acid esters of pentaerythritol , hydroxymethylcellulose and polyvinylpyrrolidone. The formulations may also include wetting agents, emulsifying and suspending agents, preservatives, sweetening agents or flavoring agents. The formulations of the invention can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient employing procedures well known in the art.

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salts for influencing the osmotic pressure, buffers and / or coloring substances and the like, which do not react in a harmful manner with the active compounds. For parenteral application, injectable solutions or suspensions are particularly suitable, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil. Tablets, dragees or capsules having talc and / or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferred carriers for tablets, dragees or capsules include lactose, corn starch, and / or potato starch. A syrup or elixir may be used in cases where a sweetened vehicle may be employed. A typical tablet, suitable for use in this method, can be prepared by conventional tablet production techniques and contains: Active Compound 5.0 mg Lactose 67.8 mg Farm.Eur Avicel® 31.4 mg Amberlite® 1.0 mg Magnesium stearate 0.25 mg Farm.Eur.

Due to the high degree of activity, the compounds of the invention can be administered to a mammal, especially a human, in need of such treatment, prevention, elimination, alleviation or reduction of various diseases as mentioned above and especially diseases of the endocrinological system such as hyperinsulinemia and diabetes. Such mammals also include animals, both domestic animals, for example domestic pets and non-domestic animals such as wild animals.

EXAMPLES Example 1. Synthesis of trifluoroacetate of N- (4-methoxybenzyl) -N'-f-enylciazole.ee tamidine To a suspension of Wang resin (20.0 g, 19.2 mmol, Novabiochem, loading: 0.96 mmol / g) in DCM (100 mL) cyanoacetic acid (30.0 g, 353 mmol) and DMF (100 mL) were added. While stirring, DIC was added in part (25 mL), so an exothermic reaction took place. When the addition of DIC was completed, 4-dimethylaminopyridine (10 mL of a 1M solution of DMF) was added, and the resulting mixture was stirred at room temperature for 15 h. The mixture was filtered then and the resin was thoroughly washed with DMF, DCM and methanol. After drying, about 20 g of Wang-0-CO-CH2-CN resin was obtained. To this resin (0.30 g, approximately 0.3 mmol, swollen in DCM) were added DMF (4 mL), diisopropylethylamine (0.8 mL) and phenylisothiocyanate (0.54 mL, 4.5 mmol). The resulting mixture was stirred for 16 h, filtered, washed with DMF (3 x 6 L) and then a mixture of EDC (0.95 g, 4.95 mmol), DMF (5 mL) and 4-methoxybenzylamine (0.40 mL, 3.03 mmol). The mixture was stirred for 24 h, filtered, and the resin was carefully washed with DMF, methanol, DCM and 10% AcOH in DCM. It was then suspended in DCM (3 mL) and TFA (2 mL) and stirred for 35 minutes. Tetrachlorocarbon (5 mL) was added, after filtration and washing with DCM the filtrates were concentrated. Thus, 84 mg (71%) of N- (4-methoxybenzyl) -N'-phenylcyanoacetamidine trifluoroacetate was obtained as an oil, which crystallized slowly at room temperature within 48 h. Recrystallization (ethyl acetate / methanol / heptane) yielded 22 mg of the title compound as uncolored crystals, mp 161-163 ° C. LCMS (Lichrosorb RP 18, acetonitrile / water gradient, verified at 214 nm): elution at 7.2 minutes; MH + calculated: 280, found: 280. X H NMR (300 MHz, CDCl 3 / DMSO-d 6 1: 1) d 3.82 (s, broad, 3H), 3.89 (s, broad, 2H, interchangeable with D20), 4.60 (s, broad, 2H), 6.95 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.30-7.55 (m, 5H), 10.25 (s, broad, 1H); 13 C NMR (75 MHz, DMSO-d 5 d 20.26 (t), 46.17 (t), 55.10 (c), 113.98 (d), 125.66 (d), 126.71 (d), 127.62 (d), 129.19 (d), 137.50 (s, broad), 154.36 (s, broad), 159.29 (s) Analysis Calculated for C? 9H18F3 3? 3 (393.36): C, 58.01; H, 4.61; N, 10.68. Found: C, 57.98; H, 4.68; N, 10.47.

Example 2. Synthesis of 2-cyano-3- (3-methylbutylamino) -3- (enylamino) -2-propennitxyl To a solution of malononitrile (0.34 g, 5.15 mmol) in DMF (5 mL) at 0 ° C was added first phenylisothiocyanate (0.60 mL, 5.02 mmol) and then triethylamine (1.4 mL). The resulting mixture was stirred at 0 ° C for 25 minutes, and then a fresh EDC mixture was added. (2.90 g, 15.1 mmol), 3-methylbutylamine (1.20 mL, 10.3 mmol) and DMF (10 mL). After stirring at room temperature during 2 days the mixture was poured into a mixture of ice water (50 mL) and concentrated HCl (3.0 mL). The product was extracted (2 x 30 mL of ethyl acetate), the combined organic extracts were washed (2 x 30 mL of brine), dried (magnesium sulfate) and concentrates. The remaining oil was mixed with methanol (3 mL), whereby a solid precipitated.

After 20 hours the solid was filtered and dried in vacuo. 0.60 g was obtained. (47%) of the title compound as light yellow crystals. Recrystallization from ethyl acetate / heptane yielded 0.40 g of an analytically pure mixture, mp 183-185 ° C. ^ LCMS: MH + calculated: 255, found: 255. _. NMR (400 MHz, DMSO-e): d = 0.83 (d, J = 7 Hz, 6H), 1.40 (c, J = 1 Hz, 2H), 1.57 (nonett, J = 7 Hz, 1H), 3.18 ( m, 2H), 7.10 (m, 3H), 7.33 (t, J = 8 Hz, 2H), 7.87 (s, broad, 1H), 9.33 (s, 1H); 13 C NMR (100 MHz, DMSO-de,): d = 22.06, 24.90, 35.34, 37.38, 41.92, 118.11, 121.46, 124.16, 129.15, 138.81, 161.43. Analysis calculated for C15H? 8N4 (254.34): C, 70.84; H, 7.13; N, 22.03. Found: C, 70.88; H, 7.28; N, 21.90.

Example 3. Synthesis of 3- [3,5-bis (trifluoromethyl) phenylamino] -2-cyano-3- (3-methylbutylamino) acrylic acid terbutyl ester To a solution of 2- butyl terbutyl ester. { N- [3,5-bis (trifluoromethyl) phenyl) thiocarbamoyl} cyanoacetic (1.12 g, 2.7 mmol, prepared from tert-butyl acid of cyanoacetic acid and 3,5-bis (trifluoromethyl) phenylisocyanate) in DCM (15 mL) were added 3-methylbutylamine (1.0 mL, 8.60 mmol), magnesium sulfate (0.5 g) and mercury oxide (II) (2.0 g). The resulting mixture was stirred to room temperature for 14 hours, diluted with DCM (30 mL), filtered over celite, washed with hydrochloric acid diluted cold with ice, with brine (2 x 20 mL), dried (magnesium sulfate) and concentrated. The residue was crystallized from heptane. 0.29 g (23%) of the title compound were obtained as colorless crystals, mp 128-129 ° C. Of the mother liquor, 0.25 g (20%) of additional products were obtained. XH NMR (400 MHz, DMSO-de): d = 0.82 (d J = 7 Hz, 6H), 1.41 (s, 9H), 1.43 (c, J = 7 Hz, 2H), 1.57 (nonett, J = 7 Hz, 1H), 3.18 (c, broad, J = 7 Hz, 2H), 7.63 (s, 2H), 7.70 (s, 1H), 8.91 (s, broad, 1H), 9.52 (s, 1H); 13 C NMR (100 MHz, DMSO-de): d = 21.96, 24.95, 28.02, 37.50, 41.84, 61.55, 79.66, 115.53, 118.67, 119.87, 123.05 (c, J = 282 Hz), 130.44 (c, J = 33 Hz), 142, 11, 160.46, 167.93. Analysis calculated for C2? H25F6N3? 2 (465.44): C, 54.19; H, 5.41; N, 9.03. Found: C, 54.27; H, 5.57; N, 8.84.

Example 4. Synthesis of 3- [3,5-bis (trifluoromethyl) phenylamino] -3- (3-methylbutylamino) -2-propenenitrile To a solution of 3- [3,5-bis (trifluoromethyl) phenylamino] terbutyl ester ] -2-cyano-3- (3-methylbutyl-amino) acrylic (194 mg, 0.417 mmol) in DCM (2 mL) was added trifluoroacetic acid (2 mL). After 30 minutes at room temperature the solution was concentrated, the residue It was redissolved in carbon tetrachloride (10 mL) and reconcentrated. The product was purified by flash chromatography (6 g of silica gel, gradient of heptane / ethyl acetate). 45 mg (30%) of the title compound was obtained as an oil. LCMS: MH + = 366. This compound was identical by LCMS to the product obtained from the solid phase synthesis.

Example 5. Synthesis of 3- [3,5-bis (trifluoromethyl) phenylamino] -2-cyano-3- (3-methylbutylamino) -2-propenenitrile To a solution of malononitrile (0.33 91 5.00 mmol) in DCM at 0 ° C was added first 3, 5-bis (trifluoromethyl) phenylisothiocyanate (1.41 g, 5.20 mmol) and then triethylamine (1.0 mL). The mixture was stirred at room temperature for 1 hour and 45 minutes and then DCM (5 L), 3-methylbutylamine (1.0 mL, 8.60 mmol), magnesium sulfate (0.57 g) and mercury (II) oxide were added ( 2.54 g, 11.7 mmol). The resulting mixture was stirred at room temperature for 17 hours, so it turned black. This mixture was then filtered (Celite), diluted with DCM (60 mL), washed with a mixture of cold water with ice (100 mL) and concentrated HCl (2.0 mL), with brine (3 x 50 mL), dried ( magnesium sulfate) and concentrated. The residue was purified by column chromatography (50 g of silica gel, heptane / acetate gradient of ethyl), to give 1.22 g (63%) of the title compound as a foam. This foam could be crystallized from toluene / heptane, yielding 1.08 g of almost colorless crystals, mp. 158-159 ° C. X H NMR (300 MHz, DMSO-d 5): d = 0.87 (d, J = 1 Hz, 6H), 1.45 (c, J = 1 Hz, 2H), 1.60 (nonett, J = 1 Hz, 1H), 3.31 (m, 2H), 7.72 (s, 2H), 7.78 (s, 1H), 8.22 (s, broad, 1H), 9.79 (s, 1H); 13 C NMR (75 MHz, DMSO-d 6): d = 22.04, 24.99, 36.85, 37.14, 59.66, 116.52, 117.52, 121.21, 123.02 (c, J = 275 Hz), 131.02 (c, J = 33 Hz), 141 , 35, 161.27. Analysis calculated for C? 7H16F6N4 (390.33): C 52.31; H, 4.13; N, 14.35. Found: C, 52.80; H, 4.29; N, 13.83.

Example 6. Synthesis of 3- [3,5-bis (trifluoromethyl) phenylamino] -3- (3-methyltbutylamino) -2- (4-chlorophenylsulfonyl) -2-propen-nitrile To a solution of 3, 5 bis (trifluoromethyl) -phenylisothiocyanate (1.44 9, 5.31 mmol) in DCM (15 mL) and acetonitrile (5 mL) was first added 4-chlorophenylsulfonylacetonitrile (1.10 g, 5.10 mmol) and then triethylamine (1.0 mL). The resulting mixture was stirred at room temperature for 2 hours and 15 minutes, and then isoamylamine (0.65 mL, 5.59 mmol), mercury (II) oxide (2.70 g, 12.47 mmol) and magnesium sulfate (0.8 g) were added. Stirring was continued for 2 days. TO Then the mixture was filtered, poured into a mixture of ice water (200 mL) and concentrated hydrochloric acid (2 L), the phases were separated, the aqueous layer was extracted twice with DCM (20 mL) and the combined extracts dried (magnesium sulfate) and concentrated. Column chromatography of the residue (100 g of silica gel, gradient elution with heptane / ethyl acetate 10: 0 to 3: 1) gives 317 mg (12%) of the title compound as an oil. XH NMR (300 MHz, DMS0-de): d = 0.79 (d, J = 1 Hz, 6H), 1.39 (c, J = 1 Hz, 2H), 1.50 (nonett, J = 7 Hz, 1H), 3.31 (m, 2H ), 7.27 (s, 2H), 7.67-7.80 (m, 5H), 8.13 (s, broad, 1H), 9.76 (s, 1H); LCMS: elution at 16.23 minutes, MH +: 540.

Example 7. Synthesis of 3- [3,5-bis (trifluoromethyl) phenylamino] -2-cyano-3- [3- (2-oxoacepan-1-yl) propylamino] acrylic acid terbutyl ester To a mixture of 3, 5-bis (trifluoromethyl) phenylisothiocyanate (2.83 g, 10.4 mmol), DCM (20 mL) and tert-butyl cyanoacetate (1.65 mL, 11.6 mmol) were added DBU (4.0 mL, 26.8 mmol), resulting in an exothermic reaction. The resulting mixture was stirred at room temperature for 2 hours, and then magnesium sulfate (2.0 g), isoamylamine (2.35 mL) and mercury (II) oxide (6.80 g, 31.4 mmol) were added. After shaking for 25 hours, the mixture was mixed with celite, filtered, and the filtrate was mixed with 0.5 M hydrochloric acid. After an additional filtration the filtrate was extracted (3 x 100 mL of DCM), the combined extracts were washed with brine (2 x 300 mL, strongly emulsified), dried (magnesium sulfate) and concentrated. Column chromatography (80 g of silica gel, gradient elution with heptane / ethyl acetate 10: 0 to 2: 3) gives 2.23 g (39%) of the title compound as a colorless solid, together with 0.72 g (15%) of 3- [3,5-bis (trifluoromethyl) phenylamino] -2-cyano-3- (3-methylbutylamino) acrylic acid terbutyl ester. A mixture of the title compound was further purified by recrystallization. Colorless solid, mp 167-168 ° C (ethyl acetate). LCMS: elution at 15.4 minutes, MH +: 549; X H NMR (400 MHz, DMSO-d): d = 1.40 (s, 9 H), 1.43 (m, 4 H), 1.57 (m, 2 H), 1.71 (c, J = 1 Hz, 2 H), 2.35 (m , 2H), 3.20 (c, J = 1 Hz, 2H), 3.31 (m, 2H), 7.66 (s, 2H), 7.68 (s, 1H), 8. 95 (s, broad, 1H), 9.52 (s, 1H), 13C NMR (100 MHz, DMSO-d6): d = 22.93, 27.93, 28.11, 28.32, 29.23, 36.44, 41.55, 44.47, 48.38, 61.93, 79.66 , 115.36, 118.75, 119.89, 123.18 (c, _7 = 275 Hz), 131.02 (c, J = 33 Hz), 142.33, 160.59, 167.95, 174.74. Analysis calculated for C25H3oF6N4? 3 (548.53). C, 54.74; H, 5.51 N, 10.21. Found: C, 54.62; H, 5.66; N, 9.97.

EXAMPLE 8. Synthesis of 3- [3,5-bis (trifluoromethyl) phenylamino] -3- [3- (2-oxoacepan-1-yl) propylamide o) acrylonitrile To a solution of 3- [3, 5-bis (trifluoromethyl) phenylamino] -2-cyano-3- [3- (2-oxo-acepan-1-yl) propylamino] acrylic (203 mg, 0.37 mmol) in DCM (6.0 mL) at 0 ° C TFA (6.0 mL) was added. The resulting mixture was stirred at 0 ° C for 30 minutes and then poured into an aqueous solution saturated with NaHCO3, cooled on ice (100 mL). After dilution with DCM (30 mL), the phases were separated, the aqueous layer was extracted (3 x 20 mL of DCM), the combined extracts were washed with brine (2 x 50 mL), dried (magnesium sulfate). and concentrated to give 190 mg (100%) of the title compound as an oil (mixture of isomers). LCMS: elution at 9.97 minutes, MH +: 449). XH NMR (300 MHz, DMSO-ds): d = 1.45-1.80 (m, 8H), 2.40 (m, 2H), 2.95 (m, 1H), 3.21 (m, 2H), 3.35 (m, 6H), 3.58 ( s, broad, 1H), 7.35-7.70 (m, 3H).

Example 9. Synthesis of 2-cyano-3- (4-methoxybenzylamino) -3- (phenylamino) acrylic acid terbutyl ester To a solution of tert-butyl cyanoacetate (1.3 mL, 9.12 mmol) in DMF (10 mL) at 0 ° First, phenylisothiocyanate (1.2 mL, 10.0 mmol) and then triethylamine (2.80 mL) were added. The resulting mixture was stirred to 0 ° C for 30 minutes and then at room temperature for 30 minutes. The mixture was then cooled to 0 ° C and EDC (5.77 g, 30.1 mmol), DMF (30 mL) and 4-methoxybenzylamine (2.65 mL, 20.3 mmol) were added. After stirring for 9 hours at room temperature, for 14 hours at 60 ° C and then for 2 days at room temperature, the mixture was poured onto ice (150 ml) and concentrated HCl (4 L). Extraction (3 x 30 mL of ethyl acetate), drying of the combined extracts (magnesium sulfate) and concentration yielded an oil, which was purified by column chromatography (50 g of silica gel, gradient elution with heptane / ethyl acetate 1: 0 to 1: 4). Obtained 0.43 g (12%) of the title compound as a colorless solid, mp 158-159 ° C (ethyl acetate / heptane). 1 HOUR NMR (400 MHz, DMSO-d6): d = 1.39 (s, 9H), 3.72 (s, 3H), 4.22 (s, broad, 2H), 6.89 (d, J = 8 Hz, 2H), 7.02-7.16 (m, 5H), 7.32 (m, 2H), 8.95 (s, broad, 0.5H), 9.18 (s, 0.5H). Analysis calculated for C 22 H 25 N 303 (379.46): C, 69.64; H, 6.64; N, 11.07. Found: C. 69.51; H, 6.80; N, 10.89.

Example 10. Automated synthesis of an array of eighty different cyanoenamines An array of eighty different cyanoenamines has been prepared as follows: in eighty reactors of multiple organic synthesizers "ACT 496" of "Advanced ChemTech" were equally distributed 100 mg of cyanoacetic acid bound to Wang resin (prepared as described in example 1). Then each of the eighty reactors was treated as described in Example 1 with one of eight different aromatic isothiocyanates, namely 4-trifluoromethylphenylisothiocyanate, 2-trifluoromethylphenylisothiocyanate, 2,3-dichlorophenylisothiocyanate, 3-chloro-4-fluorophenylisothiocyanate , 2-methoxy-4-nitrophenyliso-thiocyanate, 2,4-difluorophenylisothiocyanate, 4-cyanophenyliso-thiocyanate and 3,5-bis (trifluoromethyl) phenylisothiocyanate. The resulting thioamides were then treated with ten different primary amines, namely with 2-methylpropylamine, 1,2-dimethylpropylamine, isopropylamine, 1,3-dimethylbutylamine, 2,2-dimethylpropylamine, butylamine, 4-tert-butylcyclohexylamine, 1 , 2, 2-trimethylpropylamine, exo-2-norbornylamine and cyclohexylmethylamine in such a manner that all possible isothiocyanato-amine combinations were obtained. After intensive washing, the cyanoenamines bound to the resulting resin were cleaved from the substrate by treatment with 50% TFA in DCM (30 minutes), yielding an array of eighty different cyanoenamines with purities of 70->. 90% (CLAP (High Pressure Chromatography)). The samples were redissolved several times in methanol and concentrated again to remove traces of TFA Finally, the samples were dissolved in methanol (2 L) and triethylamine (0.05 mL), again concentrated and redissolved in DMSO (3.5 mL). The resulting solutions were used for the selection. Following the procedure given above, the following cyanoenamine derivatives have been prepared: MH + No expected R1 _____? 4- (trifluoromethyl) -2- (methylpropyl) amino phenyl 4- (trifluoromethyl) - (1,2-dimethylpropyl) • -phenyl amino 3- 4- (trifluoromethyl) -isopropylamino phenyl 4- (trifluoromethyl) (1,3-dimethylbutyl) -phenyl amino 4- (trifluoromethyl) - (2,2-dimethylpropyl) • phenyl amino MH * R1 -NR2R3 expected - sontra or 4- (trifluoromethyl) butylamino phenyl 4- (trifluoromethyl) (4-tert-butylcyclo-366 366 phenyl hexyl) amino 4- (trifluoromethyl) • (1,2,2-trimethyl-phenyl propyl) amino 4- (trifluoromethyl) -2-exo-norbornylamino phenyl 4- (trifluoromethyl) • (cyclohexylmethyl) amino phenyl 2- . { trifluoromethyl) -2- (methylpropyl) amino phenyl 2- (trifluoromethyl) (1,2-dimethylpropyl) -phenyl amino 2- (trifluoxomethyl) -isopropylamino phenyl 2- (trifluoromethyl) '(1,3-dimethylbutyl) -phenyl amino 2- (trifluoromethyl) - (2,2-dimethylpropyl) -phenyl amino MH * R1 -NR2R3 expected encentrado 2- (trifluoromethyl) 'butylamino 284 284 phenyl 2- (trifluoromethyl) - (4-tert-butylcyclohexyl hexyl) amino 2- (trifluoromethyl) - (1, 2,2-trimethylphenyl) propyl) amino 2- (trifluoromethyl) '2-exo-norbornylamino phenyl 2- (trifluoromethyl) '(cyclohexylmethyl) amino phenyl 2, 3-dichlorophenyl 2- (methylpropyl) amino 2,3-dichlorophenyl (1,2-dimethylpropyl) -amino -2, 3-dichlorophenyl isopropylamino 2, 3-dichlorophenyl (1,3-dimethylbutyl) - 2, 3-dichlorophenyl (2,2-dimethylpropyl) • 298 298 amino 2, 3-dichlorophenyl butylamino MH * No R1 -NR2R3 expected encentrado 27 2, 3-dichlorophenyl (4-tert-butylcyclohexyl) amino 28 2, 3-dichlorophenyl (1,2,2-trimethyl-propyl) amino 29 2, 3-dichlorophenyl 2-exo-norbornylamino 2, 3-dichlorophenyl (cyclohexylmethyl) amino 31 2-methoxy-4-nitrophenyl 2- (methylpropyl) amino 291 291 32 2-methoxy-4-nitrophenyl (1,2-dimethylpropyl) -amino 33 2-methoxy-4-nitrophenyl isopropylamino 34 2-methoxy-4-nitrophenyl (1,3-dimethylbutyl) -amino 2-methoxy-4-nitrophenyl (2,2-dimethylpropyl) • amino 36 2-methoxy-4-nitrophenyl butylamino 37 2-methoxy-4-nitrophenyl (4-tert-butylcyclohexyl) amino 38 2-methoxy-4-nitrophenyl (1,2,2-trimethylpropyl) amino MH * R1 -NR2R3 expected found 2-methoxy-4-nitrophenyl 2-exo-norbornylamino 2-methoxy-4-nitrophenyl (cyclohexylmethyl) amino 331 331 2,4-difluorophenyl 2- (methylpropyl) amino 2, -difluorophenyl (1,2-dimethylpropyl) - 266 266 amino 2,4-difluorophenyl isopropylamino 2,4-difluorophenyl (1,3-dimethylbutyl) • amino 2, -difluorophenyl (2, 2-dimethylpro? Il) amino 2, 4-difluorophenyl butylamino 2,4-difluorophenyl (4-tert-butylcyclohexyl) amino 2,4-difluorophenyl (1,2,2-trimethyl-propyl) amino 2,4-difluorophenyl 2-exo-norbornylamino 2,4-difluorophenyl (cyclohexylmethyl) amino 3-chloro-4-fluorophenyl 2- (methylpropyl) amino MH + No R1 -NR2R3 expected found 52 3-chloro-4-fluorophenyl (1,2-dimethylpropyl) - 282 282 amino 53 3-chloro-4-fluorophenyl isopropylamino 54 3-chloro-4-fluorophenyl (1,3-dimethylbutyl) -amino 55 3-chloro-4-fluorophenyl (2,2-dimethylpropyl) -amino 56 3-chloro-4-fluorophenyl butylamino 57 3-chloro-4-fluorophenyl (4-tert-butylcyclo-350 350 hexyl) amino 58 3-chloro-4-fluorophenyl (1,2, 2-trimethyl-propyl) amino 59 3-chloro-4-fluorophenyl 2-exo-norbornylamino 60 3-chloro-4-fluorophenyl (cyclohexylmethyl) amino 61 4-cyanophenyl 2-. { methylpropyl) amino 62 4-cyanophenyl (1 / 2- 255 255 di ethylpropyl) amino 63 4-cyanophenyl isopropylamino MH + R1 -NR2R3 expected _-__ cn_rs__o 4-cyanophenyl (1,3-dimethylbutyl) -amino 4-cyanophenyl (2,2-dimethylpro? Il) -amino 4-cyanophenyl butylamino 4-cyanophenyl (4- tert -butylcyclohexyl) amino 4-cyanophenyl (1,2,2-trimethyl-propyl) amino 4-cyanophenyl 2-exo-norbornylamino 4-cyanophenyl (cyclohexylmethyl) amino 3, 5-bis (trifluoro2-. {Methylpropyl) amino 352 352 methyl) phenyl 3, 5-bis (trifluoro (1,2-dimethylpropyl) -methyl) phenyl amino 3, 5-bis (trifluoroisopropylamino 338 338 methyl) phenyl 3, 5-bis (trifluoro (1,3-dimethylbutyl) • 380 380 methyl) phenyl amino MH + No R1 - R2R3 expected ____ e_? Trado 75 3, 5-bis. { trifluoro (2,2-dimethylpro? il) - 366 366 methyl) phenyl amino 76 3, 5-bis (trifluorobutylamino methyl) phenyl 77 3, 5-bis (trifluoro (4-tert-butylcyclo-434 434 methyl) phenyl hexyl) amino 78 3, 5-bis (trifluoro (1,2,2-trimethyl-methyl) phenyl-propyl) amino 79 3, 5-bis (trifluoro-2-exo-norbornylamino 390 390 methyl) phenyl 80 3, 5-bis (trifluoro (cyclohexylmethyl) amino methyl) phenyl 81 phenyl (4-methoxybenzyl) amino 280 280 82 • 3-fluorophenyl propylamino 220 220 83 3-fluorophenyl hexylamino 262 262 84 3-fluorophenyl propargylamino 216 216 85 3-fluorophenyl (3-methylbutyl) amino 248 248 86 3-pyridyl propylamino 203 203 87 3-hexylamino pyridyl 245 245 MH + No R1 -ItTtr expected 88 3-pyridyl propargylamine 199 199 89 3-pyridyl (3-methylbutyl) amino 231 231 90 3, 4-dichlorophenyl propylamino 271 271 91 3, 4-dichlorophenyl-hexylamino 313 313 92 3, 4-dichlorophenyl propargylamino 267 267 93 3, 4-dichlorophenyl (3-methylbutyl) amino 299 299 94 3, 5-bis (trifluoropropylamino 338 338 methyl) phenyl 95 3, 5-bis (trifluorohexylamino 380 380 methyl) phenyl 96 3, 5-bis (trifluoropropargylamino 334 334 methyl) phenyl 97 3, 5-bis (trifluoro (3-methylbutyl) amino 366 366 methyl) phenyl 98 phenylamino 236 phenyl 236 9 benzyl (4-methoxybenzyl) amino 294 294 00 phenyl 1-pyrrolidinyl 214 214 MH + No R1 -NR2R3 expected found 101 3- (trifluoromethyl) (3-methylbutyl) amino 297 297 phenyl 102 4-chloro-3- (trifluoro- (3-methylbutyl) amino 331 331 methyl) phenyl 103 3-Acetylphenyl (3-methylbutyl) amino 271 271 104 2-chloro-5- (trifluoro- (3-methylbutyl) amino 331 331 methyl) phenyl 105 3-dicyanophenyl (3-methylbutyl) amino 279 279 106 4-bromo-2- (trifluoro (3-methylbutyl) amino 376 376 methyl) phenyl 107 4,6-dimethyl-2- (3-methylbutyl) amino 259 259 pyrimidinyl 108 4-Acetylphenyl (3-methylbutyl) amino 271 271 109 3, 5-dichlorophenyl [3-methylbutyl) amino 298 298 110 3-chloro-4-methylphenyl (3-methylbutyl) amino 277 277 111 2, 5-bis (trifluoro (3-methylbutyl) amino 366 366 methyl) phenyl 112 3, 5-dichlorophenyl (2-methylpropyl) amino 284 284 113 3-chloro-4-methylphenyl (2-methylpropyl) amino 263 263 MH * No R1 -NR 2"t _-. 3 expected enomil- 114 2, 5-bis (trifluoro (2-methylpropyl) amino 351 351 methyl) phenyl 115 3, 5-bis (trifluoro (3-phenylpropyl) amino 413 413 methyl) phenyl 116 3, 5-bis (trifluoro (2,2,6,6-tetramethyl-4,443,443 methyl) phenyl piperidinyl) amino 117 3, 5-bis (trifluoroN, N-dipropylamino 379 379 methyl) phenyl 118 3, 5-bis (trifluoro2- (4-chlorophenyl) - 433 433 methyl) phenyl ethylamino 119 3, 5-bis (trifluoro2- (2-pyridyl) ethylamino 400 methyl) phenyl 120 3,5-bis (trifluoro-4-methyl-l-piperidyl 377 377 methyl ') phenyl 21 3,5-bis (trifluoro- N, N-bis (2-methyl- 407 407 methyl) phenyl propyl) amino 22 3, 5-bis (trifluoro-1-pyrrolidinyl 349 349 methyl) phenyl 23 3, 5-bis (trifluoro3- (1-imidazolyl) - 403 403 methyl) phenyl propylamino MH + No -NRT 2t.3 expected found 124 3, 5-bis (trifluoroN-methyl-N- (3-pyridyl) • 400 400 methyl) methylamino phenyl 125 3, 5-bis (trifluoro (3-amino-2, 2-dimethyl-380 380 methyl) phenyl propyl) amino 126 3, 5-bis (trifluoro3- (2-oxo-1-pyrrolidinyl) - 420 420 methyl) phenyl propylamino 127 3, 5-bis (trifluoro (4-methoxybenzyl) amino 415 415 methyl) phenyl 128 3, 5-bis (trifluoro-3-hydroxy-l-379 methyl) phenyl piperidinyl 129 3, 5-bis (trifluorotetrahydroisoquinolin-411 411 methyl) phenyl 1-yl 130 3, 5-bis (trifluoro-2, 6-cis-dimethyl-4-393-393 methyl) phenyl morpholinyl 131 3, 5-bis (trifluoro4 - [(3-trifluoromethyl) -508-508 methyl) phenyl phenyl] -1-piperazinyl 132 3, 5-bis (trifluoro-4-tert-butyl-1-419 419 methyl) phenyl piperidinyl 133 3, 5-bis (trifluoro1-acetanyl 377 377 methyl) phenyl MH * No R1 -NR2R3 expected found 134 3, 5-bis (trifluoro-4-benzoyl-l- 467 467 methyl) phenyl piperidinyl 135 phenyl tetrahydroisoquinolin- 275 275 1-yl 136 phenyl (4-methylphenyl) amino 249 249 137 3-cyanophenyl 4- (4-chlorophenyl) -1- 363 363 piperazinyl 138 3-acetylphenyl tetrahydroisoquinolin- 317 317 1-yl 139 3-cyanophenyl N-ethyl-N-phenylamino 289 289 140 phenyl (4-chlorophenyl) amino 270 270 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.

Claims (4)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:
1. A compound of the formula I characterized in that R1 is alkyl optionally substituted with halogen, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, dialkylamino, arylalkylamino or diarylamino; aralkyl, aryl optionally substituted with alkyl, trifluoromethyl, aryl-o, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkyl-sulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; heteroaryl optionally substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, nitro, alkyl- sulfonyl, aryl-sulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; R2 and R3 are independently hydrogen, alkyl optionally substituted by aryl, heteroaryl, a 5-, 6- or 7-membered heterocyclic system, halogen, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, dialkylamino, arylalkylamino or diarylamino; aryl, optionally substituted by alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkyl-sulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; heteroaryl optionally substituted by alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, nitro, alkyl-sulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; or R and R3 are linked together by (CH2) n-, where n 4-7, provided that R and R can not be hydrogen at the same time; Z is hydrogen, cyano, alkoxycarbonyl, optionally substituted with aminocarbonyl, alkylsulfonyl or arylsulfonyl optionally substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, nitro, alkyl- sulfonyl, aryl-sulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; and the pharmaceutically acceptable salts thereof. 2. The compound according to claim 1, characterized in that R1 is optionally substituted aryl. 3. The compound according to claim 2, characterized in that R1 is phenyl optionally substituted. 4. The compound according to claim 3, characterized in that R1 is phenyl by one or two halogen, perhalomethyl or cyano groups. 5. The compound according to any of the preceding claims, characterized in that Z is hydrogen. 6. The compound according to claim 1, characterized in that the compounds of formula I are selected from the group consisting of Rx 4- (trifluoromethyl) 2- (methylpropyl) amino phenyl 4- (trifluoromethyl) (1,2-dimethylpropyl) • phenyl amino 4- (trifluoromethyl) isopropylamino phenyl 4- (trifluoromethyl) • (1,3-dimemethylbutyl) -phenyl amino 4- (trifluoromethyl) • (2,2-dimethylpropyl) -phenyl amino 4- (trifluoromethyl) • butylamino phenyl 4- (trifluoromethyl) - (4- er-butylcyclo-phenyl hexyl) amino 4- (trifluoromethyl) • (1,2, 2-trimethyl-phenyl propyl) amino 4- (trifluoromethyl) -2-exo-norbornylamino phenyl 4- (trifluoromethyl) '(cyclohexylmethyl) amino phenyl 2- (trifluoromethyl) '2- (methylpropyl) amino phenyl R1 -NR2R3 2- (trifluoromethyl) • (1,2-dimethylpropyl) -phenyl 2- (trifluoromethyl) isopropylamino phenyl 2- (trifluoromethyl) (1,3-dimethylbutyl) -phenyl amino 2- (trifluoromethyl) - (2,2-dimethylpropyl) -phenyl amino 2- (trifluoromethyl) • butylamino phenyl 2- (trifluoromethyl) '(4-tert-butylcyclo-phenyl hexyl) amino 2- (trifluoromethyl) - (1,2,2-trimethyl-phenyl propyl) amino 2- (trifluoromethyl) -2-exo-norbornylamino phenyl
2. 2- (trifluoromethyl) '(cyclohexylmethyl) amino phenyl 2, 3-dichlorophenyl 2- (methylpropyl) amino 2, 3-dichlorophenyl (1,2-dimethylpropyl) -amino No x -NR2R3 23 2, 3-dichlorophenyl isopropylamino 24 2, 3-dichlorophenyl (1,3-dimethylbutyl) -amino 25 2, 3-dichlorophenyl (2,2-dimethylpropyl) -amino 26 2, 3-dichlorophenyl butylamino 27 2, 3-dichlorophenyl (4-tert-butylcyclohexyl) amino 28 2, 3-dichlorophenyl (1,2,2-trimethyl-propyl) amino 29 2, 3-dichlorophenyl 2-exo-norbornylamino 30 2, 3-dichlorophenyl (cyclohexylmethyl) amino 31 2-methoxy-4-nitrophenyl 2- (methylpropyl) amino 32 2-methoxy-4-nitrophenyl (1,2-dimethylpropyl) -amino 33 2-methoxy-4-nitrophenyl isopropylamino 34 2-methoxy-4-nitrophenyl (1,3-dimethylbutyl) -amino 35 2-methoxy-4-nitrophenyl (2,2-dimethyl-ro-pyl) - No R1 -NR2R3 36 2-methoxy-4-nitrophenyl butylamino 37 2-methoxy-4-nitrophenyl (4-tert-butylcyclohexyl) amino 38 2-methoxy-4-nitrophenyl (1,2,2-trimethylpropyl) amino 39 2-methoxy-4-nitrophenyl 2-exo-norbornylamino 40 2-methoxy-4-nitrophenyl (cyclohexylmethyl) amino 41 2, 4-difluorophenyl 2- (methylpropyl) amino 42 2, 4-difluorophenyl (1,2-dimethylpropyl) -amino 13 2, 4-difluorophenyl isopropylamino 44 2, 4-difluorophenyl (1,3-dimethylbutyl) - amino 45 2, 4-difluorophenyl (2,2-dimethylpropyl) amino 46 2, 4-difluorophenyl butylamino 47 2, 4-difluorophenyl (4-tert-butylcyclohexyl) amino 48 2, 4-difluorophenyl (1,2,2-trimethyl-propyl) amino R1 -NR2R3 2,4-difluorophenyl 2-exo-norbornylamino 2,4-difluorophenyl (cyclohexyl) amino) 3-chloro-4-fluorophenyl 2- (methylpropyl) amino 3-chloro-4-fluorophenyl (1,2-dimethylpropyl) -amino 3-chloro-4-fluorophenyl isopropylamino 3-chloro-4-fluorophenyl (1,3-dimethylbutyl) amino 3-chloro-4-fluorophenyl (2,2-dimethylpropyl) -amino 3-chloro-4-fluorophenyl butylamino 3-chloro-4-fluorophenyl (4-tert-butylcyclohexyl) amino 3-chloro-4-fluorophenyl (1,2,2-trimethylpropyl) amino 3-chloro-4-fluorophenyl 2-exo-norbornylamino 3-chloro-4-fluorophenyl (cyclohexylmethyl) amino 4-cyanophenyl 2- (methylpropyl) amino 4-cyanophenyl (1,2- di-ethylpropyl) amino R1 -NRR3 4-cyanophenyl isopropylamino 4-cyanophenyl (1,3-dimethylbutyl) • 4-cyanophenyl (2,2-dimethylpropyl) - ammo 4-cyanophenyl butylamino 4-cyanophenyl (4-tert-butylcyclohexyl) amino 4-cyanophenyl (1,2,2-trimethyl-propyl) amino 4-cyanophenyl 2-exo-norbornylamino 4-cyanophenyl (cyclohexylmethyl) amino 3, 5-bis (trifluoro2- (methylpropyl) amino methyl) phenyl 3, 5-bis (trifluoro (1,2-dimethylpropyl) • methyl) phenyl amino 3, 5-bis (trifluoroisopropylamino methyl) phenyl 3, 5-bis (trifluoro (1,3-dimethylbutyl) • methyl) phenyl amino No R1 -NR2R3 75 3, 5-bis (trifluoro (2, 2-dimethylpropyl) -methyl) phenyl amino 76 3, 5-bis (trifluorobutylamino methyl) phenyl 77 3, 5-bis (trifluoro (4-tert-butyl-cyclo-methyl) phenyl hexyl) amino 78 3, 5-bis (trifluoro- (1, 2, 2-trimethyl-methyl) -phenyl) propyl) amino 79 3, 5-bis (trifluoro-2-exo-norbornylamino methyl) phenyl 80 3, 5-bis (trifluoro (cyclohexylmethyl) amino methyl) phenyl 81 phenyl (4-methoxybenzyl) amino 82 3-fluorophenyl propylamino 83 • 3-Fluorophenyl Hexylamino 84 3-fluorophenyl propargylamino 85 3-fluorophenyl (3-methylbutyl) amino 86 3-pyridyl propylamino 87 3-hexylamino pyridyl 88 3-pyridyl propargylamine No R1-NR2R3! 9 3-pyridyl. { 3-methylbuti1) amino 90 3, 4-dichlorophenyl propylamino 91 3, 4-dichlorophenyl-hexylamino 92 3, 4-dichlorophenyl propargylamine 93 3, 4-dichlorophenyl (3-methylbutyl) amino 94 3, 5-bis (trifluoropropylamino methyl) phenyl 95 3, 5-bis (trifluorohexylamino methyl) phenyl 96 3, 5-bis. { trifluoropropargylamino methyl) phenyl 97 3, 5-bis (trifluoro (3-methylbutyl) amino methyl) phenyl 98 phenylamino phenyl 99 benzyl (4-methoxybenzyl) amino 100 phenyl 1-pyrrolidinyl 101 3- (trifluoromethyl) • (3-methylbutyl) amino phenyl 102 4-chloro-3-. { trifluoro- (3-methylbutyl) amino methyl) phenyl No R1 -NR R3 103 3-Acetylphenyl (3-methylbutyl) amino 104 2-chloro-5- (trifluoro- (3-methylbutyl) amino methyl) phenyl 105 3, 4-dicyanophenyl [3-methylbutyl) amino 106 4-bromo-2- (trifluoro- (3-methylbutyl) amino methyl) phenyl 107 4,6-dimethyl-2- (3-methylbutyl) amino pyrimidinyl 108 4-Acetylphenyl (3-methylbutyl) amino 109 3, 5-dichlorophenyl (3-methylbutyl) amino 110 3-chloro-4-methylphenyl (3-methylbutyl) amino 111 2, 5-bis (trifluoro (3-methylbutyl) amino methyl) phenyl 112 3, 5-dichlorophenyl (2-methylpropyl) amino 13 3-chloro-4-methylphenyl (2-methylpropyl) amino 14 2, 5-bis (trifluoro (2-methylpropyl) amino methyl) phenyl 15 3, 5-bis (trifluoro (3-phenylpropyl) amino methyl) phenyl No R1 116 3, 5-bis (trifluoro (2,2,6,6-tetramethylmethyl) phenyl piperidinyl) amino 117 3, 5-bis (trifluoroN, N-dipropylamino methyl) phenyl 118 3, 5-bis (trifluoro2- (4-chlorophenyl) -methyl) phenyl ethylamino 119 3, 5-bis (trifluoro2- (2-pyridyl) ethylamino methyl) phenyl 120 3, 5-bis (trifluoro-4-methyl-1-piperidyl methyl) phenyl 121 3, 5-bis (trifluoroN, N-bis (2-methyl-methyl) phenyl propyl) amino 122 3, 5-bis (trifluoro-1-pyrrolidinyl methyl) phenyl 123 3, 5-bis (trifluoro3- (1-imidazolyl) -methyl) phenyl propylamino Í24 3, 5-bis (trifluoroN-methyl-N- (3-pyridyl) -methyl) phenyl methylamino 125 3, 5-bis (trifluoro (3-amino-2, 2-dimethyl-methyl) phenyl propyl) amino 126 3, 5-bis (trifluoro-3- (2-oxo-l-pyrrolidinyl) -methyl) phenyl propylamino No R1 127 3, 5-bis (trifluoro (4-methoxybenzyl) amino methyl) phenyl 128 3, 5-bis (trifluoro-3-hydroxy-1-methyl) phenyl piperidinyl 129 3, 5-bis (trifluorotetrahydroisoquinolin-methyl) phenyl 1-yl 130 3, 5-bis (trifluoro-2, 6-cis-dimethyl-4-methyl) phenyl morpholinyl 131 3, 5-bis (trifluoro4 - [(3-trifluoromethyl) -methyl) phenyl phenyl] -1-piperazinyl 132 3, 5-bis (trifluoro-4-tert-butyl-1-methyl) phenyl piperidinyl 133 3, 5-bis (trifluoro-1-acetyl methyl) phenyl 134 3, 5-bis (trifluoro4-benzsyl-1-methyl) phenyl piperidinyl 135 phenyl tetrahydroisoquinolin-1-yl 136 phenyl (4-methylphenyl) amino 137 3-cyanophenyl 4- (4-chlorophenyl) -1- piperazinyl No R1 -NR2R3 138 3-acetylphenyl tetrahydroisoquinolin-1-yl 139 3, 5-bis (trifluoromethyl) 3- (2-oxo-l-acetanyl) - H phenyl propylamino 140 3, 5-bis (trifluoromethyl) 3- (2-oxo-l-acetanyl) - H phenyl propylamino 141 3, 5-bis (trifluoromethyl) (3-methylbutyl) amino cyano phenyl 142 3, 5-bis (trifluoromethyl) (3-methylbutyl) amino-tert-butyloxy-phenyl carbonyl 143 3, 5-bis (trifluoromethyl) (3-methylbutyl) amino (4-chlorophenyl) -phenyl sulfonyl 144 phenyl (4-methoxybenzyl) amino-tert-butyloxycarbonyl 145 phenyl (3-methylbutyl) amino cyano 136 3-cyanophenyl N-et il-N-phenylamino 147 phenyl (4-chlorophenyl) amino H and the pharmaceutically acceptable salts thereof. 7. The compounds according to any of the preceding claims, characterized in that they are active as potassium channel openers. A pharmaceutical composition, characterized in that it comprises a compound according to any of claims 1-6 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a mixture racemic, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents. 9. A pharmaceutical composition for use in the treatment of diseases of the endocrinological system such as diabetes, characterized in that it comprises a compound according to any of claims 1-6 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents. 10. The pharmaceutical composition according to claim 8 or 9, characterized in that it is in the form of an oral dosage unit or parenteral dosage unit. 11. The pharmaceutical composition according to claim 8 or 9, characterized in that the compound is administered as a dose in a range of about 0.05 mg to 1000 mg, preferably from about 0.1 mg to 500 mg and especially in the range from 50 mg to 200 mg per day. The compound according to any of claims 1-6 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for use therapeutic. The compound according to any of claims 1-6 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for use therapeutic in the treatment or prevention of diseases of the endocrinological system, such as diabetes. 14. The use of a compound according to any of claims 1-6 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms such as a medicament. 15. The use of a compound according to any of claims 1-6 to prepare a medicament. 16. The use of a compound according to any of claims 1-6 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any form tautomeric for the preparation of a medicament for the treatment or prevention of diseases of the endocrinological system, such as diabetes. 17. A method for treating or preventing diseases of the endocrinological system, such as diabetes in a subject in need thereof, characterized in that it comprises administering an effective amount of a compound according to any of claims 1-6 to the subject. 18. A process for the manufacture of a medicament to be used in the treatment or prevention of diseases of the endocrinological system, such as diabetes, a process which is characterized in that it comprises putting a compound of formula I in accordance with any of claims 1-6 or a pharmaceutically acceptable salt thereof in a galenic dosage form. 19. Any characteristic or novel combination of characteristics as described herein. 20. A compound of the general formula II characterized in that Su is a substrate, L is a chemical bond or a linker, R1, R2 and R3 are as defined above. 21. The compound according to claim 20, characterized in that it is useful for selecting the potassium channel openers. 22. A method for preparing a compound according to claim 1, characterized in that it comprises the steps of: a) the acylation of an alcohol bound to a substrate of the formula Su-LOH, where Su and L are as defined in Claim 20, with a cyanoacetic acid derivative of the general structure NC-CH2-COX, where X is a hydroxy group or a leaving group; b) the reaction of the intermediate bound to the substrate resulting from the formula Su-L-0-CO-CH2-CN where Su and L are as defined in claim 20, with an aliphatic or aromatic isothiocyanate of the general structure R1-NCS wherein R1 is as defined in claim 20, in the presence of a base; c) the reaction of the intermediate bound to the substrate resulting from the formula Su-LO-CO-CH (CN) -C (S) (NHR1) with an amine of the general structure R2R3NH, where R2 and R3 are as defined in claim 1, in the presence of a desulfurizing agent, to prepare a compound of formula II, d) subject the bound compound to the resulting substrate of formula II under cleavage conditions to prepare a compound of formula I. 23. The method of compliance with claim 22, characterized in that it further comprises the step of selecting the final product of formula I directly against a specific receptor or enzyme. 24. A method for preparing a compound according to claim 20, characterized in that it comprises the steps of: a) the acylation of an alcohol bound to a substrate of the formula Su-LOH, where Su and L are as defined in claim 20, with a cyanoacetic acid derivative of the general structure NC-CH-COX, where X is a hydroxy group or a leaving group; b) the reaction of the intermediate bound to the substrate resulting from the formula Su-L-0-CO-CH2-CN where Su and L are as defined in claim 20, with an aliphatic or aromatic isothiocyanate of the general structure R1-NCS wherein R1 is as defined in claim 20, in the presence of a base; c) the reaction of the intermediate bound to the substrate resulting from the formula Su-LO-CO-CH (CN) -C (S) (NHR1) with an amine of the general structure R2R3NH, where R2 and R3 are as defined in Claim 1, in the presence of a desulfurizing agent, for preparing a compound of formula II. 25. The method according to claim 24, characterized in that it further comprises the step of selecting the final product of formula II directly against the specific receptor or enzyme. 26. The method according to claim 20 to 25, characterized in that the desulphurising reagent is EDC. 27. The method according to claim 20 to 26, characterized in that the base for the reaction of the isothiocyanate with the cyanoacetic acid ester is a tertiary amine. 28. The method of compliance with the claim 20 to 27, characterized in that the cyanoacetic acid derivative is the symmetric anhydride. 29. An array, characterized in that it comprises m different compounds of formula I, in known positions selected in m containers, where m is an integer equal to or greater than 2. 30. An array, characterized in that it comprises m different compounds of formula II, where m is an integer equal to or greater than 2, in known positions selected on one or more substrates. 31. The arrangement according to claim 29 or 30, characterized in that m is between 60 to 100, preferably 80. 32. An arrangement comprising a compound of formula I on different compounds of formula I, characterized in that is an integer equal to or greater than 2, at known positions selected in m containers, or at selected positions selected on a substrate, and a compound of formula II or mn different compounds of formula II, where m is an integer equal to or greater than 2, and m > n, in known positions selected on one or more substrates. The arrangement according to claim 32, characterized in that m is between 60 to 100, preferably 80. 34. An array, characterized in that it comprises p different mixtures of compounds of formula I, in known positions selected in p containers, where p is an integer equal to or greater than 2. 35. An array, characterized in that it comprises p different mixtures of compounds of formula II, where p is an integer equal to or greater than 2, at known positions selected on one or more substrates 36. The arrangement according to claim 34 or 35, characterized in that p is between 60 to 100, preferably 80. 37. An array, characterized, comprises a mixture of compounds of formula I or different mixtures of compounds of formula I, where r is an integer equal to or greater than 2, in known positions selected in p containers, or in known positions selected on a substrate, and a mixture of compounds of formula II or pr different mixtures of compounds of formula II, where p is an integer equal to or greater than 2, and p > r, at known positions selected on one or more substrates. 38. The arrangement according to claim 37, characterized in that p is between 60 to 100, preferably 80. 39. The method for preparing the array according to claim 30 or 31, characterized in that it comprises, performing in known positions selected on one or more substrates the steps of: a) the simultaneous acylation of each and every one of the alcohols bound to the substrate unique to the formula Su-LOH, where Su and L are as defined in claim 20, with a cyanoacetic acid derivative of the general structure NC-CH2-COX, wherein X is a hydroxy group or a leaving group; b) the reaction of each and every one of the esters attached to the substrate resulting from the formula Su-L-0-CO-CH2-CN where Su and L are as defined in claim 20, with an aliphatic or aromatic isothiocyanate of the general structure R1-NCS where R1 is as defined in claim 20, in the presence of a base; c) the alkylation of each and every one of the intermediates bound to the substrate resulting from the formula Su-L-0-CO-CH (CN) -C (S) (NHR1) with an amine of the general structure R2R3NH, where R2 and R3 are as defined in claim 1, in the presence of a desulfurizing agent, for preparing a compound of formula II, attached, to one or more substrates. 40. A method for preparing the array according to claim 33 or 35, the method of claim 39 is further characterized in that it comprises the step of: d) subjecting the m compounds bound to the resulting substrate of formula II to cleavage conditions for prepare m compounds of formula I, in known positions selected in m containers, where m is an integer equal to or greater than 2. 41. The method for preparing the arrangement according to claim 32 or 33, the method of claim 39 is characterized in that it comprises comprises further the step of: d) subjecting the m compounds bound to the resulting substrate of formula II to cleavage conditions to prepare n compounds of formula I, and mn compounds of formula II, at known positions selected in m containers, or at selected known positions on a substrate. 42. The method according to any of claims 39, 40 or 41, characterized in that the base for the reaction of the fsothiocyanate with the cyanoacetic acid in claim 39, step b) is a tertiary amine. 43. The method according to any of claims 39 or 42, characterized in that the cyanoacetic acid derivative is the symmetric anhydride. 44. The method according to any of claims 39 to 43, characterized in that it further comprises selecting the final products directly against a specific receptor or enzyme. 45. The arrangement of compounds of formula I, according to claim 29 or 31, characterized in that Z is hydrogen and R 1 phenyl, 4-trifluoromethylphenyl, 2-trifluoromethylphenyl, 2,3-dichlorophenyl, 3-chloro-4-fluorophenyl, 2-methoxy-4-nitrophenyl, 2,4-difluorophenyl, 4-cyanophenyl, 3,5-bis (trifluoromethyl) phenyl, 3-fluorophenyl,
3. 3-pyridyl, 3-dichlorophenyl or benzyl. 46. The arrangement of compounds of formula I, according to any of claims 29, 31 or 44, characterized in that R2 is 2-methylpropyl, 1,2-dimethylpropyl, isopropyl, 1,3-dimethylbutyl, 2-, 2- dimethylpropyl, butyl,
4. 4-tert-butylcyclohexyl, 1,2,2-trimethylpropyl, exo-2-norbornyl and cyclohexylmethyl, 4-methoxybenzyl, phenyl, propyl, hexyl, propargyl or 3-methylbutyl. or R2 and R3 are linked together by - (CH2) n- where n 4-7. 47. The use of an arrangement according to any of claims 29 to 38 for selecting compounds of formula I against specific receptors or enzymes. 48. The use of an arrangement according to any of claims 29 to 38 for selecting compounds of the formula I against potassium channels.