CZ383599A3 - Substituted 3,3-diamino-2-propenenitriles, their preparation and use - Google Patents

Abstract

Substituted cyanoenamines of general formula I and their compounds pharmaceutically acceptable salts; /: their preparation. The compounds are useful for treatment diseases of the central nervous system, cardiovascular system, respiratory system, gastrointestinal system and endocrine system.

Description

Technical field

The present invention relates to 3,3-diamino-2-propenenitriles, hereinafter referred to as cyanoenamines, processes for their preparation, pharmaceutical compositions containing them, the use of these compounds as medicaments and their use in therapy, for example for the treatment of diseases of the central nervous system, cardiovascular system, respiratory system, gastrointestinal system, and endocrine system.

BACKGROUND OF THE INVENTION

Potassium channels play an important role in the membrane potential. Among the various types of potassium channels, ATP-sensitive (Katp-) channels are regulated by changes in the intracellular concentration of adenosine triphosphate. Katp channels were found in cells of various tissues - heart cells, pancreatic cells, skeletal muscle cells, smooth muscle cells, CNS neurons and adenohypophysis cells. These channels are associated with various cellular functions, such as hormone secretion (pancreatic B cell insulin, growth hormone and adenohypophysis prolactin), vasodilation (in smooth muscle cells), duration of cardiac action potential, release of neurotransmitter in the central nervous system.

KATP-channel modulators have been found to be important in the treatment of various diseases. Certain sulfonylureas, which have been used to treat noninsulin-dependent diabetes, act by stimulating insulin release by inhibiting Katp channels in pancreatic β beta cells. Potassium channel openers, including various compounds, have been found to be able to relax vascular smooth muscle and are therefore used to treat hypertension.

In addition, potassium channel openers can be used as bronchodilators in the treatment of asthma and other various diseases.

In addition, potassium channel openers are used to treat baldness as they have been shown to promote hair growth.

Potassium channel openers are also able to relax the bladder smooth muscle and therefore can be used to treat urinary incontinence. Potassium channel openers that relax the uterine smooth muscle can be used to treat premature labor pains.

Since Katp openers are capable of antagonizing vasospasm in the basilar or cerebral arteries, the compounds of the invention can be used to treat vasospastic diseases such as subarachnoid haemorrhage and migraine.

Potassium channel openers hyperpolarize neurons and inhibit neurotransmitter release, and the compounds of the invention can be expected to be used for the treatment of various central nervous system diseases such as epilepsy, ischemia and neurodegenerative diseases and for the management of pain.

• 444 4 4 4 4 4 4 4 ·· · 4 4 4 4 4 4 4 4 44 44 44 «4444 • 4 4 4 4 · 4 4 4 · 4 4

4 · 4 4 4

44 44 4 4 4. 44 44

Recently, diazoxide derivatives (7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide) and 3- (alkylamino) -4H-pyrido [4,3-e] -1, 2,4-thiadiazine 1,1-dioxide inhibits insulin release by activating Katp-channels in pancreatic beta cells (Pirotte B. et al. Biochem. Pharacol, 47, 1381-1386 (1994); Pirotte B et al., J. Med. Chem., 36, 3211-3213 (1993) In addition, diazoxide has been shown to delay the onset of diabetes in BB rats (Vlahos WD et al. Metabolism 40, 39-46 (1991)). it decreases insulin secretion and increases insulin receptor binding, resulting in increased glucose tolerance and lower weight gain (Alemzadeh R. et al., Endocrinol., 133, 705-712, (1993)). used to treat diseases characterized by overproduction of insulin, and to treat and prevent diabetes.

SUMMARY OF THE INVENTION

The present invention relates to substituted 3,3-diamino-2-propenenitriles, hereinafter referred to as cyanoenamines of formula I:

R ¹ is alkyl, optionally substituted with halogen, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, dialkylamino, arylalkylamino or diarylamino; aralkyl, aryl, optionally substituted with alkyl, trifluoromethyl, aryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; heteroaryl, optionally substituted with alkyl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl;

R ² and R ³ are independently hydrogen, alkyl optionally substituted with aryl, heteroaryl, 5-, 6- or 7-membered heterocyclic, halogen, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, dialkylamino, arylalkylamino or diarylamino; aryl, optionally substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; heteroaryl, optionally substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl;

or R ² and R ³ are taken together with the group _ (CH ₂ ) _n -, where n is 4 to 7, provided that R ² and R ³ are not simultaneously hydrogen;

Z is hydrogen, cyano, alkoxycarbonyl, optionally substituted aminocarbonyl, alkylsulfonyl, or arylsulfonyl, optionally substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, φ · Halogen, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; and pharmaceutically acceptable salts thereof.

The invention also encompasses all diastereomers and enantiomers of the compounds of Formula I, some of which are optically active as well as mixtures thereof, including racemic mixtures.

Also included within the scope of the invention are all tautomeric forms of the compounds of Formula I.

Salts include pharmaceutically acceptable addition salts, pharmaceutically acceptable metal salts or optionally alkylated ammonium salts, such as those derived from hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, amber, citric, tartaric , fumaric, almond, benzoic, cinnamon, methanesulfonic, ethanesulfonic, picric and the like, and include acids related to pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) and incorporated herein by reference, or lithium, sodium, potassium salts , magnesium, etc.

The term "5-, 6- or 7-membered heterocyclic system" as used herein includes: a monocyclic unsaturated or saturated system containing one, two or three heteroatoms selected from the group consisting of 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 2,1,3-thiadiazole; an aromatic monocyclic system containing two or more nitrogen atoms and having 6 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 and having 6 or 7 members, for example pyran, thiopyran, piperidine, dioxane, oxazine, isoxazine, dithian, oxathian, thiazine, piperazine, thiadiazine, dithiazine, oxadiazine or oxoazepane.

Alkyl includes lower straight, cyclic, fused or branched alkyl having 1 to 15 carbon atoms, preferably 1 to 6 carbon atoms. Aryl includes phenyl or phenyl substituted with alkyl or phenyl or phenyl condensed with cycloalkyl or polycyclic aromatic system such as naphthyl, anthracenyl, phenanthrenyl, fluorenyl etc. Alkylene includes lower, cyclic, fused or branched alkylene having 1 to 15 carbon atoms, preferably 1 up to 6 carbon atoms. Heteroaryl includes any possible isomeric, unsubstituted or alkylsubstituted pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl systems, or the corresponding benzo d and benzo dibenzenes, . Heteroaryl also refers to partially or fully hydrogenated derivatives of the heterocyclic systems mentioned above. Alkoxy includes O-alkyl and aryloxy includes O-aryl. Cyano includes -CN, hydroxy OH, amino -NH 2 and nitro -NO 2. Dialkylamino includes -N (alkyl) 2. Arylamino includes -N (alkyl) (aryl) and diarylamino includes -N (aryl) 2 -Halo includes -F, -Cl, -Br and -I. Aralkyl includes -alkylene-aryl. Alkylthio includes -S-alkyl and arylthio includes -S-aryl. Alkoxycarbonyl includes -CO-O-alkyl and aminocarbonyl includes -CO-N (alkyl) ₂ , -CON (alkyl) (aryl) or -CO-N (aryl) 2. Acylamino includes -N (alkyl) -CO-alkyl or 4

N (alkyl) -CO-aryl. The leaving group includes a group or atom capable of existing in solution as a negatively charged particle or a positively charged group or atom.

The compounds of the present invention act on potassium channels and thus function as openers or closers of ATPatp-driven potassium channels, making them useful for the treatment of various diseases of the cardiovascular system, e.g., cerebral ischemia, hypertension, coronary heart disease, angina and coronary heart disease; respiratory system, gastrointestinal system; the central nervous system and the endocrine system.

The compounds of the present invention may also be used to treat diseases associated with reduced blood flow in skeletal muscles such as Reynauds disease and intermittent limping.

Furthermore, the compounds of the invention can be used for the treatment of chronic respiratory diseases including asthma and for the treatment of muscle instability causing clogging of the bladder duct and the resulting kidney stones by facilitating their passage through the ureter. Potassium channel openers also relax the bladder smooth muscle so that the compounds of the present invention can be used to treat urinary incontinence.

The present compounds may also be used to treat conditions associated with gastrointestinal mobility disorders such as bowel irritation syndrome. In addition, these compounds can also be used to treat premature labor and painful menstruation.

Potassium channel openers further promote hair growth, therefore, the compounds of the present invention can be used to treat baldness.

In diseases such as insulin, in which hypersecretion of insulin causes severe hypoglycemia, the compounds of the present invention may be used to reduce insulin secretion. In obesity, hyperinsulinemia and insulin resistance often meet. This condition could lead to the development of non-insulin-dependent diabetes (NIDDM). It is expected that potassium channel openers and hence the compounds of the present invention can be used to reduce hyperinsulinemia and thereby to prevent diabetes and reduce obesity. Restoration of glucose sensitivity and normal insulin secretion can be used to treat hyperinsulinemia in apparent NIDDM using potassium channel openers and hence the present compounds.

4

In early cases of insulin-dependent diabetes (IDDM) or predibetic cases, potassium channel openers and thus the present compounds can be used to induce residual beta-cells, which may prevent the progression of autoimmune disorder.

The compounds of the present invention, which can serve as K-channel closers, can be used to treat NIDDM.

Preferably, the compounds of the present invention may be used for the treatment and prevention of diseases of the endocrine system, such as hyperinsulinemia and the treatment or prevention of diabetes.

• · · · · · · · · · · · · · · · · · · · · · · · · ·

Accordingly, in another aspect, the present invention relates to the use of compounds of Formula I or pharmaceutically acceptable acid salts thereof as a pharmaceutically acceptable agent, preferably a pharmaceutically acceptable agent, for treating hyperinsulinemia and treating or preventing diabetes.

Furthermore, the invention also relates to the use of the compounds of the formula I according to the invention as a medicament useful for the treatment of hyperinsulinemia and the treatment and prevention of diabetes.

Another aspect of the present invention are processes for preparing the above compounds. These methods include solid state synthesis of compounds and combination synthesis, particularly the synthesis of a therapeutically important class of compounds, referred to as variously substituted cyanoenamines, useful as potassium channel openers. The novel synthetic sequences of the invention allow the preparation of a new class of cyanoenamines useful as potassium channel openers.

The following terms are used with the following meanings:

1. Substrate: includes any insoluble or partially insoluble material to which the compounds may be covalently bound. The substrates may be selected from the group consisting of any organic or inorganic polymer or oligomeric compound, for example polystyrene with varying degree of cross-linking, polyethylene glycol (PEG), polystyrene-bound polyethylene glycol (for example TentaGel), polyacrylamides, polysaccharides or silicates. Alternatively, a given portion of the substrate may be attached to a cue, i.e., a material or device that allows the portion of the substrate to be uniquely identified within the portions of the substrate.

2. Linker: A molecule with at least two reaction sites that allows its covalent attachment to other molecules or to a substrate. Both the binding of the linker to the substrate and the binding of the linker to other molecules attached thereto, or the linker itself, must be cleavable upon selective exposure to an activator such as a selected chemical activator or other conditions, for example by strong acid treatment or electromagnetic radiation or metal catalysis.

3. Set: A collection of individual nitrogen compounds or mixtures of compounds with the usual structural elements, prepared simultaneously or in parallel using the same reaction sequences. The exact structure of an individual compound in the set of compounds or components of the mixture in the set or mixtures is determined by the sequence of the reactants that produce the compound or mixture and can be derived from the notation of the reaction protocol. The spatial arrangement of the file is irrelevant.

4. Cyanoenamine: An organic compound containing a structural element

RR'N-CR = CR'-CN.

5. Protecting group: Material that is chemically bound to a molecule or substrate and which can be removed by selective exposure to an activator, such as a selected chemical activator, or other conditions, for example, strong acid or exposure to electromagnetic radiation or metal catalysis.

«Β ββ

6. Combination Synthesis: An ordered strategy for parallel synthesis of a set of individual compounds or mixtures by sequential addition of reactants.

7. Abbreviations: The following frequently used abbreviations 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-dimethylformamide

EDC: N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride,' water-soluble carbodiimide '

FMoc: fluorenylmethyloxycarbonyl NMP: N-methylpyrrolidone R: organic residue TFA: trifluoroacetic acid THF: tetrahydrofuran

The present invention also provides a process for the preparation of therapeutically active compounds. The invention also provides a rapid route for combinatorial synthesis and investigation of a set of cyanoenamine derivatives as a therapeutically important class of compounds. The invention also provides solid phase synthesis of cyanoenamines that eliminates purification and isolation steps and thus greatly increases the efficiency of the synthesis. The disclosure further describes an important extension of methods for solid phase synthesis of non-oligomeric organic compounds.

Further understanding of the nature and advantages of the nature of the invention can be realized by reference to the rest of the description.

The present invention also encompasses the preparation and investigation, preferably in a parallel and simultaneous manner, of a plurality of differently substituted cyanoenamines of formula I wherein:

Z, R ^1, R ² and R ³ are as defined above formula II • 9 9 · · · · ¹ 9 9 9 * · · · · 9 0 0 '0 0

9 9 0 0 0 · 9 9'9 * *

9 · 0 0 '0 · 9 9 9 0

II

Su is a substrate,

L is a chemical bond or linker,

R ^1, R ² and R ³ are as defined above.

An overview of solid phase cyanoenamine synthesis is shown in Reaction Scheme 1.

Scheme 1 ', ^J ;

(··

R’NCS | base

(trifluoroacetate)

N

R ³

CN

R ²

In this synthesis, the substrate Su may be an insoluble or partially soluble material to which the compounds of the invention may be covalently bonded. Preferably, the substrates may be selected from the group consisting of polystyrene, polyethylene glycol (PEG), polystyrene-bound polyethylene glycol (e.g., TentaGel), polyamides, polysaccharides, and silicates. Depending on the type of substrate selected, different types of solvents or protecting groups may be selected.

The substrate-linked alcohol 1 may be acylated with a suitable cyanoacetic acid derivative of the formula NC-CH 2 -COX, wherein X is a leaving group, preferably in situ generated symmetric anhydride (Zaragoza, F. Tetrahedron Lett. 1995,

36, 8677-8678). Alternatively, other in situ generated or isolated cyanoacetic acid derivatives can be used as acylating agents, as mixed anhydrides

• · • and 9 98 9 · 4 9 9 9 9 99 9 4 . 9 4 4 ' • • 9 • 4 4 9 4 4 4 ♦ 9 • 9 • · 4 9 9 4 9 4 4 • · • · • · 44 9 9 * • 9

derived from chloroformates and cyanoacetic acid or imidazolides or other types of activated esters, such as N-hydroxybenzotriazol ester or N-hydroxysuccinyl ester or other activated derivatives, will be apparent to those skilled in the art. The esterification reactions may optionally be carried out in the presence of a catalyst, for example 4-dimethylaminopyridine, to give derivatives of the general formula (substrate) - (linker) -O-CO-CH 2-CN.

As a result, the resin-linked cyanoacetic acid derivative 2 can then be treated with an aromatic or aliphatic isocyanate of the formula R ¹ -NCS in a suitable solvent such as NMP, DMF or THF in the presence of a base, preferably diisopropylethylamine or 1,8-diazabicyclo [5.4. O] undec-7-ene (DBU).

The resulting intermediate 3 can then be treated with EDC and a primary or secondary aliphatic or aromatic amine of formula R ² R ³ NH in a suitable solvent such as NMP, DMF, acetonitrile, DCM, 1,2-dichloroethane, toluene, ethyl acetate, etc. , preferably in DMF. Alternatively, other condensing agents (e.g., benzotriazol-1-yl-oxy-tris- (dimethylamino) phosphonium hexafluorophosphate ("BOP"), carbonyldiimidazole, N-ethyl-N '- (3-trimethylammoniumpropyl) -carbodiimide, diisopropylcarbodiimide, dicyclohexylcarbodiimide , etc.), alone or in the presence of a catalyst such as pyridinium tosylate or tertiary amine salts. The reaction is closely related to published procedures for the conversion of thioureas to thioguanidines (KS Atwal, NW Ahmed, BC O'Reilly, Tetrahedron Lett. 1989, 30, 7313-7316).

Cleavage of the substrate-bound cyanoenamine II linker can release the cyanoenamine derivative I into solution. The cleavage conditions will depend on the type of substrate and the linker selected. For example, in the case of a polystyrene resin with a Wang linker or a Rink linker, treatment of carrier-bound cyanoenamine II with pure TFA or TFA / DCM mixtures may result in cleavage of the linker. Thus, the cyanoenamine I can be converted as its cyanoamidine trifluoroacetate tautomer, which can be reversibly tautomerized to a neutral tautomer upon treatment with bases or buffer.

Alternatively, other chemical transformations may be performed with the cyanoenamine derivative II. Those NH-containing cyanoenamines II can be acylated on nitrogen by treatment with an excess of activated carboxylic acid derivative or with an isocyanate or sulfonyl chloride to give the corresponding carboxamides, ureas, thioureas or sulfonamides. Each of these reactions can be carried out by conventional methods, as will be apparent to those skilled in the art.

Alternatively, other chemical transformations can be performed with the cyanoenamine derivative I, which gives high yields and pure crude products, so that no further purification of these derivatives is required for investigation purposes. For example, those NH-containing cyanoenamine derivatives can be acylated on nitrogen by treatment with an excess of activated carboxylic acid derivative or with an isocyanate or sulfonyl chloride to give the corresponding carboxamides, ureas, thioureas or sulfonamides. Each of these reactions can be carried out by conventional methods, as will be apparent to those skilled in the art.

Using the synthetic method, sets of cyanoenamine derivatives II or I can be prepared using solid phase parallel synthesis equipment. It may be either a ^1- pin method developed by Geysen et al. (J. Immunol. Meth. 1987, 102, 259-274) or multi-solid-reactor (lined-wall) reactors that allow automated or manual addition of reactants and solvents as well as removal of solvents from the reactors simultaneously or by individually applying a pressure difference between the interior and exterior of the reactor wall.

Such a kit can be prepared in a multiple organic synthesizer (e.g., "ACT 496""Advanced Chem Tech") by individual reaction, under the conditions specified below, a cyanoacetyl substrate placed in individual containers, with various isocyanates of the formula R ¹ -NCS in the presence of a base. The resulting intermediates 3 can then be reacted with various amines of the formula R ² R ³ NH in DMF in the presence of EDC to form a set of different cyanoenamines and novel derivatives II. The carrier cleavage gives a set of corresponding cyanoenamines I.

The present invention also provides the preparation of sets of mixtures of cyanoenamine derivatives. This can be achieved by the “split and mix” method (Sepetov, NF, Krchňák, V., Stankov, M., Wade, S., Lam, K, and Lebl Proc. Natl. Acad. Sci. USA 1995, 92, 54265430) or by using mixtures of the corresponding agents.

According to the present invention, two different types of sets of cyanoenamines I or II can be prepared: fully combinatorial pools (FCA) and not fully combinatorial pools (NFCA).

FCAs refer to sets of substituted cyanoenamines where all possible combinations of a set of selected building blocks (R-groups) are realized. As an example of FCA N cyanoenamines can be prepared by selecting n isothiocyanates and m amines so that η x m = N and synthesizing all possible isocyanate / amine combinations. The selection of building blocks can be made taking into account the expected properties of the members of the population.

NFCAs relate to sets of cyanoenamines where only a selection of all possible combinations of a set of selected building blocks is made. As an example, NFCA of N cyanoenamines can be prepared by first selecting n isothiocyanates and amines such that η xm> N. Then select N cyanoenamines from all η xm theoretically possible cyanoenamines by grouping all η xm possible cyanoenamines into N groups of cyanoenamines with similar expected properties and selecting from each of these groups one cyanoenamine which is then synthesized. The choice of building blocks and cyanoenamines can be made taking into account the expected properties of the members of the assembly. For the preparation of such sets of compounds, the exact positions of the substrate will, by themselves, not provide any structural information about the compound prepared in that particular dose of substrate. For this reason, the spatial arrangement of the substrate is irrelevant. The structural information will be available from the reagent sequence records added to each batch of substrate. At each stage of FCA and NFCA preparation, the exact location of one substrate-shell system in the shell package and the structure of the various reactants added to the shell are recorded so that the exact structure of the cyanoenamines resulting from the one shell can always be derived.

The resulting sets of cyanoenamines can be examined by comparing individual cyanoenamines for their ability to bind to individual receptors or induce a single biological process or catalyze a biochemical or chemical reaction. This can be achieved essentially by two different methods. One possibility is to investigate a system of cyanoenamines II bound to a substrate, for example against soluble receptors. This may be, for example, radiolabeled · · t t t t t t t t t t · · · · · · t t

9 999 9 9 · φ 9 9 '9 •' 9 9 9 9 9 <9 9 '9 9 9 • 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 bound to this peptide by washing excess radioligand used and determining the radioactivity residue of each substrate-bound cyanoenamine II-peptide complex system. Alternatively, as another example, the catalytic activity of a different substrate-bound cyanoenamine II system for a given biological process or chemical reaction can be measured by comparing the rate at which the biological process or chemical reaction proceeds in the presence and absence of the given substrate-bound cyanoenamine II system.

The second screening method may consist of screening cyanoenamines I after cleavage of the substrate-bound cyanoenamines II linker and using suitably filled and indexed microtiter plates with a similar multiwell arrangement, in solution to optionally substrate-bound receptors or enzyme. Investigation of soluble small molecules is conventional and well known. Typically, radioassays can be used to examine the competitive binding of a radiolabeled, natural ligand of a given receptor and the compound to be tested for binding to that receptor.

As an example, cyanoenamines can be examined for potassium channel opening activity. This can be achieved by first treating the aorta of the rat with ⁸⁶ Rb ⁺ , and then with the cyanoenamines I. The ratio of released ⁸⁶ Rb ⁺ into solution and the radioactivity remaining in the tissue may be proportional to the potassium channel opening activity of the tested cyanoenamine I. literature (see, for example, T. Nakajima, T. Izawa, T. Kashiwabara, S. Nakajima, Y. Munezuka, Chem. Pharm. Bull. 1994, 42, 2475-2490).

Cyanoenamines I can also be prepared in solution. The method used is shown below:

R ¹ -NCS, NEt ₃

DCM or DMF

R ² R ³ NH

--— - [EDC or HgO

TFA, DCM (Z = CO ₂ tBu)

XCN

R ³

N ^ ^R ' ^TF A

Acetonitriles substituted with an acceptor react with isothiocyanates in the presence of a base. The resulting thioamides are treated with primary or secondary amines in the presence

of a desulfurizing agent such as mercuric oxide or EDC to give cyanoenamines I. Unsubstituted cyanoacetamidines can be prepared from cyanoenamines I with Z = t-butyloxycarbonyl, by treatment with trifluoroacetic acid in dichloromethane. They are thus obtained by hydrolysis of the ester group, followed by decarboxylation to give the corresponding cyanoacetamidine trifluoroacetates.

Some derivatives of 2-cyano-3- (dimethylamino) -3-arylamino-2-propenenitriles have been claimed as angiotensin II antagonists (EP 591891), Chem. Abstr. 1995, 122, 81364; Chem. Abstr. 1994, 121, 300890). Example:

Other compounds containing this structural element are claimed as antithrombotics (EP 547517, Chem. Abstr. 1993, 119, 249845; Chem. Abstr. 1993, 119, 180666), for example:

'tí

Some 3- (arylamino) -3- (alkylamino) -2-cyano-2-propenenitriles and -2-acrylamides are claimed as fungicides and herbicides (EP 10396, Chem. Abstr. 1982, 97, 140276; Chem. Abstr. 1980 , 93, 144701), with some examples being:

Cl

Reaction of amines RRNH with malononitrile monoimidates of formula NC-CH2C (OR) = NH gives compounds of the type RR'NC (NH2) = CH-CN, where one or two The amino groups are limited to NH ₂ (Cocco, MT; Congiu, C; Maccioni, A.) · am · · · am am am am Plumitallo, A., J. Heterocycl. Chem., 1989, 26, 1859-1862; Klemm, K .; Pruesse, W .; Baron, L; Daltrozzo, E., Chem. Ber., 1981, 114, 2001; Cocco, MT, Onnis, V. Synthesis, 1993, 2, 199-201; Fanshawe, WJ et al., J. Org. Chem., 1964, 29, 308311; Troschuetz, R .; Dennstedt, T. Pharm. (Weinheim Ger.) 1994, 327, 85-90). Another method consists in reacting O-alkylated cyanoacetamides with aliphatic amines (GJ Durant et al, CH 606026, Chem. Abstr. 1979, 90, 87449, GJ Durant, US 4024260, Chem. Abstr. 1977, 87, 135327). The reaction has also been described

3,3-dimethoxyacrylonitrile with amines, which may be carried out stepwise to prepare compounds of the formula RR'NC (NRR ') = CH-CN (GJ Durant, U.S. Patent 4277485, Chem. Abstr., 1981, 95, 156591) and used to prepare ranitidine analogs.

Further, the reaction of 3,3-dichloroacrylonitrile with amines has been described to give cyanoenamines of formula (RR'N) ₂ C = CH-CN with two identical amino moieties of RR (Hashimoto et al., J. Org. Chem., 1970, 35, Takeda Chem. Ind. Ltd., JP 7022328, 1970, Chem. Abstr., 73, 98434z). Furthermore, some specific methods for the preparation of these compounds have been described (for example, Sasaki, T .; Kojima, AJ Chem.

Soc. Sec. C, 1970, 476-480; Clark, J., Parvizi, B., Southon, I.W., 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; Elgamey, A.G. A .; El-Taweel, F. M.A., J. Prakt. Chem., 1991, 333, 333-338). Several different synthetic methods have been described for the preparation of 2-acceptor-substituted 3,3-bis (alkyl / arylamino) -2-propenenitriles (Elvidge, J. A. et al., J. Chem.

Soc., Perkin Trans I, 1983, 1741-1744; Yatsishin, A. A. et al., Zh. Org. Khim. 1979, 15, 1381-1384; Hartke, K., Angew. Chem. 1964, 76, 781)

Links

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11. J.A. Ellman, Solid Phase and Combinatorial Synthesis of Benzodiazepine Compounds on Solid Support, US Patent 5,288,514; 22. 2.1994.

Pharmacological methods

The ability of these compounds to act on potassium channels can be determined in several ways. When using the patch-clamp technique (Hamill O. P., Marty A., Nefer E., Sakman B. and Sigworth F. J., Plugers Arch., 391, 85-100 (1981)), ionic current can be recorded in one cell channel.

Potassium channel openers activity of these compounds can also be measured as aortic ring relaxation according to the following procedures:

The section of the rat thoracic aorta between its arch and diaphragm was excised and folded into a circle as described in TaylorP. D. et al., J. Brit Pharmacol, 111, 42-48 (1994).

After 45 min under a tension of 2 g, these preparations were found to reach 80% of the maximal response, using a certain concentration of phenylephrine. When the response to phenylephrine reached plateau, alleged vasodilators were added in small volumes at 2 min intervals. Relaxation was expressed as a percentage of the measured

p. The ability of the substance was expressed as the concentration causing 50% tissue relaxation.

In pancreatic b cells, the opening of the Katp channels can be determined by measuring the subsequent concentration of free cytoplasmic Ca ²⁺ , according to the method described by Arkhammer P. et al., J. Biol. Chem., 262, 5448-5454 (1987).

and*

Release of ⁸⁶ Rb ⁺ from beta cells

and. The RIN 5F cell line was grown in RPM11640 with glutamax I supplemented with 10% & fetal calf serum (from GibcoBRL, Scotland, UK) and was maintained at i; 37 ° C in 95% air-5% CO2. Cells were separated with Trypsin | EDTA (from GibcoBRL, Scotland, UK), resuspended in medium, 1mCi / ml ΐ ⁸⁶ Rb ⁺ was added and plated on microtiter plates (96 wells 3596, sterilized, from Costar

Corporation, Ma, USA) at a density of 50,000 cells / well and at 100 μΙ / well and grew 24 hours before the experiment.

r | Plates were washed 4 times with Ringer buffer (150 mM NaCl, 10 mM Hepes, 3.0 mM KCl, 1.0 mM CaCl 2, 20 mM sucrose, pH 7.1) and 1 µΙ of control or test compound dissolved in DMSO was added. After incubation for 1 hour at room temperature with a lid, 50 μΙ of the supernatant was transferred to Pico plates (Packard Instrument) (Packard Instrument). · · · · · · · · · · · · · · * · * ·

Company, CT, USA) and 100 µΙ of MicroScint 40 (Packard Instrument

Company, CT, U.S.A.). Plates were counted in a TopCount (Packard Instrument

Company, CT, USA) for 1 min / well in the ³² P.

EC50 and EC _{m and} x were calculated by Slide Writ (Advanced Grapfics Software, Inc., USA) using a four-parameter logistic curve: y = (ad) / (1+ (x / c) ^b ) + d, where a = activity at a concentration of zero, b = slope, c = concentration at the center of the curve and d = activity given for infinite concentration. EC50 = c and ECmax = d when the curve reaches an infinite concentration.

The compounds of the present invention are effective over a wide dosage range. In general, satisfactory results are obtained at dosages of from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg per day. The most preferred dosage is from about 5 mg to about 200 mg per day. The exact dose will depend on the route of administration, the form in which the substance is administered, the subject of treatment and the body weight of the subject being treated, and the judgment and experience of the physician or veterinarian.

The route of administration may be any route that effectively transfers the active compound to a suitable or desired site of action, such as oral or parenteral, eg, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal. The oral route is preferred.

A typical composition comprises a compound of Formula I, or a pharmaceutically acceptable acid salt thereof, associated with a pharmaceutically acceptable vehicle, which may be a carrier or diluent, or diluted in a carrier, or enclosed within a carrier, which may be in the form of a capsule, paper or other container. Conventional methods of preparing pharmaceutical compositions can be used to make these compositions. E.g. the active compound is usually mixed with the carrier, or is dissolved in the carrier, or is enclosed with a carrier, which may be in the form of an ampoule, capsule, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid substance which serves as a binder, vehicle, or medium for the active compound. The active compound may be soaked in a granular solid shell. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polymethylcellulose. The composition may also contain humectants, emulsifying and suspending agents, preservatives, sweeteners or flavoring agents. This mixture

The invention may also be designed to provide rapid, sustained or delayed release

Even the active ingredients after administration to the patient by methods well known to the skilled artisan.

£ | These pharmaceutical compositions can be sterilized and mixed with adjuncts

Substances, emulsifiers, salts affecting the osmotic pressure, buffers and / or coloring agents, etc. which do not react harmfully with the active compounds.

For parenteral use, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions of the active compound dissolved in polyhydroxylated castor oil.

• 9 9999 98 9 99 9 9 9 « 9 9 9 • 9 9 • • • ♦ 9 9 9 9 9 · 9 • · • • 9 • 9 • · · · 9 9 • • 9 tt ·· ·· 999 99 ··

Tablets, dragees, or capsules having a talc and / or hydrocarbon carrier or reinforcing agent, etc. are particularly suitable for oral use. Preferred carriers for tablets, dragees, or capsules are lactose, corn starch and / or potato starch. A syrup or elixir may be used as a sweetener.

A typical tablet suitable for use in this manner can be prepared by conventional techniques and comprises;

Active Compound 5.0 mg Lactosum 67.8 mg Ph. Eur.

Avicel ^R 31.4 mg

Amberlite ^R 1.0 mg

Magnesii stearas 0.25 mg Ph. Eur.

Because of their high degree of activity, the compounds of the invention can be administered to an animal in need of such treatment, prevention, eradication, amelioration or amelioration of a number of the diseases mentioned above and in particular endocrine system diseases such as hyperinsulinemia and diabetes. These animals can be both domestic animals such as dogs and cats, as well as wild animals.

DETAILED DESCRIPTION OF THE INVENTION

Example 1.

Preparation of N- (4-methoxybenzyl) -N´-phenylcyanoacetamidine trifluoroacetate

To a suspension of Wang resin (20.0 g, 19.2 mmol, Novabiochem, 0.96 mmol / g content) in DCM (100 mL) was added cyanoacetic acid (30.0 g, 353 mmol) and DMF (100 mL). . While stirring, DIC (25 mL) was added portionwise, causing an exothermic reaction. After the addition of DIC was complete, 4-dimethylaminopyridine (10 mL of a 1M solution in DMF) was added and the resulting mixture was stirred at room temperature for 15 hours. The mixture was filtered and the resin was washed thoroughly with DMF, DCM and methanol. After drying, approximately 20 g of Wang-O-CO-CH ₂ CN resin is obtained.

To this resin (0.30 g, approximately 0.3 mmol, swollen in DCM) was added DMF (4 mL), diisopropylethylamine (0.8 mL), and phenyl isothiocyanate (0.54 mL, 4.5 mmol). The resulting mixture was shaken for 16 hours, filtered, washed with DMF (3 x 6 mL) and a mixture of EDC (0.95 g, 4.95 mmol), DMF (5 mL) and 4 methoxybenzylamine (0.40 mL, 3) was added. 03 mmol). The mixture was shaken for 24 hours, 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 shaken for 35 minutes. Carbon tetrachloride (5 mL) was added and, after filtration and washing with DCM, the filtrates were concentrated. This afforded 84 mg (71%) of N- (4-methoxybenzyl) -N'-phenylcyanoacetamidine trifluoroacetate as an oil which slowly crystallized at room temperature over 48 hours. Recrystallization (ethyl acetate / methanol / heptane) gave 22 mg of the title compound as colorless crystals, mp 161-163 ° C.

· ····

9 ·

9 9 € • € · · Φ € ·

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LCMS (Lichrosorb RP 18, acetonitrile / water gradient, observed pH 214 nm): elution at 7.2 min; MH ⁺ calculated: 280, found: 280. ¹ H NMR (300 MHz, CDCl 3 / DMSO-d 6 1: 1) δ 3.82 (s, br, 3H), 3.89 (s, br, 2H, exchangeable with D2O), 4.60 (s, br, 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, br. 1H); ¹³ C NMR (75 MHz, DMSO-d 6) δ 20.26 (t), 46.17 (t), 55.10 (q), 113.98 (d), 125.66 (d), 126.71 (d), 127.62 (d), 129.19 (d), 137.50 (s, br), 154.36 (s, br), 159.29 (s). Calcd for C19H18F3N3O3 (393.36): C, 58.01; N, 10.68. Found: C, 57.98; H, 4.68; N, 10.47.

Example 2.

Preparation of 2-cyano-3- (3-methylbutylamino) -3- (phenylamino) -2-propenenitrile

To a solution of malononitrile (0.34 g, 5.15 mmol) in DMF (5 mL) at 0 ° C was added phenylisothiocyanate (0.60 mL, 5.02 mmol) first, followed by triethylamine (1.4 mL). The resulting mixture was stirred at 0 ° C for 25 minutes and then a freshly prepared mixture of EDC (2.90 g, 15.1 mmol), 3-methylbutylamine (1.20 mL, 10.3 mmol) and DMF (10 mL) was added. ml). After stirring at room temperature for 2 days, the mixture was poured into a mixture of ice and water (50 mL) and conc. HCl (3 mL). The product was extracted (2 x 30 mL ethyl acetate), the combined organic extracts were washed (2 x 30 mL brine), dried (magnesium sulfate) and concentrated. The remaining oil was mixed with methanol (3 mL) to form a solid precipitate. After 20 hours, the solid was filtered off under vacuum. This afforded 0.60 g (47%) of the title compound as pale yellow crystals. Recrystallization from ethyl acetate / heptane gave 0.40 g of analytically pure sample, mp 183-185 ° C.

LCMS: MH ⁺ calculated: 255, found: 255. ¹ H NMR (400 MHz, DMSO-d 6): δ = 0.83 (d, J = 7 Hz, 6H), 1.40 (q, J = 7 Hz) (2H), 1.57 (nonett, J = 7Hz, 1H), 3.18 (m, 2H),

7.10 (m, 3H), 7.33 (t, J = 8Hz, 2H), 7.87 (s, br, 1H), 9.33 (s, 1H); ¹³ C NMR (100

L MHz, DMSO-d 6): δ = 22.06, 24.90, 35.34, 37.38, 41.92, 118.11, 121.46, 124.16, | 124.16, 129.15, 138.81, 161.43. Calcd for C ₁₅ H ₈ N ₄ (254.34): C, 70.84;

* H, 7.13; N, 22.03. Found: C, 70.88; H, 7.28; N, 21.90.

"Example 3.

Tert-Butyl 3- [3,5-bis (trifluoromethyl) phenylamino] -2-cyano-3- (3 ⁷ methylbutylamino) acrylic acid

From a solution of 2 {N- [3,5-bis (trifluoromethyl) phenyl] thiocarbamoyl} cyanoacetic acid tert-butyl ester ⁷ (1.12 g, 2.7 mmol, prepared from tert-butyl cyanoacetate and 3,5bis (trifluoromethyl)) phenylisothiocyanate in DCM (15 mL) was added 3-methylbutylamine (1.0 in mL, 8.60 mmol), magnesium sulfate (0.5 g), and mercuric oxide (2.0 g). room for 14 hours, diluted with DCM (30 mL), filtered through Celite,

I: washed with ice - cold diluted hydrochloric acid, brine (2 x 20 ml)

1 ml), dried (magnesium sulfate) and concentrated. The residue was crystallized from heptane, and (0.29 g (23%) of the title compound was obtained as colorless crystals, mp 128-129 ° C. An additional 0.25 g (20%) of the product was obtained from the mother liquor.

¹ H NMR (400 MHz, DMSO-d 6): δ = 0.82 (d, H = 7Hz "6H"), 1.41 (s, 9H), 1.43 (q, J = 7Hz, 2H), 1.57 (nonett, J = 7Hz, 1H), 3.18 (q, br, J = 7Hz, 2H), 7.63 (s, 2H), 7.70 (s,

1H), 8.91 (s, br. 1H), 9.52 (s, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 21.96, 24.95, 28.02, 37.50, 41.84.61.55, 79.66, 115.53, 118.67 , 119.87, 123.05 (q, J = 282 Hz), <<>,

9 9 9 9 9 9 9 9 9 9 9 9 9 9

999 99 99

130.44 (q, J = 33 Hz), 142.11, 160.46, 167.93. Calcd for C21H25F6N3O2 (465.44): C, 54.19; H, 5.41; N, 9.03. Found: C, 54.27; H, 5.57; N, 8.84.

Example 4.

Preparation of 3- [3,5-bis (trifloromethyl) phenylamino] -3- (3-methylbutylamino) -2-propenenitrile

To a solution of 3- [3,5-bis (trifluoromethyl) phenylamino] -2-cyano-3- (3-methylbutylamino) -acrylic acid tert-butyl ester (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 was redissolved in carbon tetrachloride (10 mL) and concentrated again, and the product was purified by flash chromatography (6 g silica gel, heptane / ethyl acetate gradient) to give 45 mg (30 mg). LCMS: MH ⁺ = 366. This compound is identical (LCMS) to the product obtained from the solid phase synthesis.

Example 5.

Preparation of 3- [3,5-bis (trifloromethyl) phenylamino] -2-cyano-3- (3-methylbutylamino) -2-propenenitrile

To a solution of malononitrile (0.33 g, 5.00 mmol) in DCM at 0 ° C was first added 3,5-bis (trifluoromethyl) phenyl isothiocyanate (1.41 g, 5.20 mmol) followed by triethylamine (1.0 mL). . The mixture was. stirred at room temperature for 1 hour 45 minutes and then DCM (5 mL) was added,

3-methylbutylamine (1.0 mL, 8.60 mmol), magnesium sulfate (0.57 g) and mercuric oxide (2.54 g, 11.7 mmol). The resulting mixture was stirred at room temperature for 17 hours, becoming dark. The mixture was then filtered (Celite), diluted with DCM (60 mL), washed with ice / water (100 mL) and concentrated HCl (2.0 mL), brine (3 x 50 mL), dried (sulfate) magnesium) and concentrated. The residue was purified by column chromatography (50 g silica gel, heptane / ethyl acetate gradient) to give 1.22 g (63%) of the title compound as a foam. The foam was crystallized from toluene / heptane to give 1.08 g of almost colorless crystals, m.p. 158-159 ° C. ¹ H NMR (300 MHz, _DMSO-R d _6): δ = 0.87 (d, J = 7 Hz, 6H), 1.45 (q, J = 7 Hz, 2H), 1.60 (nonett, J = 7Hz,

1H), 3.31 (m, 2H), 7.72 (s, 2H), 7.78 (s, 1H), 8.22 (s, br, 1H), 9.79 (s, 1H); ¹³ C NMR (75 MHz, DMSO-d 6): δ = 22.04, 24.99, 36.85, 37.14, 59.66, 116.52, 117.52, 121.21,

L 123.02 (q, J = 275Hz), 131.02 (q, J = 33Hz), 141.35, 161.27. Analysis: Calculated

For C17H16F6N4 (390.33): C, 52.31; H, 4.13; N, 14.35. Found: C, 52.80; H, 4.29; N,

13.83.

i v

ί Example 6.

I Preparation of 3- [3,5-bis (trifluoromethyl) phenylamino] -3- (3-methylbutylamino) -2- (4-chlorophenylsulfonyl) -2-propenenitrile | To a solution of 3,5-bis (trifluoromethyl) phenyl isothiocyanate (1.44 g, 5.31 mmol) in DCM (15; mL) and acetonitrile (5 mL) was first added 4-chlorophenylsulfonylacetonitrile (1.10 g, 5.10). ΐ mmol) followed by triethylamine (1.0 mL). The resulting mixture was stirred at room temperature for 2 hours 15 minutes and then isoamylamine (0.65 mL, 5.59 mmol), mercuric oxide was added.

(2.70 g, 12.47 mmol) and magnesium sulfate (0.8 g). Stirring is continued for 2 days. The mixture was then filtered, poured into a mixture of ice and water (20 ml) and concentrated hydrochloric acid (2 ml), the phases were separated, the aqueous phase was extracted twice with DCM (20 ml) and the combined extracts were dried (magnesium sulfate) and concentrated. . Column chromatography of the residue (100 g silica gel, heptane / ethyl acetate 10: 0 to 3: 1 gradient) afforded 317 mg (12%) of the title compound as an oil. ¹ H NMR (300 MHz, DMSO-d 6): δ = 0.79 (d, J = 7Hz, 6H), 1.39 (q, J = 7Hz, 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, br, 1H), 76 (s, 1 H); LCMS: eluting at 16.23 min, MH ⁺ : 540.

Example 7.

Preparation of 3- [3,5-bis (trifloromethyl) phenylamino] -2-cyano-3- [3- (2-oxoazepan-1-yl) propylamino] acrylic acid tert-butyl ester

To a mixture of 3,5-bis (trifluoromethyl) phenyl isothiocyanate (2.83 g, 10.4 mmol), DCM (20 mL) and tert-butyl cyanoacetate (1.65 mL, 11.6 mmol) was added DBU (4.0 ml, 26.8 mmol) exotherm. The resulting mixture was stirred at room temperature for 2 hours and then magnesium sulfate (2.0 g), isoamylamine (2.35 mL) and mercuric oxide (6.80 g, 31.4 mmol) were added. After stirring for 25 hours, the mixture was mixed with celite, filtered, and the filtrate was mixed with 0.5 M hydrochloric acid. After further filtration, the filtrate was extracted (3 x 100 mL DCM), the combined extracts were washed with brine (2 x 300 mL, strong emulsification), dried (magnesium sulfate) and concentrated. Column chromatography (80 g silica gel, gradient elution with heptane / ethyl acetate 10: 0 to 2: 3) afforded 2.23 g (39%) of the title compound as a colorless solid, along with 0.72 g (15%). 3- [3,5-Bis (trifluoromethyl) phenylamino] -2-cyano-3- (3-methylbutylamino) acrylic acid tert-butyl ester. A sample of the title compound is further purified by recrystallization. Colorless solid, m.p. 167-168 ° C (ethyl acetate). LCMS:

F elution at 15.4 min; MH ⁺ : 549; ¹ H NMR (400 MHz, DMSO-d 6): δ = 1.40 (s, 9H), 1.43 b (m, 4H), 1.57 (m, 2H), 1.71 (q, J = 7 Hz, 2H), 2.35 (m, 2H), 3.20 (q, J = 7Hz, 2H), 3.31 (m, 2H), 7.66 (s, 2H), 7, 68 (s, 1H); 8.95 (s, br, 1H); 9.52 (s, 1H); ¹³ C NMR (100

MHz, DMSO-d _6): δ = 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 (q, J = 33 Hz), 142.33, 160.59, 167.95 174.74. Analysis: Calculated for C 25 H 30 F 6 N 4 O 3 (548.53): C, 54.74; H, 5.51; N, 10.21.

_R Found: C, 54.62; H, 5.66; N, 9.97.

| Example 8.

I Preparation of 3- [3,5-bis (trifloromethyl) phenylamino] -3- [3- (2-oxoazepan-1-yl) propylamino] acrylonitrile

1 'To a solution of 3- [3,5-bis (trifluoromethyl) phenylamino] -2-cyano-3- [3- (2-oxoazepan-1-yl) propylamino] acrylic acid tert-butyl ester (203 mg, 0.37 mmol) ) in DCM (6.0 mL)

TFA (6.0 mL) was added at 0 ° C. The resulting mixture was stirred at 0 ° C for 30 minutes and

It was then poured into ice-cooled aqueous NaHCO ₃ (100 mL). After dilution with DCM (30 mL)) the phases were separated, the aqueous layer was extracted (3 x 20 mL), combined

the organic extracts are washed with brine (2 x 50 ml), dried (magnesium sulfate) and

Concentration gave 190 mg (100%) of the title compound as an oil (mixture of isomers). LCMS: elution at 9.97 min, MH ⁺ : 449). ¹ H NMR (300 MHz, DMSO 19)

• · · · · · • · · • · · · • · · • · · • · · · • · · · • '· · • · · · • · · · • · · · · • · «·

d ₆ ): δ = 1.45-1.80 (m, 8H), 2.40 (m, 2H), 2.95 (m, 1H), 3.21 (m, 2H), 3.35 (m, 2H) m, 6H), 3.58 (s, br, 1H), 7.35-7.70 (m, 3H).

Example 9.

Preparation of 2-cyano-3- (4-methoxybenzylamino) -3- (phenylamino) acrylic acid tert-butyl ester

To a solution of tert-butyl cyanoacetate (1.3 mL, 9.12 mmol) in DMF (10 mL) at 0 ° C was added first phennyl isothiocyanate (1.2 mL, 10.0 mmol) followed by triethylamine (2.80 mL). ). The resulting mixture was stirred at 0 ° C for 30 minutes. The mixture was then cooled below 0 ° C and EDC (5.77 g, 30.1 mmol), DMF (30 mL) and 4-methoxybenzylamine (2.65 mL, 20.3 mmol) were added. The mixture was stirred at room temperature for 9 hours, at 60 ° C for 14 hours and then at room temperature for 2 days. The mixture was poured onto ice (150 mL) and concentrated HCl (4 mL). Extraxication (3 x 30 mL ethyl acetate), drying of the combined extracts (magnesium sulfate) and concentration gave an oil which was purified by column chromatography (50 g silica gel, gradient elution with heptane / ethyl acetate 1: 0 to 1: 4) to give 0 43 g (12%) of the title compound as a colorless solid, m.p. 158-159 ° C (ethyl acetate / heptane). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 1.39 (s, 9H), 3.72 (s, 3H), 4.22 (s, br, 2H), 6.89 (d, J = 8 * Hz, 2H), 7.02-7.16 (m, 5H), 7.32 (m, 2H), 8.95 (s, br, 0.5H), 9.18 (s, 0.5H). Analysis:

Calcd. For C ₂ H 25 N ₃ O ₃ (379.46): C, 69.64; H, 6.64; N, 11.07. Found: C, 69.51;

H, 6.80; N, 10.89.

He did

Automated preparation of a set of eight different cyanoenamines

A set of eight different cyanoenamines was prepared as follows: 100 mg of Wang resin resin-bound cyanacetic acid (prepared as described in Example 1) was evenly distributed to eight £ reactors of the "ACT 496" Advanced Chem Tech multiple organic synthesizer. Then, each of the eight reactor worked up as described in Example 1 with 8 different aromatic isothiocyanates, in particular 4trifluormethylfenylisothiokyanátem 2-trifluormethylfenylisothiokyanátem 2.3 dichlorfenylisothiokyanátem ^6, 3-chloro-4-fluorfenylisothiokyanátem, 2-methoxy-4L nitrophenyl isothiocyanate, 2.4 -difluorophenylisothiocyanate, 4I cyanophenylisothiocyanate and 3,5-bis (trifluoromethyl) phenylisothiocyanate. The resulting thioamides are then treated with various primary amines, in particular 2-methylpropylamine, 1,2-dimethylpropylamine, isopropylamine, 1,3-dimethylbutylamine, 2,2-dimethylpropylamine, butylamine, 4f tert-butylcyclohexylamine, 1,2,2-trimethylpropylamine, exo- 2-norbornylamine and cyclohexylmethylamine in such a way that all possible combinations of isothiocyanate amine are formed. After thorough washing, the resulting resin-bound cyanoenamines are cleaved from the substrate by treatment with 50% TFA in DCM (30 minutes) to give a f set of eight different cyanoenamines of 70-> 90% purity (HPLC). The samples were redissolved several times in methanol and concentrated again to remove residual TFA.

Finally, the samples were redissolved in methanol (2 mL) and triethylamine (0.05 mL), concentrated again and redissolved in DMSO (3.5 mL). The resulting solutions were used for examination.

The following cyanoenamine derivatives I are prepared according to the above procedures:

AND

C R ¹ -NR ² R ³ MH ⁺ exp. finding. 1 4- (trifluoromethyl) phenyl 2- (methylpropyl) amino 2 4- (trifluoromethyl) phenyl (1,2-dimethylpropyl) amino 3 4- (trifluoromethyl) phenyl isopropylamino 4 4- (trifluoromethyl) phenyl (1,3-dimethylbutyl) amino 5 4- (trifluoromethyl) phenyl (2,2-dimethylpropyl) amino 6 4- (trifluoromethyl) phenyl butylamino 7 4- (trifluoromethyl) phenyl (4-tert-butylcyclohexyl) amino 366 366 8 4- (trifluoromethyl) phenyl (1,2,2-trimethylpropyl) amino 9 4- (trifluoromethyl) phenyl 2-exo-norbomylamino 10 4- (trifluoromethyl) phenyl (cyclohexylmethyl) amino 11 2- (trifluoromethyl) phenyl 2- (methylpropyl) amino 12 2- (trifluoromethyl) phenyl (1,2-dimethylpropyl) amino 13 2- (trifluoromethyl) phenyl isopropylamino 14 2- (trifluoromethyl) phenyl (1,3-dimethylbutyl) amino 15 Dec 2- (trifluoromethyl) phenyl (2,2-dimethylpropyl) amino 16 2- (trifluoromethyl) phenyl butylamino 284 284 17 2- (trifluoromethyl) phenyl (4-tert-butylcyclohexyl) amino 18 2- (trifluoromethyl) phenyl (1,2,2-trimethylpropyl) amino 19 Dec 2- (trifluoromethyl) phenyl 2-Exo-norbornylamino 20 May 2- (trifluoromethyl) phenyl (cyclohexylmethyl) amino 21 2,3-dichlorophenyl 2- (methylpropyl) amino 22nd 2,3-dichlorophenyl (1,2-dimethylpropyl) amino 23 2,3-dichlorophenyl isopropylamino 24 2,3-dichlorophenyl (1,3-dimethylbutyl) amino 25 2,3-dichlorophenyl (2,2-dimethylpropyl) amino 298 298 26 2,3-dichlorophenyl butylamino 27 Mar: 2,3-dichlorophenyl (4-tert-butylcyclohexyl) amino 28 2,3-dichlorophenyl (1,2,2-trimethylpropyl) amino 29 2,3-dichlorophenyl 2-Exo-norbornylamino 30 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 35 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 39 2-methoxy-4-nitrophenyl 2-Exo-norbornylamino 40 2-methoxy-4-nitrophenyl (cyclohexylmethyl) amino 331 331

• β

41 2,4-difluorophenyl 2- (methylpropyl) amino 42 2,4-difluorophenyl (1,2-dimethylpropyl) amino 266 266 43 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-trimethylpropyl) amino 49 2,4-difluorophenyl 2-Exo-norbornylamino 50 2,4-difluorophenyl (cyclohexylmethyl) amino 51 3-chloro-4-fluorophenyl 2- (methylpropyl) amino 52 3-chloro-4-fluorophenyl (1,2-dimethylpropyl) amino 282 282 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-butylcyclohexyl) amino 350 350 58 3-chloro-4-fluorophenyl (1,2,2-trimethylpropyl) 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-dimethylpropyl) amino 255 255 63 4-cyanophenyl isopropylamino 64 4-cyanophenyl (1,3-dimethylbutyl) amino 65 4-cyanophenyl (2,2-dimethylpropyl) amino 66 4-cyanophenyl butylamino 67 4-cyanophenyl (4-tert-butylcyclohexyl) amino 68 4-cyanophenyl (1,2,2-trimethylpropyl) amino 69 4-cyanophenyl 2-Exo-norbornylamino 70 4-cyanophenyl (cyclohexylmethyl) amino 71 3,5- bis (trifluoromethyl) phenyl 2- (methylpropyl) amino 352 352 72 3,5- bis (trifluoromethyl) phenyl (1,2-dimethylpropyl) amino 73 3,5- bis (trifluoromethyl) phenyl isopropylamino 338 338 74 3,5- bis (trifluoromethyl) phenyl (1,3-dimethylbutyl) amino 380 380 75 3,5- (2,2-dimethylpropyl) amino 366 366 76 bis (trifluoromethyl) phenyl 3,5- bis (trifluoromethyl) phenyl butylamino 77 3,5- bis (trifluoromethyl) phenyl (4-tert-butylcyclohexyl) amino 434 434 78 3,5- bis (trifluoromethyl) phenyl (1,2,2-trimethylpropyl) amino 79 3,5- bis (trifluoromethyl) phenyl 2-Exo-norbornylamino 390 390 80 3,5- bis (trifluoromethyl) phenyl (cyclohexylmethyl) amino 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

and

I • · · ·

· <)))))))))))))))

86 3-pyridyl propylamino 203 203 87 3-pyridyl hexylamino 245 245 88 3-pyridyl propargylamino 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 (trifluoromethyl) phenyl propylamino 338 338 95 3,5- bis (trifluoromethyl) phenyl hexylamino 380 380 96 3,5- bis (trifluoromethyl) phenyl propargylamino 334 334 97 3,5- bis (trifluoromethyl) phenyl (3-methylbutyl) amino 366 366 98 phenyl phenylamino 236 236 99 benzyl (4-methoxybenzyl) amino 294 294 100 ALIGN! phenyl 1-pyrrolidinyl 214 214 101 3- (trifluoromethyl) phenyl (3-methylbutyl) amino 297 297 102 4-Chloro-3- (trifluoromethyl) - phenyl (3-methylbutyl) amino 331 331 103 3-acetylphenyl (3-methylbutyl) amino 271 271 104 2-Chloro-5- (trifluoromethyl) - phenyl (3-methylbutyl) amino 331 331 105 3,4-dicyanophenyl (3-methylbutyl) amino 279 279 106 4-Bromo-2- (trifluoromethyl) - phenyl (3-methylbutyl) amino 376 376 107 4,6-dimethyl-2-pyrimidinyl (3-methylbutyl) amino 259 259 108 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 (trifluoromethyl) phenyl (3-methylbutyl) amino 366 366 112 3,5-dichlorophenyl (2-methylpropyl) amino 284 284 113 3-chloro-4-methylphenyl (2-methylpropyl) amino 263 263 114 2,5- bis (trifluoromethyl) phenyl (2-methylpropyl) amino 351 351 115 3,5- bis (trifluoromethyl) phenyl (3-Phenylpropyl) amino 413 413 116 3,5- bis (trifluoromethyl) phenyl (2,2,6,6-tetramethyl-4-piperidinyl) amino 434 434 117 3,5- bis (trifluoromethyl) phenyl N, N-dipropylamino 379 379 118 3,5- bis (trifluoromethyl) phenyl 2- (4-chlorophenyl) ethylamino 433 433 119 3,5- bis (trifluoromethyl) phenyl 2- (2-pyridyl) ethylamino 400 120 3,5- bis (trifluoromethyl) phenyl 4-Methyl-1-piperidyl 377 377 121 3,5- bis (trifluoromethyl) phenyl N, N-bis (2-methylpropyl) amino 407 407 122 3,5- 1-pyrrolidinyl 349 349

bis (trifluoromethyl) phenyl •

123 3,5- bis (trifluoromethyl) phenyl 3- (1-Imidazolyl) propylamino 403 403 124 3,5- bis (trifluoromethyl) phenyl N-methyl-N- (3-pyridyl) methyl- 400 400 125 3,5- bis (trifluoromethyl) phenyl (3-Amino-2,2-dimethylpropyl) - amino 380 380 126 3,5- bis (trifluoromethyl) phenyl 3- (2-Oxo-1-pyrrolidinyl) propylamino 420 420 127 3,5- bis (trifluoromethyl) phenyl (4-methoxybenzyl) amino 415 415 128 3,5- bis (trifluoromethyl) phenyl 3-hydroxy-1-piperidinyl 379 129 3,5- bis (trifluoromethyl) phenyl tetrahydroisoquinolin-1-yl 411 411 130 3,5- bis (trifluoromethyl) phenyl 2,6-cis-dimethyl-4-morpholinyl 393 393 131 3,5- bis (trifluoromethyl) phenyl 4 - [(3-trifluoromethyl) phenyl] -1-508 piperazinyl 508 132 3,5- bis (trifluoromethyl) phenyl 4-tert-butyl-1-piperidinyl 419 419 133 3,5- bis (trifluoromethyl) phenyl 1-azepanyl 377 377 134 3,5- bis (trifluoromethyl) phenyl 4-Benzoyl-1-piperidinyl 467 467 135 phenyl tetrahydroisoquinolin-1-yl 275 275 136 phenyl (4-methylphenyl) amino 249 249 137 3-cyanophenyl 4- (4-Chloro-phenyl) -1-piperazinyl 363 363 138 3-acetylphenyl tetrahydroisoquinolin-1-yl 317 317 139 3-cyanophenyl N-ethyl-N-phenylamino 289 289 140 phenyl (4-chlorophenyl) amino 270 270

Claims (48)

1 4- (trifluoromethyl) phenyl 2- (methylpropyl) amino H 2 4- (trifluoromethyl) phenyl (1,2-dimethylpropyl) amino H 3 4- (trifluoromethyl) phenyl isopropylamino H 4 4- (trifluoromethyl) phenyl (1,3-dimethylbutyl) amino H 5 4- (trifluoromethyl) phenyl (2,2-dimethylpropyl) amino H 6 4- (trifluoromethyl) phenyl butylamino H 7 4- (trifluoromethyl) phenyl (4-tert-butylcyclohexyl) amino H 8 4- (trifluoromethyl) phenyl (1,2,2-trimethylpropyl) amino H 9 4- (trifluoromethyl) phenyl 2-Exo-norbornylamino H 10 4- (trifluoromethyl) phenyl (cyclohexylmethyl) amino H 11 2- (trifluoromethyl) phenyl 2- (methylpropyl) amino H 12 2- (trifluoromethyl) phenyl (1,2-dimethylpropyl) amino H 13 2- (trifluoromethyl) phenyl isopropylamino H 14 2- (trifluoromethyl) phenyl (1,3-dimethylbutyl) amino H 15 Dec 2- (trifluoromethyl) phenyl (2,2-dimethylpropyl) amino H 16 2- (trifluoromethyl) phenyl butylamino H 17 2- (trifluoromethyl) phenyl (4-tert-butylcyclohexyl) amino H 18 2- (trifluoromethyl) phenyl (1,2,2-trimethylpropyl) amino H 19 Dec 2- (trifluoromethyl) phenyl 2-Exo-norbornylamino H 20 May 2- (trifluoromethyl) phenyl (cyclohexylmethyl) amino H 21 2,3-dichlorophenyl 2- (methylpropyl) amino H 22nd 2,3-dichlorophenyl (1,2-dimethylpropyl) amino H 23 2,3-dichlorophenyl isopropylamino H 24 2,3-dichlorophenyl (1,3-dimethylbutyl) amino H 25 2,3-dichlorophenyl (2,2-dimethylpropyl) amino H 26 2,3-dichlorophenyl butylamino H 27 Mar: 2,3-dichlorophenyl (4-tert-butylcyclohexyl) amino H 28 2,3-dichlorophenyl (1,2,2-trimethylpropyl) amino H 29 2,3-dichlorophenyl 2-Exo-norbornylamino H 30 2,3-dichlorophenyl (cyclohexylmethyl) amino H 31 2-methoxy-4-nitrophenyl 2- (methylpropyl) amino H 32 2-methoxy-4-nitrophenyl (1,2-dimethylpropyl) amino H 33 2-methoxy-4-nitrophenyl isopropylamino H Substituted 3,3-diamino-2-propenenitrile of formula I ¹ * 2 HR ² I kde / R ¹ is alkyl, optionally substituted with halogen, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, dialkylamino, arylalkylamino or diarylamino; aralkyl, aryl, optionally substituted with alkyl, trifluoromethyl, aryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; heteroaryl, optionally substituted with alkyl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; R ² and R ³ are independently hydrogen, alkyl optionally substituted with aryl, heteroaryl, 5-, 6- or 7-membered heterocyclic, halogen, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, dialkylamino, arylalkylamino or diarylamino; aryl, optionally substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; heteroaryl, optionally substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; or R ² and R ³ are joined together by a - (CH ₂ ) n - group wherein n is 4 to 7, provided that R ² and R ³ are not simultaneously hydrogen; Z is hydrogen, cyano, alkoxycarbonyl, optionally substituted aminocarbonyl, alkylsulfonyl or arylsulfonyl, optionally substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or cyano; and pharmaceutically acceptable salts thereof. A substituted 3,3-diamino-2-propenenitrile of formula I according to claim 1, wherein R ¹ is optionally substituted aryl. 3,3-diamino-2-propenenitriles of formula I, wherein r is an integer equal to or greater than 2, at selected known positions in the packaging or selected known positions on the substrate, and one mixture of compounds of formula II or pr of various mixtures of compounds of formula II wherein p is an integer equal to or greater than 2 and p> r, at selected known positions on one or more substrates. 3,3-diamino-2-propenenitriles of the general formula I or of various mixtures substituted Of the 3,3-diamino-2-propenenitriles of formula I at selected known positions in m packages wherein m is an integer equal to or greater than 2. 3. A compound according to claim 2, wherein R @ ¹ is optionally substituted phenyl. A compound of formula I as claimed in claim 2, wherein R @ ¹ is optionally substituted phenyl. · ·· 44 'm is an integer equal to or greater than 2 and m> n, at selected known positions on one or more substrates. The substituted 3,3-diamino-2-propenenitrile of formula I according to claim 3, wherein R ¹ is phenyl substituted with one or two halogen, perhalogen or cyano groups. A substituted 3,3-diamino-2-propenenitrile of formula I according to any one of the preceding claims, wherein Z is hydrogen. The substituted 3,3-diamino-2-propenenitrile of formula I according to claim 1, wherein formula I is selected from the group consisting of: ¹ HR ² NO R ¹ -NR ² R ³ Substituted 3,3-diamino-2-propenenitriles of the general formula I according to any one of the preceding claims, which are active potassium channel openers. A pharmaceutical composition comprising a substituted 3,3-diamino-2-propenenitrile of formula I according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable acid or base, or an optical isomer or a mixture of optical isomers, including racemic mixtures, or any tautomeric form, together with one or more pharmaceutically acceptable carriers or diluents. Pharmaceutical composition for use in the treatment of diseases of the endocrine system, characterized in that it comprises a substituted 3,3-diamino-2-propenenitrile of the general formula I according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base or optical. isomer or a mixture of optical isomers, including a racemic mixture or any tautomeric form, together with one or more pharmaceutically acceptable carriers or diluents. 9 · 9 9 ί · 9 9 «9 9 9 9 9 9 9 9 · 9 99 ♦ 4 9 9 9'9 · ··· 9 · · · · · Pharmaceutical composition according to claim 8 or 9, characterized in that it is in the form of an oral dosage unit or a parenteral dosage unit. Pharmaceutical composition according to claim 8 or 9, characterized in that said substituted 3,3-diamino-2-propenenitrile of the formula I is administered as a dose in the range 0.05 mg to 1000 mg, preferably from 0.1 mg to 1 mg. 500 mg and in particular in the range of 50 mg to 200 mg per day. A substituted 3,3-diamino-2-propenenitrile of formula I according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including racemic mixtures or tautomeric forms thereof. therapeutic use. A substituted 3,3-diamino-2-propenenitrile of formula I according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including racemic mixtures or tautomeric forms thereof. therapeutic use in the treatment or prevention of diseases of the endocrine system, such as diabetes. Use of a substituted 3,3-diamino-2-propenenitrile of formula I according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including racemic mixtures or tautomeric forms. as medicines. Use of a substituted 3,3-diamino-2-propenenitrile of the general formula I according to any one of claims 1 to 6 for the preparation of a medicament. Use of a substituted 3,3-diamino-2-propenenitrile of formula I according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including racemic mixtures or tautomeric forms. for the preparation of a medicament for the treatment or prevention of diseases of the endocrine system such as diabetes. 17. A method of treating or preventing endocrine system diseases, such as diabetes in a subject, in need thereof, comprising administering ·· ···· · «·. • · «· · · • · · · · · · • ^f ♦ · · · '9 • · · · · · · ·· ··« · ·· "·· ·· *' · '*' · An effective amount of a substituted 3,3-diamino-2-propenenitrile of formula I according to any one of claims 1 to 6. A process for the preparation of a medicament for use in the treatment or prevention of endocrine system diseases, such as diabetes, characterized in that said process comprises converting a substituted 3,3-diamino-2-propenenitrile of formula I according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, into a galenic dosage form. 19. Any new feature or combination of features as described herein. A compound of formula II I ''. ¹¹ ......._ where Su is a substrate L is a chemical bond or linker R, R ² and R ³ are as defined above. The compound of claim 20 useful for investigating potassium channel openers. A process for the preparation of a substituted 3,3-diamino-2-propenenitrile of formula (I) according to claim 1, comprising the steps of: a) acylating the alcohol bonded to the substrate of the formula Su-LOH, wherein Su and L ^f are as defined in claim 20 with a cyanoacetic acid derivative of the general formula CN-CH2COX wherein X is hydroxy or a leaving group; (b) reacting the resulting substrate bound intermediate of the formula Su-LO-CO-Chh-CN, wherein Su and L are as defined in claim 20, with an aliphatic or aromatic | an isothiocyanate of the general formula R ¹ -NCS, wherein R ¹ is as defined in claim 20, in the presence of a base; c) reacting the resulting substrate bound substrate Su-LO-CO-CH (CN) C (S) (NHR ¹ ) with an amine of the formula R ² R ³ NH, wherein R ² and R ³ are as defined in claim 1 1, in the presence of a desulfurizing agent, to give a compound of formula II, i d) treating the resulting compound bound to the substrate of formula II by cleavage to give the substituted 3,3-diamino-2-propenenitrile of formula I. 23. The method of claim 22, further comprising the step of screening the final substituted 3,3-diamino-2-propenenitrile of formula I directly against a specific receptor or enzyme. 24. A process for the preparation of a substituted 3,3-diamino-2-propenenitrile of the formula I as claimed in claim 20, comprising the steps of: a) acylating a substrate-bound alcohol of formula Su-L-O-H, wherein Su and L are as defined in claim 20 with a cyanoacetic acid derivative of the formula NC-CH 2 COX, wherein X is hydroxy or a leaving group; b) reacting the resulting substrate bound intermediate of the formula SU-LO-CO-CH2-CN, wherein Su and L are as defined in claim 20, with an aliphatic or aromatic isothiocyanate of the formula R ¹ -NCS, wherein R ¹ is as defined in claim 20, in the presence of a base; c) reacting the resulting substrate bound substrate Su-LO-CO-CH (CN) C (S) (NHR ¹ ) with an amine of the formula R ² R ³ NH, wherein R ² and R ³ are as defined in claim 1, in the presence of a desulfurizing agent, to give a compound of formula II. 25. The method of claim 24, further comprising the step of screening the final product of Formula II directly against a specific receptor or enzyme. 26. The method of claims 20 to 25 wherein the desulfurizing agent is EDC. 27. The process of claims 20 to 26 wherein the base for reacting the isothiocyanate with a cyanoacetic acid ester is a tertiary amine. 28. The process of claims 20 to 27 wherein the cyanoacetic acid derivative is a symmetrical anhydride. 29. A collection comprising m different substituted 30. An assembly comprising various compounds of formula (II) wherein m is an integer equal to or greater than 2 at selected known positions on one or more substrates. 31. An assembly according to claim 29 or 30, wherein m is between 60 and 100, preferably 80. 32. A set comprising one substituted 3,3-diamino-2-propenenitrile of formula I or n various substituted 3,3-diamino-2-propenenitriles of formula I wherein n is an integer equal to or greater than 2 in selected known positions in m shells, or selected known positions on the substrate, and one compound of formula II or mn of various compounds of formula II? where 33. The assembly of claim 32, wherein m is between 60 and 100, preferably 80. 34. A set comprising p different mixtures of substituted 3,3-diamino-2-propenenitriles of formula I, at selected known positions in p packages, wherein p is an integer equal to or greater than 2. 34 2-methoxy-4-nitrophenyl (1,3-dimethylbutyl) amino H 35 2-methoxy-4-nitrophenyl (2,2-dimethylpropyl) amino H 36 2-methoxy-4-nitrophenyl butylamino H 37 2-methoxy-4-nitrophenyl (4-tert-butylcyclohexyl) amino H 38 2-methoxy-4-nitrophenyl (1,2,2-trimethylpropyl) amino H 39 2-methoxy-4-nitrophenyl 2-Exo-norbornylamino H 40 2-methoxy-4-nitrophenyl (cyclohexylmethyl) amino H 41 2,4-difluorophenyl 2- (methylpropyl) amino H 42 2,4-difluorophenyl (1,2-dimethylpropyl) amino H 43 2,4-difluorophenyl isopropylamino H 44 2,4-difluorophenyl (1,3-dimethylbutyl) amino H 45 2,4-difluorophenyl (2,2-dimethylpropyl) amino H 46 2,4-difluorophenyl butylamino H 47 2,4-difluorophenyl (4-tert-butylcyclohexyl) amino H 48 2,4-difluorophenyl (1,2,2-trimethylpropyl) amino H 49 2,4-difluorophenyl 2-Exo-norbornylamino H 50 2,4-difluorophenyl (cyclohexylmethyl) amino H 51 3-chloro-4-fluorophenyl 2- (methylpropyl) amino H 52 3-chloro-4-fluorophenyl (1,2-dimethylpropyl) amino H 53 3-chloro-4-fluorophenyl isopropylamino H 54 3-chloro-4-fluorophenyl (1,3-dimethylbutyl) amino H 55 3-chloro-4-fluorophenyl (2,2-dimethylpropyl) amino H 56 3-chloro-4-fluorophenyl butylamino H 57 3-chloro-4-fluorophenyl (4-tert-butylcyclohexyl) amino H 58 3-chloro-4-fluorophenyl (1,2,2-trimethylpropyl) amino H 59 3-chloro-4-fluorophenyl 2-Exo-norbornylamino H 60 3-chloro-4-fluorophenyl (cyclohexylmethyl) amino H 61 4-cyanophenyl 2- (methylpropyl) amino H 62 4-cyanophenyl (1,2-dimethylpropyl) amino H 63 4-cyanophenyl isopropylamino H 64 4-cyanophenyl (1,3-dimethylbutyl) amino H 65 4-cyanophenyl (2,2-dimethylpropyl) amino H 66 4-cyanophenyl butylamino H 67 4-cyanophenyl (4-tert-butylcyclohexyl) amino H 68 4-cyanophenyl (1,2,2-trimethylpropyl) amino H 69 4-cyanophenyl 2-Exo-norbornylamino H 70 4-cyanophenyl (cyclohexylmethyl) amino H 71 3,5- bis (trifluoromethyl) phenyl 2- (methylpropyl) amino H 72 3,5- bis (trifluoromethyl) phenyl (1,2-dimethylpropyl) amino H 73 3,5- bis (trifluoromethyl) phenyl isopropylamino H 74 3,5- bis (trifluoromethyl) phenyl (1,3-dimethylbutyl) amino H 75 3,5- bis (trifluoromethyl) phenyl (2,2-dimethylpropyl) amino H 76 3,5- bis (trifluoromethyl) phenyl butylamino H 77 3,5- bis (trifluoromethyl) phenyl (4-tert-butylcyclohexyl) amino H 78 3,5- bis (trifluoromethyl) phenyl (1,2,2-trimethylpropyl) amino H 79 3,5- 2-Exo-norbornylamino H bis (trifluoromethyl) phenyl ♦ l · Ir ^r 80 3,5- bis (trifluoromethyl) phenyl (cyclohexylmethyl) amino H 81 phenyl (4-methoxybenzyl) amino H 82 3-fluorophenyl propylamino H 83 3-fluorophenyl hexylamino H 84 3-fluorophenyl propargylamino H 85 3-fluorophenyl (3-methylbutyl) amino H 86 3-pyridyl propylamino H 87 3-pyridyl hexylamino H 88 3-pyridyl propargylamino H 89 3-pyridyl (3-methylbutyl) amino H 90 3,4-dichlorophenyl propylamino H 91 3,4-dichlorophenyl hexylamino H 92 3,4-dichlorophenyl propargylamino H 93 3,4-dichlorophenyl (3-methylbutyl) amino H 94 3,5- bis (trifluoromethyl) phenyl propylamino H 95 3,5- bis (trifluoromethyl) phenyl hexylamino H 96 3,5- bis (trifluoromethyl) phenyl propargylamino H 97 3,5- bis (trifluoromethyl) phenyl (3-methylbutyl) amino H 98 phenyl phenylamino H 99 benzyl (4-methoxybenzyl) amino H 100 ALIGN! phenyl 1-pyrrolidinyl H 101 3- (trifluoromethyl) phenyl (3-methylbutyl) amino H 102 4-Chloro-3- (trifluoromethyl) - phenyl (3-methylbutyl) amino H 103 3-acetylphenyl (3-methylbutyl) amino H 104 2-Chloro-5- (trifluoromethyl) - phenyl (3-methylbutyl) amino H 105 3,4-dicyanophenyl (3-methylbutyl) amino H 106 4-Bromo-2- (trifluoromethyl) - phenyl (3-methylbutyl) amino H 107 4,6-dimethyl-2-pyrimidinyl (3-methylbutyl) amino H 108 4-acetylphenyl (3-methylbutyl) amino H 109 3,5-dichlorophenyl (3-methylbutyl) amino H 110 3-chloro-4-methylphenyl (3-methylbutyl) amino H 111 2,5- bis (trifluoromethyl) phenyl (3-methylbutyl) amino H 112 3,5-dichlorophenyl (2-methylpropyl) amino H 113 3-chloro-4-methylphenyl (2-methylpropyl) amino H 114 2,5- bis (trifluoromethyl) phenyl (2-methylpropyl) amino H 115 3,5- bis (trifluoromethyl) phenyl (3-Phenylpropyl) amino H 116 3,5- bis (trifluoromethyl) phenyl (2,2,6,6-tetramethyl-4- piperidinyl) amino H 117 3,5- bis (trifluoromethyl) phenyl N, N-dipropylamino H 118 3,5- bis (trifluoromethyl) phenyl 2- (4-chlorophenyl) ethylamino H 119 3,5- 2- (2-pyridyl) ethylamino H bis (trifluoromethyl) phenyl * · • • · ' • ···· · ' • »» • • • · ♦ • • · • • • • • · • Φ • • • • • • · • • • • · ' • ·· • · «· • Φ · • · «· 120 3,5- bis (trifluoromethyl) phenyl 4-Methyl-1-piperidyl H 121 3,5- bis (trifluoromethyl) phenyl N, N-bis (2-methylpropyl) amino H 122 3,5- bis (trifluoromethyl) phenyl 1-pyrrolidinyl H 123 3,5- bis (trifluoromethyl) phenyl 3- (1-Imidazolyl) propylamino H 124 3,5- bis (trifluoromethyl) phenyl N-methyl-N- (3-pyridyl) methylamino H 125 3,5- bis (trifluoromethyl) phenyl (3-Amino-2,2-dimethylpropyl) amino H 126 3,5- bis (trifluoromethyl) phenyl 3- (2-Oxo-1-pyrrolidinyl) propylamino H 127 3,5- bis (trifluoromethyl) phenyl (4-methoxybenzyl) amino H 128 3,5- bis (trifluoromethyl) phenyl 3-hydroxy-1-piperidinyl H 129 3,5- bis (trifluoromethyl) phenyl tetrahydroischinolin-1-yl H 130 3,5- bis (trifluoromethyl) phenyl 2,6-cis-dimethyl-4-morpholinyl H 131 3,5- bis (trifluoromethyl) phenyl 4 - [(3-Trifluoromethyl) phenyl] -1- piperazinyl H 132 3,5- bis (trifluoromethyl) phenyl 4-tert. butyl-1-piperidinyl H 133 3,5- bis (trifluoromethyl) phenyl 1-azepanyl H 134 3,5- bis (trifluoromethyl) phenyl 4-Benzoyl-1-piperidinyl H 135 phenyl tetrahydroisoquinolin-1-yl H 136 phenyl (4-methylphenyl) amino H 137 3-cyanophenyl 4- (4-chlorophenyl) -1-piperazinyl H 138 3-acetylphenyl tetrahydroisoquinoliri-1-yl H 139 3,5- bis (trifluoromethyl) phenyl 3- (2-oxo-1-azepanyl) propylamino H 140 3,5- bis (trifluoromethyl) phenyl 3- (2-Oxo-1-azepanyl) propylamino tert-butyloxy- carbonyl 141 3,5- bis (trifluoromethyl) phenyl (3-methylbutyl) amino cyano 142 3,5- bis (trifluoromethyl) phenyl (3-methylbutyl) amino tert-butyloxy- carbonyl 143 3,5- bis (trifluoromethyl) phenyl (3-methylbutyl) amino (4-chlorophenyl) sulfonyl 144 phenyl (4-methoxybenzyl) amino tert-butyloxy- carbonyl 145 phenyl (3-methylbutyl) amino cyano 146 3-cyanophenyl N-ethyl-N-phenylamino H 147 phenyl (4-chlorophenyl) amino H 35. An assembly comprising p different mixtures of a compound of formula II, wherein p is an integer equal to or greater than 2, at selected known positions on one or more substrates. 36. The assembly according to claim 34 or 35, wherein p is between 60 to 100, preferably 80. 37. An assembly comprising one mixture of substituted Kit according to claim 37, characterized in that p is between 60 to 100, preferably 80. 39. A method for preparing a package according to claim 30 or 31, comprising performing at selected known positions on one or more substrates the following steps: (a) simultaneous acylation of each and each individual substrate-bound alcohol of formula Su-L-OH, wherein Su and L are as defined in claim 20 with a cyanoacetic acid derivative of formula NC-CH 2 -COX, wherein X is hydroxy or a leaving group; b) reacting each and each individual formed intermediate substrate bound to the formula Su-LO-CO-CH ₂ -CN, wherein Su and L are as defined in claim 20, with an isothiocyanate of the formula R ¹ -NCS, wherein R ¹ is as defined in claim 20, in the presence of a base; c) alkylation of each and each of the individual formed intermediate substrate-bound Su-LO-CO-CH (CN) -C (S) (NHR ¹ ) with an amine of formula R ² R ³ NH, wherein R ² and R ³ are as defined above said in claim 1, in the presence of a desulfurizing agent, to obtain a compound of formula II attached to one or more substrates. 40. The method of claim 33 or 35, further comprising the step of: d) treating the resulting m compounds bound to the substrate of formula II by cleavage to obtain m substituted 3,3-diamino-2-propenenitriles of formula I at selected positions in m packages wherein m is an integer equal to or greater than 2. 41. The method of claim 32 or 33, further comprising the step of; d) treating the resulting m compounds bound to the substrate of formula II by cleavage to obtain n substituted 3,3-diamino-2-propenenitriles of the general formula I and mn compounds of the formula II, at selected positions in m packages or m packages, or substrate. Process according to any one of claims 39, 40 or 41, characterized in that the base for reacting the isothiocyanate with cyanacetic acid in claim 39, step b) is a tertiary amine. 43. The process of any one of claims 39 to 42, wherein the cyanoacetic acid derivative is a symmetrical anhydride. 44. The method of any one of claims 39 to 43, further comprising the step of screening the final product directly against a specific receptor or enzyme. , A set of substituted 3,3-diamino-2-propenenitriles of formula I according to any one of claims 29 or 31, wherein: Z is hydrogen and R ^f is phenyl, 4-trifluoromethylphenyl, 2-trifluoromethylphenyl, 2,3-dichlorophenyl, 3-chloro-4-fluorophenyl, 2-methoxy-4-nitrophenyl, 2,4-difluorophenyl, 4-cyanophenyl, 3,5bis (trifluoromethyl) phenyl , 3-fluorophenyl, 3-pyridyl, 3,4-dichlorophenyl or benzyl. A set of substituted 3,3-diamino-2-propenenitriles of formula I according to any one of claims 29, 31 or 44, wherein, R ² is 2-methylpropyl, 1,2-dimethylpropyl, isopropyl, 1,3-dimethylbutyl, 2,2k dimethylpropyl, butyl, 4-tert-butylcyclohexyl, 1,2,2-trimethylpropyl, exo-2-norbornyl and the! [cyclohexylmethyl, 4-methoxybenzyl, phenyl, propyl, hexyl, propargyl or 3-methylbutyl, or R ² and R ³ are connected to each other by - (CH 2) _n -, wherein n is 4-7. 47. Use of a kit according to any one of claims 29 to 38 to investigate substituted 3,3-diamino-2-propenenitriles of formula I against specific receptors or enzymes. (B) Use of a collection according to any one of claims 29 to 38 for examination of substituted 3,3-diamino-2-propenenitriles of formula I against potassium channels.