MXPA98010633A - Heterociclilmetilamino derivatives of ciclobuten-3,4-dionas as pota channel modulators - Google Patents

Abstract

The compounds of the formula (I) wherein R 1 and R 2 are independently, hydrogen, a straight alkyl chain, a branched chain of alkyl, cycloalkyl, bicycloalkyl, or aralkyl, wherein the aromatic portion of the aralkyl group, can be optionally substituted, with one to three straight chains of alkyl, a branched chain of alkyl, halogen, nitro, cyano, alkoxy, an alkoxycarbonyl, groups of trifluoromethylotrifluoromethoxy, R3 is hydrogen, formyl, alkanoyl, alkenoyl, alkylsulfonyl, aroyl, arylalkenoyl, arylsulfonyl, arylalkanoylaryl, alkylsulfonyl; A is selected from the group consisting of (a), (b), (c), (d) and (e) wherein n is 0 or 1; R4, R5 and R6 are independently, cyano, amino, alkyl, perfluoroalkyl, alkoxy, perfluoroalkoxy, alkylamino, dialkylamino, sulfamyl, alkylsulfonamido, arylsulfonamido, alkylcarboxamido, arylcarboxamido, alkanoyl, alkylsulfonyl, arylsulfonyl, chloro, bromo, fluoro, yodi, 1-imidazolyl, carboxylohydrogen; Therapeutically acceptable, relax the muscles suav

Description

HETEROCICLILMETILAMINO DERIVATIVES OF CICLOBUTEN-3, 4-DIONAS AS POTASSIUM CHANNEL MODULATORS Background of the Invention The present invention relates to novel cyclobutene heterocyclyl 3-4-dion derivatives having a pharmacological activity, a process of their preparation, pharmaceutical compositions containing these and their use in the treatment of disorders associated with the soft muscle contraction, through the modulation of the potassium channel. These disorders include urinary incontinence, asthma, premature labor, intestinal irritation syndrome, cardiac congestion deficiency, angina, cerebral vascular disease and hypertension. Stemp et al. , (EP-426379) discloses a class of derivatives of substituted amino cyclobutenodiones, of crómanos, dibed to have a blood pressure lowering activity and a bronchodilatory activity. Takeno et al. , reports a series of diaminocyclobutene-3, 4-diones in the Public Patent Discovery Bulletin No. 6-92915. Our own efforts in this area have been discovered in the following United States Patents: 5,464,867; 5,466,712: 5,403,853: 5,403,854: 5,397,790 and REF .: 29014 5,401,753. Many series of l-amino-2-phenoxyalkylamino derivatives have been reported as antagonists of the H-2 receptor, by Aligieri et al. , in U.S. Patent Number 4,390,701. Several 1-amino-2-phenoxyalkylamino derivatives have been discovered by Nohara et al. , in U.S. Patent Number 4,673,747. Additionally, several related l-amino-2-pyridyloxyalkylamino derivatives have been discovered by Nohara et al. , in EP-112704 and were reported as H-2 antagonists. A 4-pyridinylmethylamino derivative of cyclobutenodion was discovered by Chandr Akumar et al. , in US Pat. No. 5,354,746, for having analgesic activity. The compounds of the Chandrakúmar series require the presence of a tricyclic dibenzoxazepine moiety. A 3-pyridinylmethylamino derivative of cyclobutenodion was discovered by Ife in Ep-112704 and was reported to be an antagonist of H-2. The compounds of the Ife series require the presence of a portion of N'-pyridyl diamine. The synthesis of the variably substituted 1,2-diamino-cyclobutene-3,4-dions is dibed in the following publications: Tietze et al. , Chem Ber. 1991, 124, 1215; Tietze et al. , Bloconjugate Chem. 1991, 2, 148; Ehrhardt et al. , Chem Ber. 1977, 110, 2506 and Neuse et al. , Liebigs Ann. Chem. 1973, 619.

Diption of the invention In accordance with the present invention, there is provided a group of compounds, represented by the formula (I): where: R? And R2 are independently hydrogen, a straight chain of alkyl of 1 to 10 carbon atoms, a branched chain of alkyl of 3 to 10 carbon atoms, a cycloalkyl of 3 to 8 carbon atoms, a bicycloalkyl of 4 to 10. carbon atoms, or an aralkyl of 7 to 20 carbon atoms, wherein the aromatic portion of the aralkyl group, can be optionally substituted, with one to three straight alkyl chains of 1 to 10 carbon atoms, a branched alkyl chain , from 1 to 10 carbon atoms, halogen, nitro, cyano, alkoxy of 1 to 6 carbon atoms, an alkoxycarbonyl of 2 to 7 carbon atoms, or trifluoromethyl or trifluoromethoxy groups; R3 is hydrogen, formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms , arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkysulfonyl of 7 to 12 carbon atoms; A is selected from the group consisting of: wherein: n is 0 or 1: R4 / R5 and R6 are independently, cyano, amino, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, sulfa il, alkylsulfonamido of 1 to 6 carbon atoms, arylsulfonamido from 6 to 12 carbon atoms, alkylcarboxamido of 2 to 7 carbon atoms, arylcarboxamido of 7 to 13 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, arylsulfonyl of 6 to 12 atoms of carbon, chlorine, bromine, fluorine, iodine, 1-imidiazolyl, carboxyl or hydrogen; or a pharmaceutically acceptable salt thereof. A preferred aspect of this invention includes the compounds of the formula (I) wherein: R? and R2 are as stated above; R3 is hydrogen; A is selected from the following group: wherein R, R5 and R6 are as defined above; or a pharmaceutically acceptable salt thereof. The preferred values of R x and R 2 are independently hydrogen, methyl, ethyl, n- or isopropyl, n-, iso-, sec- or tert-butyl, straight or branched chain of pentyl, or phenylalkyl, wherein the methylene alkyl or ethylene, and wherein the phenyl portion may be optionally substituted by one to three substituents selected from methyl, ethyl, fluorine, chlorine, bromine, nitro, cyano, methoxy, ethoxy, methoxy-oxycarbonyl, ethoxy-oxycarbonyl, trifluoromethyl, and trifluoromethoxy. R3 is preferably hydrogen, n is preferably 0. Preferred values of R4, R5 and Re are independently hydrogen, cyano, nitro, araino, methyl, methoxy, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethoxy or carboxyl.

The compounds of the formula (I) with a particular interest are: 3- (1, 1-dimethylpropylamino-4- [(pyridin-4-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dione or a pharmaceutically acceptable salt thereof 3- (1, 1-dimethylpropylamino-4- [(pyridin-3-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion or a pharmaceutically acceptable salt thereof. - (1,1-dimethylpropylamino-4- [(pyridin-2-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion or a pharmaceutically acceptable salt thereof 3-tert-butylamino-4- [ (pyridin-4-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion or a pharmaceutically acceptable salt thereof 3-tert-butylamino-4- [(pyridin-3-ylmethyl) -amino] - Cyclobut-3-ene-1, 2-dion or a pharmaceutically acceptable salt thereof 3-tert-butylamino-4- [(iridin-2-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion or a pharmaceutically acceptable salt thereof 3- (isopropyl-methyl-amino) -4- [(pyridin-4-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dione or a pharmaceutical salt acceptable for this, 3- [(5-nitro-benzofuran-2-ylmethyl) -amino-4- (1,2,2-trimethylpropylamino) cyclobut-3-ene-1, 2-dione or a pharmaceutically acceptable salt of East. 3- (1, 1-dimethyl-propylamino) -4- [(5-nitro-benzofuran-2-ylmethyl) -amino] -cyclobut-3-ene-1,2-dion or a pharmaceutically acceptable salt thereof. 3-tert-butylamino-4- [(5-nitro-benzofuran-2-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion or a pharmaceutically acceptable salt thereof. 2-. { [2- (1, 1-dimethyl-propylamino) -3,4-dioxo-cyclobut-1-enylamino] -methyl} -benzofuran-5-carbonitrile or a pharmaceutically acceptable salt thereof. 2-. { [3,4-dioxo-2- (1,2, 2-trimethyl-propylamino) -cyclobut-1-enylamino] -methyl} -benzofuran-5-carbonitrile or a pharmaceutically acceptable salt thereof. 2- [(2-tert-butylamino-3,4-dioxo-cyclobutyl-1-yl) -methyl] -benzofuran-5-carbonitrile or a pharmaceutically acceptable salt thereof. 2-. { [2- (1, 1-dimethyl-2-phenyl-ethylamino) -3,4-dioxo-cyclobut-1-enylamino] -methyl} -benzofuran-5-carbonitrile or a pharmaceutically acceptable salt thereof. 3- [(pyridin-4-ylmethyl) -amino] -4- (1,2,2-trimethyl-propylamino) -cyclobut-3-ene-1,2-dion or a pharmaceutically acceptable salt thereof. 2-. { [2- (1,1-dimethyl-propylamino) -3,4-dioxo-cyclobut-l-enynyl] -methyl} 3-chloro-benzofuran-5-carbonitrile or a pharmaceutically acceptable salt thereof.

It should be understood that the definition of the compounds of the formula (i), wherein R 1 f R 2, R 3, R 4, R 5 or R 6 contain asymmetric chiral centers, covers all possible mixtures and stereoisomers thereof, which possess the activity discussed later. In particular, it encompasses the racemic modifications and any of the optical isomers having the indicated activity. The optical isomers can be obtained in pure form, by means of normal separation techniques, or specific enantiomer synthesis. It should be understood that this invention encompasses all crystalline forms of the compounds of the formula (I). The compounds of this invention, by this specification, are equivalently called 3,4-diones or 1,2-diones. The pharmaceutically acceptable salts of the basic compounds of this invention, are those derived from organic and inorganic acids, such as: lactic, citric, acetic, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic and similarly acceptable and known acids. Where R, R5 or Rβ contains a carboxyl group, the salts of the compounds of this invention can be formed with bases such as alkali metals (Na, K, Li) or the alkaline earth metals (Ca or Mg). The present invention also provides a process for the preparation of a compound of the formula (I). More particularly, the compounds of the formula (I) can be prepared by reacting the compound of the formula (II): wherein X is an appropriate leaving group, for example, methoxy, ethoxy, isopropoxy, butoxy, halogen, or a similar leaving group with a compound of the formula (III): and ^ ai HNs a2 »32 (III) where Ral and Ra2 are Rx and R2, respectively, as defined above, or a group of atoms convertible thereto. In a subsequent intermediate, it can be reacted with a compound of the formula (IV): TO? CH2NH2 jy ^ where Ai is A, as defined above, or a group of atoms convertible to these. The reactions mentioned above can be carried out in a solvent such as acetonitrile, methanol, ethanol, tetrahydrofuran or dioxane, at elevated or ambient temperatures. Moreover, the reaction order can be inverse, that is, a compound of the formula (ii) can be reacted initially with a compound of the formula (IV). The subsequent intermediate can then be reacted with a compound of the formula (III) as described above to give a compound of the formula (I). The compounds of the formula (I) and their pharmaceutically acceptable salts are mild muscle relaxants, which function through activation of the potassium channel. They are, therefore, useful in the treatment of disorders associated with soft muscle contraction, disorders involving excessive contraction of the soft muscles in the urinary tract (urinary incontinence), or the gastrointestinal tract (intestinal irritation syndrome). , asthma or hair loss. Moreover, the compounds of formula (I) are, in the form of potassium channel activators, useful in the treatment of peripheral vascular disease, hypertension, cardiac congestion deficiency, stroke, anxiety attack, cerebral anoxia and others. neurodegenerative disorders. The present invention accordingly provides a pharmaceutical composition, in combination or association with a pharmaceutically acceptable excipient. In particular, the present invention provides a pharmaceutical composition, which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable excipient. The compositions are preferably adapted for oral administration. However, these can be adapted for other modes of administration, for example, parenteral administration for patients suffering from cardiac deficiency. In order to obtain administration consistency, it is preferred that a composition of the invention be in the form of a unit dose. Suitable unit dosage forms include tablets, capsules and powders in bags or ampoules. Said dosage unit forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg. Unitary dosage forms, still mostly preferred, contain from 5 to 25 mg of a compound of the present invention. The compounds of the present invention can be administered orally at a dosage range of approximately between 0.01 and 100 mg / kg. or preferably at a dosage range of between 0.1 and 100 mg / kg. Said compositions can be administered from 1 to 6 times a day, more commonly from 1 to 6 times a day. The compositions of the invention can be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent and the like. These are formulated in a conventional manner, for example, in a manner similar to that used for known hypertensive agents, diuretics and β-blocking agents. The present invention, furthermore, provides a method for the treatment of soft muscle disorders in mammals, including man, which comprises administering to the affected mammal, an effective amount of a compound of a pharmaceutical composition of the invention. The following examples are presented to illustrate, but not limit, the production methods of the representative compounds of the invention.

Example 1 3- (1, 1-Dimethylpropylamino) -4- (pyridin-4-ylmethyl) -amino] -cyclobut-3-ene-l, 2-dion A solution of 3,4-dibutoxycyclobut-3-ene-1, 2-dion (4.526 g, 20 mMol) and 1,1-dimethylpropylamine (1743 g, 20 mMol) in tetrahydrofuran (20 mL) was stirred at room temperature for 19.5 hours. The solvent was removed and the residue was subjected to chromatography (gravity, chloroform-hexane) on neutral silica, activity III (150 g). The white solid was isolated from the appropriate eluents and recrystallized from hexane to give 4.105 g (86%) of a white product: mp. 56.5-57.5 ° C (softens at 55.5 ° C), One gram of this material was recrystallized twice from hexane, to provide 0.794 g of 3-butoxy-4- (1,1-dimethylpropylamino) cyclobut-3-ene-1 , 2-dion, in the form of a white solid: mp. 56-57 ° C (softens at 55 ° C); 1H NMR (DMSO-d6): d 8.63 and 8.48 (two br S, rotomeres), 4.67 (m, br, 2H), 1. 67 (m, br, 4H), 1.39 (m, 2H), 1.26 (m, br, 6H), 0.91 (t, 3H), 0.78 (t, 3H). IR (KBr): 3170, 1790, 1700 cm "1; MS (m / z) 239 (M *) A solution of 3-butoxy-4- (1,1-dimethylpropylamino) -cyclobut-3-ene-1, 2-dione (1197 g, 5.0 mMol) and 4-a inomethylpyridine (0.541 g) in tetrahydrofuran (10 mL) were stirred at room temperature for 23 hours.The mixture was freed from the solvent and the residue was triturated with diethyl ether and dried provide 1154 g of a soft solid. Recrystallization (ods times) of the crude product from methanol gave 0.832 g (61%) of 3- (1,1-dimethylpropylamino) -4- [(pyridin-4-ylmethyl) -amino] cyclobut-3-ene-1, 2-dion, in the form of a white compound:: mp. 258. 0-259.5 C (softens to 257.5CC); XH NMR (DMSO-d6): 5 8.56 (m, 2H), 7.86 (m, br, 1H), 7.46 (s, br, 1H), 7.32 (m, 2H), 4.77 (d, 2H), 1.32 ( s, 6H), 0.83 (t, 3H). IR (KBr): 3270, 1790, 1650 cm "1; MS (m / z) 273 (M *) Elemental Analysis of Calculated C15Hi9N0: C, 65.91; H, 7.01; N, 15.37 Found: C, 65.55; H, 6.88; N, 15.12 Example 2 3- (1, 1-Dimethylpropylamino) -4-T (pyridin-3-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion Tetrahydrofuran (10 mL), 3-butoxy-4- (1,1-dimethylpropylamino) cyclobut-3-ene-1, 2-dion (1197 g, 5.0 mMol, as prepared in Example 1) and 3-aminomethyl- pyridine (0.541 g) were stirred together at room temperature for 24 hours. The reaction mass was freed from the solvent and the residue was triturated with diethyl ether and dried to obtain 1228 g of a cream colored solid. The two recrystallizations of this material, from methanol, gave 0.887 g (65%) of 3- (1,1-dimethylpropylamino) -4- [(pyridin-3-ylmethyl) amino] cyclobut-3-ene-1, 2-dion, in the form of a white solid: mp. 263.5-264.5 ° C (softens to 260. 0 ° C); 1H NMR (DMS0-d6): d 8.57 (m, HH), 8.52 (m, HH), 7.80 (m, br, HH), 7.76 (m, HH), 7.41 (m, HH), 7.39 (s, br, ÍH), 4.72 (d, 2H), 1.66 (q, 2H), 1.30 (S, 6H), 0.82 (t, 3H). IR (KBr): 3230, 1790, 1650 cm "1; MS (m / z) 274 (M + H) *.

Elemental Analysis of C ^ H ^ N ^ Calculated: C, 65.91; H, 7.01; N, 15.37 Found: C, 66.23; H, 7.08; N, 15.38 Example 3 3- (1, 1-Dimethylpropylamino) -4-r (pyridin-2-ylmethyl) -amino-cyclobut-3-ene-l, 2-dion A solution of 3-butoxy-4- (1,1-dimethylpropylamino) cyclobut-3-ene-1,2-dion (0.622 g, 2.6 mMol) in tetrahydrofuran (5 mL) was stirred at room temperature for 22 hours. Removal of the solvent, trituration of the residue and drying afforded 0.656 g of a white solid. Recrystallization (twice) of the crude product, from acetonitrile, gave 0.447 g (63%) of 3- (1,1-dimethylpropylamino) -4- [(pyridin-2-ylmethyl) amino] cyclo-but-3 -eno-l, 2-dion, in the form of a white solid: mp. 192.0-192.5 ° C (softens at 188.5 ° C); E NMR (DMSO-d6): d 8.58 (m, ÍH), 8.00 (m, br, ÍH), 7.82 (m, ÍH), 7.58 (s, br, 1H), 7.37 (m, ÍH), 7.33 ( m, ÍH), 4.85 (d, 2H), 1.31 (s, 6H), 0.83 (t, 3H). IR (KBr): 3210, 1790, 1660 cm "1; MS (m / z) 273 (M +).

Elemental Analysis of Calculated C15H19N302: C, 65.91; H, 7.01; N, 15.37 Found: C, 65.78; H, 6.94; N, 15.48 Example 4 3-tert-Butylamino-4-r (pyridin-4-ylmethyl) -amino-cyclobut-3-ene-l, 2-dion In a process similar to that described in Example 1, using the appropriate starting materials, a 3-tert-Butylamino-4- [(pyridin-4-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion , was prepared in the form of a white solid: mp. 271. 0-271.5 ° C (softens at 269.5 ° C).

Example 5 3-tert-Butylamino-4- (pyridin-3-ylmethyl) -amino] -cyclobut-3-ene-l, 2-dion In a process similar to that described in Example 1, using the appropriate starting materials, a 3-tert-butylamino-4- [(pyridin-3-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion , was prepared in the form of a white solid: mp. 296.0 ° C (softens at 290.5 ° C).

Example 6 3-tert-Butylamino-4- f (pyridin-S-ylmethyl) -aminol-cyclobut-3-ene-1, 2- dion In a process similar to that described in Example 1, using the appropriate starting materials, a 3-tert-Butylamino-4- [(pyridin-2-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion , was prepared in the form of a white solid: mp. 236.0-236.5 ° C (softens at 233.5 ° C).

Example 7 3- (Isopropyl-methyl-amino) -4-r (pyridin-4-ylmethyl? -amino-1-cyclobut-3-ene-l, 2-dion In a process similar to that described in Example 1, using the appropriate starting materials, a 3- (Isopropyl-methyl-amino) -4- [(pyridin-4-ylmethyl) -amino] -cyclobut-3-ene-1 , 2-dion, was prepared in the form of a white solid: mp. 214.5-215.0 ° C (softens at 211.5 ° C).

Example 8 3-T (5-Nitro-benzofuran-2-ylme-yl) -amino] -4- (1,2,2-trimethyl-propylamino) -cyclobut-3-ene-l, 2-dion To a suspension of NaH (3.41 g, 80%, 113.6 mMol) in dimethylformamide (400 mL) at 0 ° C, acetone oxime (7.61 g, 104.1 mMol) was added. After stirring for one hour at 0 ° C, 4-nitrofluorobenzene (10.00 mL, 94.6 mMol) was introduced through a syringe and the resulting mixture was stirred for 1 hour. Saline water (400 mL) was added and the resulting precipitate was collected by filtration. The product was washed with water and dried in vacuo to obtain 18 g (100%) of a white solid: H NMR (DMS0-d6): d 8.20 (d, 2H), 7.25 (d, 2H), 2.06 ( s, 3H), 2. 11 (s, 3H). The above-mentioned oxime (10.39 g, 53.56 mMol) was heated in saturated ethanolic acid HCl (200 mL) under reflux. After 3 hours, the reaction mixture was cooled and concentrated to its volume. Water was added and the precipitated cyclization product was collected by filtration to obtain 9.0 g (95%) of 2-methyl-5-neitrobenzofuran: 2H NMR (DMS0-d6): d 8.39 (d, 1H), 8.15 (dd, ÍH), 7.45 (d, ÍH), 6.49 (s, ÍH), 2.48 (s, 3H).

To a stirred solution of the above benzofuran (5.00 g, 28.25 mMol) and benziol peroxide (0.68 g, 2.83 mMol) in carbon tetrachloride (200 mL) was added 1,3-dibromo-5,5-dimertylhydantoin (4.04). g, 14.12 mMol). The mixture was irradiated with a 200-well lamp, while stirring for 1 hour, cooled and partitioned between dichloromethane / water. The organic phase was washed with water (2 x 100 L) and saline water (2 x 100 mL), dried (MgSO 4), decolorized (char) and concentrated in vacuo to obtain 7.12 g of crude product. Recrystallization from ethyl acetate / hexane gave 4.38 g (61%) of 2-bromomethyl-5-nitro-benzofuran, in the form of an off-white solid; 1 HOUR NMR (CDC13): d 8.49 (d, ÍH), 8.25 (dd, ÍH), 7.58 (D, 1H), 6. 91 (s, ÍH) 4.59 (s, 2H). A mixture of 2-bromomethyl-5-nitrobenzofuran (1.57 g, 6.13 mMol) was stirred in acetonitrile (15 mL) overnight at room temperature. The solvent was removed by aspiration and the residue was partitioned between ethyl acetate and saline water. The organic phase was washed with 0. IN sodium hydroxide (2 x 50 mL), then with saline water (2 x 50 mL), dried (MgSO), and concentrated to obtain an off-white solid. The crude product was triturated with ether / diethyl acetate / ethyl acetate to obtain 1.47 g (74%) of the aforementioned phthalimide, in the form of a white solid: XH NMR (DMS0-d6): d 8.55 2 (d, ÍH), 8.17 (dd, ÍH), 7.88 (m, 4H), 7.75 (d, ÍH), 5.00 (s, 2H). The aforementioned phthalimide (1.45 g, 4.49 mMol) was treated with hydrazine hydrate (0.38 mL) and refluxing ethanol (15 mL) for 1.5 hours. The reaction was cooled to 0 ° C and acidified (conc. HCl) to pH = 1. The mixture was filtered and the solid was washed with 6N HCl and water. The filtrate was basilated with potassium carbonate and then extracted with ethyl acetate. The organic phase was dried (MgSO), and concentrated to obtain 0.74 g (86%) of 2-methylamino-5-nitrobenzofuran, in the form of a light yellow solid: 1H NMR (DMS0-d6): d 8.55 (d, ÍH), 8.11 (dd, ÍH), 7.72 (d, 1H) 6.85 (s, ÍH), 3.84 (s, 2H), 2.00 (brs, 2H). To 2-methylamino-5-nitrobenzofuran (0.74 g, 3.85 mMol) which was being stirred in tetrahydrofuran (15 mL) at 0 ° C, 3, 4-dibutoxy-3-cyclobutene-1, 2-dion (1.25 L, 5.78 mMol) was added via syringe. The mixture was stirred for 5 hours at room temperature, and then concentrated in vacuo. The residue was recrystallized from ether / diethyl hexane / ethyl acetate, to obtain 0.83 g of the mentioned compound, in the form of an off-white solid. A second fragment (0.17 g) was isolated from the main liquor. Total production: 75%. HH NMR (DMSO-d6): d 9.40 and 9.20 (2 brm, HH rotamérico), 8.60 (d, 1H), 8.20 (dd, ÍH), 7.80 (d, ÍH), 7.04 (s, ÍH), 4.88 and 4.67 (2 br, 2H, rotamérico), 4.60 (t, 2H), 1.67 (m, 2H), 1.30 (m, 2H), 0.85 (m, 3H). 3- [(5-Nitro-benzofuran-2-ylmethyl) -amino] -cyclobut-3-ene-1,2-dion (0.250 g, 0.727 mMol) was dissolved in an ethanolic solution of R (+) - 2 -amino-3, 3-dimethylbutane (0.167 N, 6.0 mL, 1.00 mMol). The mixture was diluted with ethanol (1 mL) and tetrahydrofuran (1 mL). After 3 hours 6.0 mL of additional ethanolic amine (1.00 mMol) were added to the mixture and the mixture was allowed to stir for 48 hours at room temperature. The heterogeneous mixture was diluted with 1: 1 diethyl ether / ethyl acetate and filtered to obtain 0.20 g (74%) of (R) isomer of 3- [(5-Nitro-benzofura-2-ylmethyl) -amino] -4 - (1,2, 2-trimethylpropylamino) -cyclobut-3-ene-1,2-dion: mp. > 300 ° C; h (DD; H); 7.88 (d and m, 2 H), 7.35 '(br d, H H), 7.06 (s, H H), 4.98 (m, 2 H), 3.92 (m, H H), 1.10 (d, 3 H), 0.86 (s, 9 H) . IR (KBr): 3180, 2950, 1800, 1650, 1550 cm "1; MS (m / z) 371 (M +).

Elemental Analysis of Calculated C19H21N305: C, 61.45; H, 5.70; N, 11.31 Found: C, 60.52; H, 5.50; N, 11.21 Example 9 3-1, 1-Dimethyl-propylamino) -4- [(5-nitro-benzofuran-2-ylmethyl) -amino-1-cyclobut-3-ene-l, 2-dion To 3-butoxy-4- [(5-nitrobenzofuran-2-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion (0.25 g, 0.727 mmol), as prepared in Example 8, in ethanol (5 mL), tert-amylamine (0.53 mL, 4.54 mMol) was added. The reaction was stirred at 70 ° C for 18 hours and then at room temperature for 48 hours. The precipitated product was filtered and washed with ethyl acetate, diethyl ether and petroleum ether to obtain 0.22 g (85%) of 3- (1,1-dimethyl-propylamino) -4- [(5-nitro-benzofuran- 2-ylmethyl) -amino] -cyclobut-3-ene-l, 2-dion, in the form of an off-white solid: mp. 283.5-287.5 ° C (dec.): XH NMR (DMS0-d6): d 8.61 (d, 1H), 8.18 (dd, ÍH), 7.96 (br t, ÍH), 7.81 (d, ÍH), 7.46 (d. br s, ÍH), 7.07 (s, ÍH), 4.99 (d, 2H), 1.66 (q, 2H), 1.30 (s, 6H) 0.82 (t, 3H). IR (KBr): 3220, 2950, 1800 cm-1; MS (m / z) 357 (M +).

Elemental Analysis of C ^ H ^ N ^ s Calculated: C, 60.50; H, 5.36; N, 11.76 Found: C, 59.31; H, 5.15; N, 11.53 Example 10 3-tert-Butylamino-4-r (5-nitro-benzofuran-2-ylmethyl) -amino ~ | - cyclobut-3-ene-l, 2-dion To 3-butoxy-4- [(5-nitrobenzofuran-2-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion (0.25 g, 0.727 mMol), as prepared in Example 8, in ethanol (5 mL), tert-butylamine (0.51 mL, 4.58 mmol) was added. The reaction was stirred at 70 ° C for 18 hours and then at room temperature for 48 hours. Obtained by working in a manner identical to Example 9, 0.20 g (80%) of 3-tert-Binylamino-4- [(5-nitro-benzofuran-2-ylmethyl) -amino] -cyclobut-3-ene-1 , 2-dion, in the form of a whitish solid: mp. > 300 ° C; XH NMR (DMS0-d6): d 8.61 (d, 1H), 8.20 (dd, ÍH), 7.91 (br t, ÍH), 7.81 (d, ÍH), 7.59 (br S, ÍH), 7.07 (s, ÍH) ), 4.98 (d, 2H), 1.36 (s, 9H). IR (KBr): 3220, 2930, 1800, 1675 cm "1; MS (m / z) 344.3 [M + H] +.

Elemental Analysis of C17H? 7N305 Calculated: C, 59.47; H, 4.99; N, 12.24 Found: C, 58.86; Hm, 4.78; N, 11.88 2 Example 11 2-. { [2- (.1-Dimethyl-propylamino> -3,4-dioxo-cyclobut-1-enylamino] -methyl] -benzofuran-5-carbonitrile Acetone oxime (6.34 g, 86.64 mMol) was added to a suspension of sodium hydride (as an 80% dispersion in a mineral oil, 2.72 g, 90.82 mMol) in N, N-dimethylformamide (400 mL) at 0 °. C. The foamed suspension was stirred for one hour, while the mixture was heated to 25 ° C. P-Fluorobenznitrile (10.00 g, 82.51 mMol) was added and the reaction mixture was stirred at 0 ° C for 15 minutes and then allowed to warm to ambient temperature. After stirring overnight, the reaction mixture was poured into saline water (300 mL). The resulting white precipitate was collected by filtration, washed with water and dried in vacuo. Yield: 13.97 g (98%): XH NMR (DMS0-d6): d 7.78 (d, 2H), 7.76 (d, 2H), 2.04 (s, 3H), 2. 00 (s, 3H). To the product of the previous paragraph (13.97 g, 80.28 mMol) an ethanolic hydrochloric acid (400 mL) was added.

The mixture was heated under reflux for 4 hours. The reaction mixture was cooled and concentrated to 1/3 of its volume.

The reaction mixture was diluted with water, resulting in instantaneous formation of a precipitate. The precipitate was collected by means of filtration, washed with water and dried in vacuo. The crude product was purified by HPLC (ethyl acetate / hexane 10: 1). Yield: 7.26 g (58%): XH NMR (CDC13): d 7.79 (dd, ÍH), 7.43 (d, ÍH), 6.44 (s, ÍH), 2.47 (s, 3H). To a solution of the product of the previous paragraph (3.00 g, 19.08 mMol) in carbon tetrachloride (80 mL) was added benzoyl peroxide (0.46 g, 1.91 mMol) and 1,3-dibromo-5,5-dimethylhydantoin (2.73 g). 9.54 mMol). The reaction mixture was irradiated with a 200 watt lamp, for 1 hour. The reaction mixture was cooled and partitioned between ethyl acetate and sodium bicarbonate. The organic layer was dried over magnesium sulfate, treated > with Norite® (activated carbon), filtered and concentrated in a solid. The crude product was recrystallized from hexane / ethyl acetate. Production: 2.40 g (59%): 1H NMR (DMSO-d6): d 8.49 (d, ÍH), 8.25, (dd, ÍH), 7.58 (d, ÍH), 6.91 (s, ÍH), 4.59 (s, 2H). To a solution of the product of the previous paragraph (2.63, 10.27 mMol) in acetonitrile (30 mL) was added potassium phthalimide (2.85 g, 15.41 mMol) and 18-crown-6 (0.27 g, 1.03 mMol). After stirring overnight, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and saline, and a precipitate immediately formed. The precipitate was collected by filtration, washed with diethyl ether and dried. The organic phase was washed with 0.1 N sodium hydroxide (2 x 50 mL) and then saline water (2 x 50 L). The solution was concentrated in vacuo, to get another part of a solid. Yield: 2.50 g (76%): 1 H NMR (DMSO-d 6): d 8.18 (d, HH) 7.91 (m, 4H), 7.77 (dd, HH), 7.74 (d, HH), 7.07 (d, HH) ), 5.00 (s, 2H). To a solution of the product of the previous paragraph (2.50 g, 7.74 mMol) in ethanol (20 mL) was added hydrazine hydrate (0.66 mL). The mixture was heated under reflux for 1.5 hours. The reaction mixture was cooled to 0 ° C and acidified with a concentrated hydrochloric acid to a pH of 1. The mixture was filtered and the filter mass was washed with 6N hydrochloric acid and then water. The filtrate% was basilated with potassium carbonate and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, treated with Norite® and concentrated to obtain an off-white solid. Production: 0.85 g, (62%): - "? NMR (DMS0-d6): d 8. 17 (d, ÍH), 7.78 (dd, ÍH), 7.74 (d, ÍH) 6.82 (s, ÍH), 3.85 (s, 2H), 2.10 (br s, 2H). To a solution of the product of the previous paragraph (2.50 g, 7.74 mMol) in tetrahydrofuran (15 mL) was added 3,4-diethoxy-3-cyclobutene-1,2-dion (1.13 g, 6.60 mMol) at 0 ° C. The reaction mixture was heated to room temperature and stirred for 4 hours. The reaction mixture was concentrated in vacuo and the crude product was triturated with hexane / diethyl ether / ethyl acetate to yield an off white solid. The solid was filtered and dried to obtain the desired product. Production: 1.05 g (76%):? NMR (DMSO-d6): d 9.41 and 9.21 (br m, ÍH, rotá eros), 8.22 (d, 1H), 7.81 (dd, 1H), 7.00 (s, 1H), 4.88 and 4.68 (2 br m, 2H, rotamers), 4.65 (t, 2H), 1.39 (m, 3H). To a solution of the product of the previous paragraph (0.25 g, 0.79 mMol) in ethanol (17 mL) was added tert-amyl amine (0.14 g, 2.37 mMol). The reaction mixture was heated to 70 ° C and stirred overnight. The solid that formed was filtered and washed with ethyl acetate, diethyl ether and hexane to yield 0.18 g (67%) of 2-. { [2- (1, 1-Dimethyl-propylamino) -3,4-dioxo-cyclobut-1-enylamino] -methyl],} -benzofuran-5-carbonitrile, in the form of an off-white solid: mp. 171.1-173.2 ° C; H NMR (DMS0-d5): d 8.19 (d, ÍH), 7.96 (t, ÍH), 7.81 (d, ÍH), 7.74 (dd, ÍH), 7.45 (s, ÍH), 6.96 (s, ÍH) , 4.97 (d, 2H), 1.67 (q, 2H), 1.29 (s, 6H), 0.83 (t, 3H). IR (KBr): 3230, 2950, 2220, 1800 cm "1; MS (m / z) 337 (M +).

Elemental Analysis of C? GH? GN03 Calculated: C, 67.64; H, 5.68; N, 12.46 Found: C, 66.87; H, 5.32; N, 12.37 Example 12 2-. { T3, -DÍQXO-2- (1,2, 2-trimethyl-propylamino) -cyclobut-1-enylamino] -me il} -benzofuran-5-carbonitrile To a solution of the product of paragraph 6 of Example 11 (0.250 g, 0.79 mMol) in ethanol (2 mL) was added (R) -2-amino-3,3-dimethylbutane ethanolic (0.166 N in EtOH, 9.50 mL, 1.58 mMol). The reaction mixture was heated to 70 ° C and stirred overnight. The solid that formed was filtered and washed with ethyl acetate, diethyl ether and hexane. The solid was dried in vacuo, to obtain 0.22 g (79%) of the isomer (IR) of 2-. { [3,4-Dioxo-2- (1, 2, 2-trimethyl-propylamino) -cyclobut-1-enylamino] -methyl} -benzofuran-5-carbonitrile, in the form of an off-white solid: mp. > 300; XH NMR (DMSO-d6): d 8.18 (d, ÍH), 7.80 (dd, ÍH), 7.74 (dd, 1H), 7.31 (br d, ÍH), 6.95 (s, ÍH), 4.96 (m, 2H ), 3.91 (br m, ÍH), 1.11 (d, 3H, 0.72 (s, 9H), IR (KBr): 3170, 2950, 2250, 1850, 1650, 1560, cm "1; MS (m / Z) 351 (M +).

Elemental Analysis of C20H2? N3O3 Calculated: C, 68.36; H, 6.02; N, 11.96 Found: C, 68.00; H, 5.83; N, 12.00 Example 13 2- [(2-tert-Buylamino-3, -dioxo-cyclobut-l-enylamino) -methyl] -benzofuran-5-carbonitrile To a solution of the product of paragraph 6 of Example 11 (0.250 g, 0.79 mMol) in ethanol (2 mL) was tert-butyl amine (0.17 g, 2.37 mMol). The reaction mixture was heated to 70 ° C and was stirred overnight. The solid that formed was filtered and washed with ethyl acetate, diethyl ether and hexane. The solid was dried in vacuo, to obtain 0.12 g (51%) of 2- [(2-tert-butylamino-3,4-dioxo-cyclobut-1-enylamino) -methyl] -benzofuran-5-carbonitrile, in the shape of a slightly pink solid: mp.298.8-300.3 ° C; H NMR (DMSO-d6): d 8.18 (d, ÍH), 7.96 (t, ÍH), 7.81 (dd, ÍH), 7.74 (dd, ÍH), 7.57 (s, ÍH), 6.95 (s, ÍH), 4.96 (d, 2H), 1.35 (S, 9H). IR (KBr): 3300, 2950, 2210, 1800, 1660, 1525 cm "1; MS (m / z) 323 (M +).

Elemental Analysis of Calculated C18H17N303: C, 66.86; H, 5.30; N, 13.00 Found: C, 65.64; H, 4.93; N, 12.57 Example 14 2-. { [2- (1, l-Dimethyl-2-phenyl-ethylamino) -3,4-dioxo-cyclobut-1-enylamino "| -methyl.}. -benzofuran-5-carbonitrile To a solution of the product of paragraph 6 of Example (0.23 g, 0.73 mMol) in ethanol (20 mL) was added alpha, alpha-dimethylphenethylamine (0.33 g, 2.19 mL). The reaction mixture was heated to 70 ° C and stirred overnight. The solid that formed was filtered and washed with ethyl acetate, diethyl ether and hexane. The solid was dried in vacuo, to obtain 0.11 g (41%) of 2-. { [2- (1, 1-Dimethyl-2-phenyl-ethylamino) -3,4-dioxo-cyclobut-1-enylamino] -methyl} -benzofuran-5-carbonitrile, in the form of an off-white solid: mp. 233. -235.2 ° C; lE NMR (DMS0-d6): d 8.20 (d, 1H), 7.89 (t, ÍH), 7.81 (dd, ÍH), 7.74 (dd, ÍH), 7.36 (s, 1H), 7.23 (m, 3H) , 7.06 (d, 2H), 6.94 (s, ÍH), 4.97 (d, 2H), 2.98 (s, 2H), 1.31 (s, 6H). IR (KBr): 3300, 3000, 2200, 1800, 1660, 1590 cm "1; MS (m / z) 399 (M +).

Elemental Analysis of C24H? N303 Calculated: C, 72.17; H, 5.30; N, 10.52 Found: C, 71.28; H, 5.20; N, 10.33 Example 15 3- T (Pyridin-4-ylmethyl) -amino-4- (1,2,2-trimethyl-propylamino-cyclobut-3-ene-l, 2-dion In a process similar to that described in Example 1, using the appropriate starting materials, a 3- [(Pyridin-4-ylmethyl) -amino-4- (1,2,2-trimethyl-propyl-amino) - cyclobut-3-ene-1, 2-dion, in the form of a white solid: mp. 282.5-283.0 ° C dec. (softens at 287.5 ° C) Example 16 2 2-. { f2- (1,1-Dime-il-propylamino) -3,4-dioxo-cyclobut-1-enylamino-methyl} -3-chloro-benzofuran-5-carbonitrile The benzofuran product prepared in Example 11, paragraph 2, was used to synthesize a 3-chloro-2-methylbenzofuran-5-carbonitrile (Cross, P.E., Dickinson, R.P., Parry, M.J., Randall, M.J.J. Med. Chem., 1986, 29, 1643-1650). Production: 23%:? E NMR (CDC13): d 7.81 (d, ÍH), 7. 47 (dd, ÍH), 2.49 (s, 3H). A 3-chloro-2-bromomethyl-bonzofuran-5-carbonitrile was prepared, in a manner similar to 2-bromomethyl-benzofuran-5-carbonitrile, synthesized in Example 11, paragraph 3. Production: 53%: 1H NMR (DMSO -d6): d 8.24 (d, ÍH), 7.93 (d, 1H), 7.93 (d, 2H), 4.94 (s, 2H). The product from the previous paragraph was reacted with potassium phthalamide, in a manner similar to that of Example 11, paragraph 4, to produce the phthalamide product. Production: 72%: NMR (DMSO-d6): d 8.18 (d, ÍH), 7. 89 (m, 6H), 5.03 (s, 2H). 3-Chloro-2-methylamino-benzofuran-5-carbonitrile was prepared in a manner similar to that of Example 11, paragraph 5. Production: H NMR (DMSO-d6): d 8.18 (d, ÍH), 7.81 (dd) , 2H), 3.85 (s, 2H, 3.21 (br s, 2H) The amino compound above was reacted with 3,4-dibutoxy-3-cyclobutene-1,2-dion in a similar manner to Example 11, paragraph 6. Production: 75%: 1H NMR (DMS0-d6): d 9.40 and 9.18 (br m, ÍH, rotamers), 8.21 (d, 1H9, 7.91 (dd, 2H), 4.98 and 4.75 (2 br m, 2H, rotamers), 4.61 (t, 2H), 1.63 (, 2H), 1.35 (m, 2H), 0.87 (m, 3H) To a solution of the product of the previous paragraph (0.14 g, 0.37 mMol) in ethanol (12 mL) was added tert-amyl amine (0.065 g, 0.74 mMol) .The reaction mixture was heated to 70 ° C and stirred for 13 hours.The solid that formed was filtered and Washing with ethyl acetate, diethyl ether and hexane The solid was dried in vacuo to obtain a slightly orange solid Production: 0.11 g (74%): mp 257.3 -258.1 ° C; XH NMR (DMS0-d6): d 8.22 (d, ÍH), 7.93 (t, ÍH), 7.90 (d, 1H), 7.87 (dd, ÍH), 7.40 (s, ÍH), 5.05 (d, 2H), 1.66 (q, 2H), 1.29 (s, 6H), 0.80 (t, 3H). IR (KBr): 3230, 2950, 2220, 1800 cm "1; MS (m / z) 371 (M +).

Elemental Analysis of C19Hi8Cl? N303 Calculated: C, 61.98; H, 4.88; N, 11.30 Found: C, 60.75; H, 4.81; N, 11.11 The soft muscle relaxant activity of the compounds of this invention was established according to standard, pharmaceutically acceptable test procedures, with representative compounds, as follows: Sprague-Dawley rats (150-200 g) are smothered with C0 until they are unconscious and then they kill without pain, by cervical dislocation. The bladder is removed in a warm physiological salt solution (PSS) (37 ° C) of the following composition (mM): NaCl, 118.4; KCl, 4.7; CaCl2, 2.5; MgSO4, 4.7; H20, 1.2; NaHCO3 / 24.9; KH2P04, 1.2; glucose, 11.1; EDTA, 0.023; Gassed with 95% of 02; 2/5% of C02; pH 7.4. The bladder is opened and then cut into slices 1-2 mm wide by 7-10 mm long. The slices are subsequently suspended in 10 mL of tissue bath, under an initial resting tension of 1.5 g. The slices were held in place by two surgical clips, one of which is attached to a fixed hook, while the other is attached to an isometric force transducer. The preparations, which usually exhibit small spontaneous contractions, are allowed to recover for a period of 1 hour, before a provocation with 0.1 uM of carbachol. The carbacol is then washed and the tissue is allowed to relax to its resting level of activity. Following an additional 30-minute rest period, 15 mM of additional KCl is introduced into the tissue bath. This increase in the concentration of KCl results in a large increase in the amplitude of spontaneous contractions (and the initiation of contractions in the slices previously at rest) superimposed because of a small increase in the basal tone. Following the stabilization of this improved level of contraction activity, the increasing increases in the concentration of the test compound or vehicle are introduced into the fabric bath. The contraction activity is measured for each concentration of compound or vehicle, during the last minute of a 30-minute challenge. The isometric force developed by the bladder slices is measured using a concentration required to remove 50% inhibition of contraction activity before the drug (concentration IC50) and is calculated from its concentration response curve. . The inhibition of the maximum percentage of contraction activity, suggested by the test compound, is also collected for test compound concentrations less than or equal to 30 μM. The results of this study are shown in the Table 1.

Table 1 Inhibition of Contractions in Isolated Rat Bladder Slices.

Compound n ICs0 μM Example 1 4 0.42 ± 0.06 Example 2 5 1.25 + 0.39 Example 3 4 1.25 ± 0.34 Example 4 6 3. O ± O .2 Example 5 4 2.63 ± 0.22 • Example 6 4 11.45 ± 4.3 Example 7 4 * I = 27.3 ± 7% Eg 8 4 ** C = 8.5 ± 1.4% Example 9 3 * I = 22.2i7.4% Example 10 4 * I = 11.5 ± 3.2% Example 11 4 1.56 ± 0.16 Example 12 2 3.75 ± 1.44 2 * I = 5.5r4% Example 13 3 * I = 19.94 ± 8.5% Example 14 2 * I = 31.9 ± 6.4% Example 15 4 2.45 ± 0.99 Example 16 2 1.3 ± 0.63 Percent inhibition at 30 μM Percent contraction at 30 μM In addition, we tested the ability of the compound of Example 1, as a representative of other compounds of this invention, to inhibit hyperactivity of hypertrophied soft muscle bladder (detrusor) in conscious female rats with hypertrophied bladders and thus, heal urinary incontinence, according to the protocol described by Malmgrem et al. , J. Urol. 142: 1989. Female Sprague-Dawley rats are used, with a weight in the range of 190 to 210 g. Up to 25 animals are prepared each time. After the development of bladder hypertrophy, 4 to 8 animals are used per test. The compounds are dissolved in PEG-200 and administered by a gastric tube or gavage, or intravenously, in a volume of 5 ml / kg. To purify first, all drugs are administered in an arbitrary dose of 10 mg / kg. p.o., to groups of 4 rats. The animals are anesthetized with halothane. Through a mid-incision, the bladder and urethra are exposed and a 4-0 silk ligature is tied around the proximal urethra, in the presence of a stainless steel roller (1 mm in diameter), to produce an occlusion partial. Then the roller is removed. The abdominal region is closed using surgical staples and each rat receives 150,000 units of C-R biciline. The animals are released for 6 weeks to develop sufficient bladder hypertrophy. After six weeks the ligature is removed, under anesthesia with halothane and a catheter (PE 60) with cuff is placed in the dome of the bladder and secured with a bag string suture. The catheter is tunnelled under the skin and removed through a hole in the neck. The abdominal incision is sutured and the free end of the catheter is sealed. In order to avoid infection, the rats receive an injection of C-R biciline (150,000 units / rat). Two days later, the animals are used in cystometric evaluations. The animals are placed in metabolic cages and the catheter is fixed (using a "t" connector) to a Statham pressure transducer (Model P23Db) and to a Harvard infusion pump, a plastic beaker attached to a force displacement transducer. (Grass FT03) is placed under the rat's cage, it will trust to collect and record the volume of urine.The animals are allowed to rest for 15 to 30 minutes, before infusion of saline (20 ml / hr for 20 minutes) which is started for the first period of cystometry Two hours after the first period of cystometry, the rats were given one dose of the test compound and one hour later, a second cystometry was performed.

The following urodynamic variables were recorded: Basal bladder pressure = lowest bladder pressure, during cystometry Threshold pressure = bladder pressure immediately before urination Volume of micturition = volume expelled Micturition pressure = peak pressure when refusing Spontaneous activity = mean amplitude of fluctuations in bladder pressure during filling Presentation of the results: The average value of each variable is calculated before and after each administration. For each compound, the changes in the measured variables are compared to the values obtained before the treatment and expressed as percentage inhibition. The data are also subjected to a two-way variation analysis, to determine significant changes (p <0.05) in the measured variable.

The results of this study are shown in the Table II: Table II Inhibition of Spontaneous Contractions In Vivo Compound # of animals dose mg / kg. % network (F) * (p.o.) Example 1 3 10 -8 ± 4 * percentage reduction in the total number of spontaneous contractions in the hypertrophied rat bladder model Accordingly, the compounds of this invention have a pronounced effect on soft muscle contractility and are useful in the treatment of urinary incontinence, bowel irritation syndrome and veji, ga, asthma, hypertension, stroke and similar diseases such and as mentioned above, which are alleviated with the treatment of the potassium channel activating compounds, by means of oral administration, p-enteral or by aspiration to a patient in need thereof. It is noted that, with regard to this date, the best method known by the requested, to carry out the present invention, is that which is clear from the present, discovering the invention. Having described the invention as above, the content of the following is claimed as property.

Claims (5)

CLAIMS A compound of the formula: characterized because: R? and R2 are independently, hydrogen, a straight chain of alkyl of 1 to 10 carbon atoms, a branched chain of alkyl of 3 to 10 carbon atoms, a cycloalkyl of 3 to 8 carbon atoms, a bicycloalkyl of 4 to 10 atoms of carbon, or an aralkyl of 7 to 20 carbon atoms, wherein the aromatic portion of the aralkyl group, can be optionally substituted, with one to three straight alkyl chains of 1 to 10 carbon atoms, a branched alkyl chain, from 1 to 10 carbon atoms, halogen, nitro, cyano, alkoxy of 1 to 6 carbon atoms, an alkoxycarbonyl of 2 to 7 carbon atoms, or trifluoromethyl or trifluoromethoxy groups; R3 is hydrogen, formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms , arylsulfonyl of 6 to 12 carbon atoms, arylalcanoyl of 8 to 12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms; A is selected from the group consisting of: where: n is 0 or 1: R4, R5 and Rg are independently, cyano, amino, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, sulfamyl, alkylsulfonamido of 1 to 6 carbon atoms, arylsulfonamido of 6 to 12 carbon atoms, alkylcarboxamido of 2 to 7 carbon atoms, arylcarboxamido of 7 to 13 atoms of carbon, alkanoyl of 2 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, chlorine, bromine, fluorine, iodine, 1-imidiazolyl, carboxyl or hydrogen; or a pharmaceutically acceptable salt thereof. A compound according to claim 1, characterized in that R3 is hydrogen and A is selected from the following group: or a pharmaceutically acceptable salt thereof. A compound according to claim 1 or 2, characterized in that R x and R 2 are, independently, hydrogen, methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl, straight or branched chain of pentyl, or phenylalkyl, wherein the alkyl is methylene or ethylene, and wherein the phenyl portion may be optionally substituted by one to three substituents selected from methyl, ethyl, fluorine, chlorine, bromine, nitro, cyano, methoxy, ethoxy, methoxy-oxycarbonyl , ethoxyloxycarbonyl, trifluoromethyl and trifluoromethoxy. A compound according to claim 1, 2 or 3, characterized in that R4, R5 and R ?, are, independently, hydrogen, cyano, nitro, amino, methyl, methoxy, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethoxy or carboxyl. A compound according to any of the preceding claims, characterized in that it is selected from: 3- (1, 1-dimethylpropylamino-4- [(pyridin-4-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion or a pharmaceutically acceptable salt thereof. 3- (1, 1-dimethylpropylamino-4- [(pyridin-3-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion or a pharmaceutically acceptable salt thereof. 3- (1, 1-dimethylpropylamino-4- [(pyridin-2-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion or a pharmaceutically acceptable salt thereof. 3-tert-butylamino-4- [(pyridin-4-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion or a pharmaceutically acceptable salt thereof. 3-tert-butylamino-4- [(iridin-3-ylmethyl) -amino] -syclobut-3-ene-1, 2-dion or a pharmaceutically acceptable salt thereof. 3-tert-butylamino-4- [(pyridin-2-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion or a pharmaceutically acceptable salt thereof. 3- (isopropyl-methyl-amino) -4- [(pyridin-4-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion or a pharmaceutically acceptable salt thereof. 3- [(5-Nitro-benzofuran-2-ylmethyl) -amino-4- (1,2,2-trimethylpropylamino) cyclobut-3-ene-1, 2-dion or a pharmaceutically acceptable salt thereof. 3- (1, 1-dimethyl-propylamino) -4- [(5-nitro-benzofuran-2-ylmethyl) -amino] -cyclobut-3-ene-1,2-dion or a pharmaceutically acceptable salt thereof. 3-tert-butylamino-4- [(5-nitro-benzofuran-2-ylmethyl) -amino] -cyclobut-3-ene-1, 2-dion or a pharmaceutically acceptable salt thereof. 2-. { [2- (1,1-dimethyl-propylamino) -3,4-dioxo-cyclobut-1-enylamino] -methyl} -benzofuran-5-carbonitrile or a pharmaceutically acceptable salt thereof. 2- . { [3,4-dioxo-2- (1,2, 2-trimethyl-propylamino) -cyclobut-

1-enylamino] -methyl} -benzofuran-5-carbonitrile or a pharmaceutically acceptable salt thereof. 2- [(2-tert-butylamino-3,4-dioxo-cyclobutyl-enynyl) -methyl] -benzofuran-5-carbonitrile or a pharmaceutically acceptable salt thereof.

2-. { [2- (1, 1-dimethyl-2-phenyl-ethylamino) -3,4-dioxo-cyclobut-1-enylamino] -methyl} -benzofuran-5-carbonitrile or a pharmaceutically acceptable salt thereof.

3- [(pyridin-

4-ylmethyl) -amino] -4- (1, 2,2-trimethyl-propylamino) -cyclobut-3-ene-1, 2-dion or a pharmaceutically acceptable salt thereof. 2-. { [2- (1,1-dimethyl-propylamino) -3,4-dioxo-cyclobut-1-enylamino] -methyl} 3-chloro-benzofuran-

5-carbonitrile or a pharmaceutically acceptable salt thereof. A pharmaceutical composition, characterized in that it comprises a compound of the formula (I), according to claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient therefor. A method for reducing the adverse effects of soft muscle contractions, characterized in that it comprises, orally or parenterally administering to a patient, in need thereof, a compound of the formula (I) or a pharmaceutically acceptable salt thereof, in accordance with with claims 1 to 5. The method according to claim 7, characterized in that in the muscle that contracts adversely, it causes urinary incontinence. The method according to claim 7, characterized in that in the muscle that contracts adversely, it causes intestinal irritation syndrome. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 5, characterized in that it is used as a pharmaceutical or therapeutic active substance. A compound of the formula (I), or a saj. Pharmaceutically acceptable thereof, according to any of claims 1 to 5, characterized in that it is used in the reduction of the adverse effects of soft muscle contractions. A compound of the formula (I), according to claim 11, characterized in that in the muscle that contracts adversely, it causes urinary incontinence. A compound of the formula (I), according to claim 11, characterized in that in the muscle that contracts adversely, it causes urinary incontinence. The process for the preparation of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 5, characterized in that it comprises reacting a compound of the formula (II): (II) wherein X is an appropriate leaving group, with a compound of the formula (III): ^ Rai HN. 'a2 (m) wherein Ral and Ra2 are R1 and R2, respectively, as defined above, or a group of atoms convertible thereto. In the subsequent intermediate it can be reacted with a compound of the formula (IV): wherein i is A, as defined above, or a group of atoms convertible thereto, to give a compound of the formula (I) and, optionally converting them to a pharmaceutically acceptable salt thereof; or alternatively, reacting the compound of the formula (II) as described above, with a compound of the formula (IV) as defined above and then reacting with a compound of the formula (III) as defined above, to give a compound of the formula (I) and optionally, convert to a pharmaceutically acceptable salt thereof.