MXPA97003093A - N-arilo and n-heteroarilo-1,2-diaminociclobuten-3,4-dionas with relaxing activities of the muscle l - Google Patents

Abstract

The present invention relates to new 1,2-diamino derivatives of cyclobutene-3,4-diones having pharmacological activity to a process for their preparation to the pharmaceutical compositions containing them and to their use in the treatment of disorders associated with contraction of the muscle li

Description

N-ARILO AND N-HETER0ARIL0-1,2-DIAMIN0CICL0BUTEN-3,4-DI0NAS WITH RELAXING ACTIVITIES OF SMOOTH MUSCLE.

Background of the Invention The present invention relates to novel 1,2-diamino derivatives of cyclobutene-3,4-diones having pharmacological activity, to a process for their preparation, to the pharmaceutical compositions they contain, and to their use in the treatment of disorders associated with the contraction of smooth muscle; via modulation of the potassium channel. Such disorders include, but are not limited to: urinary incontinence, hypertension, asthma, premature labor, irritable bowel syndrome, congestive heart attack, angina, and cerebrovascular disorders.

Stemp et al. discloses in patent EP-426379-A-2, a class of amino-substituted cyclobutenedione derivatives of chronomannals described as having an activity of decreasing or decreasing arterial blood pressure or bronchodilator activity. Several series of 1-amino-2-f eni lalky-cyclobuten-3-diones are reported as antagonists of the H-2 receptor by Aligieri et al. in the North American Patent REP: 24556 4,390,710 and its numerous sections and CIPs. Several 1-imino-2-phenoxyalkylene lamino derivatives related to 1-amino-2-phenoxyalkyl lamino are disclosed by Nohara et al. in U.S. Patent 4,673,747.

The synthesis of representative 1, 2-diamino-cyclobuten-3,4-diones in the following publications: Tietze et al., 1991, 124, 1215; Tietze et al., Bioconjugate Chem. 1991, 2, 148; Ehrhardt et al., Chem. Ber 1977, 110.2506, and Neuse et al., Liebigs Ann. Chem. 1963,619.

Description of the invention.

In accordance with the present invention, it describes compounds represented by the formula (I) Ri R. (D where: R 1 is hydrogen, straight or branched chain alkyl C 1, cyclic or bicyclic C 3 alkyl 1, alkanoyl of 2 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl from 7 to 12 carbon atoms, arylalkinium from 9 to 20 carbon atoms, arylsulphony from 6 to 12 carbon atoms, arylalkano from 8 to 12 carbon atoms or ary1 alkyl sulfony from 7 to 12 carbon atoms; R is hydrogen, branched or straight-chain CI_IQ alkyl or, cyclic or bicyclic CO IQ alkyl; is a group of the following formula: wherein: R-, and R- independent of each of the others, are selected from the following: cyano, nitro, amino, alkyl C., perfluoroalkyl C. g, alkoxy. g, perf luoroalkoxy C ^ g, amino, Ci.i? mono or dialkylamino, sulfonamide, alkylsulfonamide C. g, arylsulfonamide Cfi.i? ' C 1 -C 12 alkylcarboxamide C 1 -C 12 alkylsulfonyl, perfluoroalkyl sulphonyl C. g, arylsulfone 12 C, chloro, bromo, fluoro, iodo, 1-imidazole, carboxyl, carboalkoxy to 7 carbon atoms, hydroxyl or hydrogen; or, A is Het where Het is selected from the following: wherein: Rg is hydrogen, alkyl C. g, perfluoroalkyl lo C. g, alkoxy C. g, perfluoroalkoxy C a »amino, t * _ * 2 mono-dialkylamino, alkylsulfonamide. g, C6-6 alkylcarboxamide 'nitro, cyano, carboxyl, chloro, bromo, fluoro, iodo; is an integer from 0 to 6; R3 and R are, independently of each other, hydrogen, branched or straight chain C, 1Q alkyl, or C3_alkyl? cyclic bicyclic; perfluoroalkyl C? _? n »hydroxyalkyl C 1 _ 1«, alkoxyalkyl Cp-IO 'fluoro; or, where together they take the form of a spirocyclic ring containing a total of 3-7 carbon atoms; R? and Rß, independent of each of the others, are selected from the following: cyano, nitro. amino, alkyl ^ g, perfluoroalkyl C, g, alkoxy C, g, perf luoroalkoxy C. g, amino, C,, 2 mono or dialkylamino, sulfonamide, alkylsulphone ida C. g, arylsulphone ida Cfi-1 ' alkylcarboxamide C-6 'arylcarboxamide ^ 7-12' alkylsulfonyl C. g, perfluoroalkyl sulfonyl C, g, arylsulphonium CR-12 'chlorine, bromine, fluorine, iodine, 1-imidazolyl, carboxyl, carboalkoxy ? -7 'hydroxyl, or hydrogen; or a pharmaceutically acceptable salt thereof.

A preferred aspect of this invention includes compounds of the formula (I) where: R and R? they are as stated above; It is a group of the following formula where: R7 and RQ. independent of each of the others, are selected from the following: cyano, nitro, amino, chloro, bromo, fluoro, iodo, 1-imidazolyl, carboxyl, hydrogen; or A is Het where Het is selected from the following: where: Rg is a state like the previous one; n = 0; R3 and R. are, independently of each other, hydrogen, C1- or branched-chain alkyl or straight, perfluoroalkyl c? _? N 'hydroxyalkyl 1-10 or fluoro; Re and Rg, independent of each of the others, are selected from the following: cyano, nitro, amino, C ^ g alkyl, perfluoroalkyl. g, C.sub.g. alkoxy, C.sub.L.sub.mo.alkyl, amino, chloro, bromo, fluoro, iodo, carboxyl, carboalkoxy, c.sub.7 hydroxyl, hydrogen; or a pharmaceutically acceptable salt thereof.

It is understood that the definition of the compounds of the formula (I), where R ^ R2, R3 »*. R5 or Rg contain asymmetric carbons, or where R is different from R. It embraces all possible stereoisomers and mixtures thereof. In particular, the optical isomers and racemic modifications encompassed. The optical isomers can be obtained in the pure form by standard separation techniques. The pharmaceutically acceptable salts are those derived from such organic and inorganic acids such as: lactic, citric, acetic, tartaric, succinic, maleic, malic, hydrochloric, hydrochloric, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids. Where R3, R-, Rg or Rg are carboxyl groups, the salts of the compounds of this invention can be formed with bases such as alkali metals (Na, K, Li) or alkaline earth metals (Ca or Mg).

The acyl groups represented by R. are derivatives of such acids such as acetic, propionic, butyric, valeric, caproic, methanesulfonic, ethanesulfonic, benzoic, thalic, cinnamic, phenol sulfonic, phenylacetic, naphthyl lactic, benzulphonic and the like. lares.

Examples of alkyl as a group or as part of a group, for example, alkoxy, aryl are alkyl groups of 1-4 carbon atoms such as methyl, ethyl, propyl and butyl.

The term "aryl" was used for a group or as part of a group, for example, arylalkyl, aroyl, including aromatic carbocyclic groups of 6 to 10 carbon atoms, for example, phenyl and naphthyl such as 1-naphthyl.

Examples of perfluoroalkyl group are those groups having 1-4 carbon atoms, for example, perfluoromethyl and perfluoroethyl.

The present invention also provides processes for the preparation of compounds of the formula (I). Accordingly, this invention provides a process for preparing a compound of the formula I which comprises: a) reacting a c ompue to the f or rmu l a: TO «) where X is a starting group, and A and 'R1 are as defined above, with a compound of the formula: (III) wherein n and R2_6 are as defined above to give a compound of formula I; or b) reacting a compound of the formula I wherein R 1 is hydrogen with an alkylating or acylating agent it contains. where R1 is as defined ant eri < Deferring a hydrogen in the presence of a base to give a compound of the formula I wherein R. is different from hydrogen; or c) convalescing an acidic compound of the formula I wherein at least one of R? -Rg is a carboxy group to a salt with a base, for example, alkali metal, alkaline earth metal or an optionally substituted ammonium salt; or d) converting a basic compound of formula I to a pharmaceutically acceptable acid addition salt; or e) isolating an active isomer optically from a compound of formula I of a mixture of isomers; or f) reacting a compound of the formula I having a reactive site or a substitute group to give a different compound of formula I.

Conveniently, the compounds of the formula I can be prepared by reacting a compound of the formula II.

As previously mentioned, is h? found that the compounds of the formula (I) relax the smooth muscle. There is therefore utility in the treatment of disorders associated with smooth muscle contraction, disorders involving excessive contractions of the smooth muscle of the urinary tract (such as incontinence), or of the gastrointestinal tract (such as irritable bowel syndrome), asthma and hair loss. In addition, the compounds of the formula I are active as activators of the potassium channel, which then give uses for the treatment of vascular disorders of the periphery, congestive attack to the heart, anxiety, shock, cerebral anoxia and other neurogenerative disorders.

The present invention, accordingly, provides a pharmaceutical composition which comprises a compound of this invention and a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier.

The compositions are preferably adapted for oral administration. However, they can be adapted for other modes or forms of administration, for example parenteral administration for patients suffering from heart attacks.

In order to obtain consistency of administration, 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 pads or in jars. such unit dosage forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg. Additionally still, the preferred unit dosage forms contain from 5 to 25 mg of a compound of the present invention. The compounds of the present invention can be administered orally in a dose range of about 0.01 to 100 mg / kg or preferably at a dose range of 0.1 to 10 mg / kg. Such compositions can be administered 1 to 6 times a day, more usually 1 to 4 times a day.

The compositions of the invention can be formulated with conventional excipients, such as a filler, a disintegrating agent, binders, lubricants, flavoring agents and the like. They are formulated in a conventional manner, for example, in a manner similar to those used for known anti-hypertensive agents, diuretics and B-blocking agents.

The present invention further provides a compound of the invention for uses as an active therapeutic substance. The compounds of the formula (I) are of particular use in the induction of smooth muscle relaxation.

The present invention further provides a method of treating disorders of smooth muscle in mammals including man, which comprises administering to the affected mammal an effective amount of a compound or a pharmaceutical composition of the invention.

The following examples are presented to illustrate rather than limit the production methods of the representative compounds of the invention.

EXAMPLE 1 4- [3,4-Dioxo-2 - ((R) -1-phenyl-ethylamino) -cyclobutyl-1-enylamino-benzonitrile Step 1) Preparation of 4- (3,4-Dioxo-2-ethoxy-cyclobut-1-enylane) -benzonitrile. 4-Aminobenzonitri lo (3.47 g, 29.4 mmol) were added to a solution of 3,4-diethoxy-3-cyclobuten-1, -dione (5.00 g, 29.4 mmol) in absolute ethanol (100 mL). The mixture was heated to reflux overnight. The mixture was cooled, and the resulting yellow precipitate was collected by vacuum filtration ... yielding: 2.60 g (37%): mp 218-22 ° C; 1 H NMR (DMSO-dg) or 11.07 (s, 1 H), 7.81 (d, 2 H), 7.56 (d, 2 H), 4.79 (c, 2 H), 1.46 (t, 3 H).

Step 2) Preparation of 4- [3,4-dioxo-2- ((R) -1- phenyl-1-ylamino) -cyclobut-1-eny] -benzonitriyl.

To the previous reagent (0.50 g, 2.06 mmol) in ethanol (10 mL) were added (R) -f-methylbenzene (0.27 mL, 2.1 mmol). The mixture was heated to reflux for 16 hours and filtered in vacuo. The precipitate was recrystallized from the methanol to gauge 0.17 g (26%) of the product as a pale yellow solid: m.p. 273-274 ° C; M25D-53.20 (DMSO); 1 H NMR (DMSO-dg): o "9.91 (s, 1H), 8.21 (d, 1H), 7.72 (d, 1H), 7.79-7.31 (m, 9H), 5.29 (m, 1H), 1.59 (d , 3H). IR (KBr): 3200.2230, 1790, 1670, 1600 cm "-1 MS (m / z) 317 (M +).

Elemental analysis for c 9 15N3 ° 2 Cale: C, 17-91; H. 4.76; N, 13.24. Found: C, 71.26; H, 4.86; N, 13.49.

EXAMPLE 2 3- (5-Bromo-pyridin-3-ylamino) -4 - ((R)) - 1-phenyl-ethylamino) -cyclobut-3-en-1,2-dione.

Step 1) Preparation of 3- (5-bromo-pyridin-3-ylamino) -4-ethoxy-cyclobut-3-en-1,2-dione) 3-Amino-5-bromopyridine (1.92 g, 11.3 mmol) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (2.24 g, 11.1 mmol) in absolute ethanol (30 mL). The mixture was heated to reflux for 18 hours, cooled and filtered. The filtrate was concentrated and the resulting residue chromatographed (CH30H / CH2C12) to gauge 2.06 g (62%) of the product as a crude solid: 1 H NMR (DMSO-dg): d 11.00 (s, 1H), 8.56 (s) , 1H), 8.42 (s, 1H), 8.09 (s, 1H), 4.79 (c 2H), 1.42 (t, 3H).

Step 2) Preparation of 3- (5-Bromo-pyridin-3-ylamino) -4- ((R) -1-pheny1-ethylamino) -cyclobut-3-en-1, 2-dione To the previous reagent (0.815 g, 2.74 mmol) in ethanol (25 L) were added (R) -c'-meti Ibenci lamina (0.36 mL, 2.8 mmol). The mixture was heated to reflux for 23 hours. The precipitate was filtered remotely and rinsed with ethanol to gauge 0.92 g (90%) of the product as a crude-colored solid: mp 268-271 ° C (dec); fot) 25D + 6.57 (DMSO); 1 H NMR (DMSO-dg): & 9.85 (s, 1H), 8.44-8.15 (m, 4H), 7.43-7.27 (m, 5H), 5.29 (m, + H), 1.59 (d, 3H). IR (KBr): 3200, 1790, 1670, 1590 cm "1; MS (m / z) 372 (MH +).

Elemental analysis for C17H1.BrN302 Cale: C, 54.86; H, 3.79; N, 11.29. Find: C54.88; H, 3.67; N, 11.20.

EXAMPLE 3 3- (2-Methoxy-5-trifluoromethyl Io-phenylamino) -4 - ((R) -1-phenyl-ethylamino) -cyclobut-3-en-1,2-dione.

Step 1) Preparation of 3-ethoxy-4- (2-methoxy-5-trifluoromethyl-phenylamino) -cyclobut-3-en-1,2-dione 2-methoxy-5-trif luorometi lani 1 ina (5.62 g, 29.4 mmol) 'were added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4 mmol) in absolute ethanol (100 mL). The mixture was heated to reflux for 66 hours, cooled and filtered. The precipitate was purified by chromatography (CH30H / CH2C12) to gauge 1.88 g (20%) of the product as a yellow solid: 1 H NMR (DMSO-dg): o 10.42 (s, 1H), 764-720 (m, 3H) , 4.69 (c 2H), 3.90 (s, 3H), 1.34 (t 3H).

Step 2) Preparation of 3- (2-methoxy-5-trif luorometi lo-pheny the ino) -4- ((R) -1-pheny1-ethylamine) -cyclobut-3-en-1,2-dione To the previous reagent (0.806 g, 2.56 mmol) in ethanol (10 mL) were added (R) -? - methylbenzene sheet (0.33 L, 2.6 mmol). The mixture was heated to reflux for 23 hours. The light yellow solution was concentrated and the resulting foam purified by chromatography (CH30H / CH2C12) to gauge 0.84 g (84%) of the product as a white solid: m.p. 115-124 C; | «* - | n -33.61 (DMSO); 1 H NMR (DMSO-dg); or 9.37 (s, 1H), 8.72 (d, 1H), 8.24 (s, 1H), 7.42-7.19 (, 7H), 5.33 (m, 1H), 3.97 (s, 1H), 1.59 (d, 3H). IR (KBr): 3250, 1790, 1690, 1610 cm "1; MS (m / z) 391 (MH +).

Elemental Analysis for C2QH17F3N203 Cale: C, 61.54; H, 4.39; N, 7.18 Found: C, 61.42; H, 4.26; N, 7.23.

EXAMPLE 4 3 - ((R) -1-Phenyl-ethylamino) -4- (pyridin-4-yl) -cyclobut-3-en-1,2-dione Step 1) Preparation of 3-ethoxy-4- (pyridin-4- (pyridin-4-ylamino) -cyclobut-3-en-1,2-dione To a solution of 3,4-diethoxy-3-cyclobuten-1,2-dione (5.00 g, 29.4 mmol) in ethanol (100 mL) was added a suspension of 4-aminopyridine (2.77 g, 29.4 mmol) in ethanol ( 50 mL). The reaction mixture was heated to reflux for 4 hours. Concentration and chromatography (EtOAc) of the resulting residue was 0.632 g (10%) of the product obtained as a white solid: H NMR (DMSO-dg): o * 11.18 (br s, 1H), 8.45 (d, 2H), 7.40 (d, 2H), 4.80 (c, 2H), 1.43 (t, 3H).

Step 2) Preparation of 3- ((R) -1-phenyl-1-ethylamino) -4- (pyridin-4-yla ino) -cyclobut-3-en-1,2-dione To the previous reagent (0.850 g, 3.90 mmol) in ethanol (25 mL) was added (R) -? - methylbenzene (0.51 mL, 4.0 mmol). The mixture was heated to reflux for 23 hours. The precipitate was filtered remotely and rinsed with ethanol. Chromatography (CH 30 H / CH 2 C 12) 0.276 g (24%) of the product as a crude solid: m.p. 252-254 ° C (dec); | 25D -31.45 (DMSO); 1 H NMR (DMSO-dg): & 9.82 (s, 1H), 8.40 (d, 2H), 8.22 (d, 1H), 7.45-7.38 (m, 7H), 5.28 (, 1H), 1.59 (d, 3H). IR (KBr); 3200, 1800, 1675, 1590 cm "1; MS (m / z) 293 (MH +).

Elemental Analysis for ci7Hi5N3? Cale: C, 69.61; H, 5.15; N, 14.33. Encon ,: C, 69.49; H, 5.06; N, 14.18.

EXAMPLE 5 4- [3,4-Dioxo-2 - ((S) -1-phenyl-ethylamino) -cyclobut-1-enylamino-benzonitrile.

To the reagent of Example 1, step 1 (0.50 g, 2.06 mmol) in ethanol (10 mL) was added (S) - »-methylbenzyl-sheet (0.27 L, 2.1 mmol). The mixture was heated to reflux for 16 hours and filtered under vacuum. The filtrate was recrystallized from methanol to gauge 0.17 g (26%) of the product as a pale yellow solid: mp 269-270 ° C; | < H25n +46.47 (DMSO); 1 H NMR (DMSO-dg): & 9.91 (s, 1H), 8.21 (d, 1H), 7.72 (d, 1H), 7.79-7.31 (m, 9H), 5.29 (m, 1H), 1.59 (d, 3H). IR (KBr): 3200, 2230, 1790, 1670, 1600 cm'1; MS (m / z) 317 (M +).

Elemental Analysis for C? GH15N302 Cale: C, 71.91; H, 4.76; N, 13.24. Found: C, 71.17; H, 4.83; N, 13.34.

EXAMPLE 6 3- (4-Trif luoromethoxy-phenylamino) -4 - ((R) (-) - 1 pheny1-ethylamino) -cyclobut-3-en-1,2-dione Step 1) Preparation of 3-ethoxy-4- (4-trifluoromethoxy phenylato) -cyclobut-3-en-1,2-dione 4-trifluoromethoxyanilin (5.00 g, 28.2 mmol) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4 mmol) in absolute ethanol (50 L). The mixture was heated to reflux overnight, then heated, filtered in vacuo. The filtrate was redicted in volume and the resulting precipitate was filtered to gauge 4.50 g (53%) of white solid: mp 145-146 ° C; 1 H NMR (DMSO-dg): 6 10.87 (S, 1H), 7.45 (d, 2H), 7.36 (d, 2H), 4.75 (c, 2H), 1.41 (t, 3H).

Step 2) Preparation of 3- (4-trifluoromethoxy 'phenylamino) -4- (() -l-phenyl-ethylamine) -cyclobut-3-en-1,2-dione To the previous reagent (0.330 g, 1.10 mmol) in ethanol (25 mL) was added (R) -oe ^ methyl benzene (0.135 mg, 1.11 mmol). The reaction was refluxed for 23 hours. Upon cooling, the product was precipitated as a white solid 0.350 g (84%): mp 258-260 ° C; M 5 D -17.52 (DMSO); 1 H NMR (DMSO-dg): & 9.70 (s, 1H), 8.12 (d, 1H), 7.51-7.28 (m, 9H), 5.28 (m, 1H), 1.59 (d, 3H). IR (KBr): 3250, 1800, 1675, 1600 cm "1; MS (m / z) 377 (MH +).

Elemental Analysis for c? GHi5 [r3N203 Cale: C, 60.64; H, 4.02; N, 7.44 Found: C, 60.40; H, 4.01; N, 7.21.

EXAMPLE 7 (R) -4- (2- | 1- (4-Ithro-phenyl) -eti lamino | -3,4-dioxo-cyclobut-1-enylamino-benzonitrile To the reagent of Example 1, step 1 (0.598 g, 2.47 mmol) in ethanol (50 mL) was added (R) -0-methyl-4-nitrobenzyl hydrochloric acid (0.50 g, 2.5 mmol) and N, N-di. isopropi leti lamina (0.43 g, 2.5 mmol). The mixture was heated to reflux for 16 hours. After cooling, the precipitate was filtered remotely to gauge 0.70 g (78%) of product as an orange solid; p.f. 290-295 C; | o | 25 -100.52 (DMSO); 1? NMR (DMSO-dg): (9.98 (s, 1H), 8.32 (d, 1H), 8.25 (d, 2H), 7.79 (d, 2H), 7.68 (d, 2H), 7.57 (d, 2H) , 5.42 (m, 1H), 1.61 (d, 3H), IR (KBr): 3200, 2220, 1790, 1670, 1600 cm'1, MS (m / z) 362 (M +).

Elementary Analysis for C.QH..N.0. Cale: C, 62.98; H, 3.89; N, 15.46. Found: C, 62.38; H, 3.73; N, 14.95, EXAMPLE 8 3- [3, 4-Dioxo-2- ((R) -1-phenyl-ethylamino) -cyclobut-1-enylamino] -benzonitri lo Step 1) Preparation of 3- (3,4-dioxo-2-ethoxy-cyclobut-1-enynyl) -benzonitrile 3-Aminobenzonitri lo (2.06 g, 17.4 mmol) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (2.97 g, 17.5 mmol) in absolute ethanol (50 L). The mixture was heated to reflux overnight.

The mixture was cooled and the resulting yellow precipitate was collected by vacuum filtration. Obtaining: 3.40 g (81%): 1 H NMR (DMSO-dg): & 10.95 (s, 1H), 7.75-7.40 (m, 4H) \ 4.73 (c, 2H), 1.39 (t, 3H).

Step 2) Preparation of 3- [3,4-dioxo-2- ((R) -1- phenyi-etilamino) -cic lobut- 1 -en i lamino.] - benzonitri lo To the previous reagent (1.00 g, 4.13 mmol) in ethanol (100 mL) was added (R) - (X-methylbenzene plate (0.53 mL, 4.1 mmol) .The mixture was heated to reflux overnight and filtered in vacuo. The precipitate was filtered twice with hot methanol to gauge 0.80 g (61%) of the product as a pale yellow solid: mp 289-290 ° C (dec), M250"13.9 (DMSO), 1 H NMR (DMSO-dg): &9.72 (s, 1H), 8.25 (d, 1 H), 7.90-7.28 (m, 9H), 5.30 (, 1H), 1.60 (d, 3H). IR (KBr): 3200, 2220, 1790. 1650, 1600 cm "1; MS (m / z) 317 (M +).

Elemental Analysis for C19H15N3 ° 2 Cale: C, 71.91; H, 4.76; N, 13.24. Found: C, 71.80; H, 4.61; N, 13.33, EXAMPLE 9 4- | 3,4-Dioxo-2- (1-methyl-1-phenyl-ethylamino) -cyclobut-1 enylamino! -benzonitri To the reagent of Example 1, step 1 (0.81 g, 3.3 mmol) in ethanol (30 mL) was added β-dimethyl-1-benzylamine (0.45 g, 3.3 mmol). The mixture was heated to reflux for 20 hours. After cooling, the precipitate was filtered off and chromatographed (CH30H / CH2C12) to gauge 0.41 g (37%) of product as a solid: m.p. 300 ° C; 1 H NMR (DMSO-dg) S 10.08 (s, 1H), 8.38 (s, 1H), 7.79 (d, 2H), 7.61 (d.2H), 7.48-7.27 (m, 5H), 1.78 (s, 6H) ). IR (KBr): 3200. 2230 1790, 1675, 1600 cm "MS (m / z) 331 (M +) Elemental Analysis for 2QH17N302 (0.1 CH30H). (0.05 CH2Cl2) Cale: C, 71.43; H. 5.21; N, 12.40. Found: C, 71.30; H, 5.33; N, 12.69.

EXAMPLE 10 4- | 3,4-Dioxo-2 - ((R) -1-phenyl-propylamino) -cyclobut-1-enylamino | -benzonitrile To the reagent of Example 1, step 1, (1.79 g, 7.39 mmol) in ethanol (30 mL) was added (R) -1-phenyl-1-propylamine (1.00 g, 7.40 mmol). The mixture was heated to reflux for 18 hours, cooled insignificantly and filtered in vacuo to gauge 1.76 g (72%) of product as a yellow solid: mp 242-243 ° C; M25D -52.73 (DMSO); 1 H NMR (DMSO-dg): d 9.84 (s, 1H), 8.12 (br d, 1H), 7.76 (d, 2H), 7.56 (d, 2H), 7. 42-7.27 (m, 5H), 5.06 (m, 1H), 1.94 (m, 2H), 0.90 (t, 3 3 HH)) .. IIRR ((KKBBrr)) :: 332200? 0, 2220, 1790, 1670, 1600 cm "1; MS (m / z) 331 (M +).

Elemental Analysis for C20H17N3 ° 2 Cale: C, 72.49; H, 5.17; N, 12.68. Found: C, 72.42; H, 5.01; N, 12.73.

EXAMPLE 11 4- | 3, 4-di oxo-2- ((S) -1-phenyl-propy1-amino) -cyclobut-1-enylamino-benzonitrile To the reagent of Example 1, step 1 (1.79 g, 7.39 mmol) in ethanol (30 mL) were added (S) -1-phenyl-1-pro-phenylamine (1.00 g, 7.40 mmol). The mixture was heated to reflux for 18 hours, hardly cooled and filtered under vacuum to gauge 1.61 g (66%) of the product as a yellow solid: m.p. 241-243 ° C; l? - | 25D + 52.33 (DMSO); 1 H NMR (DMSO-dg): 8 9.84 (s, 1 H), 8.21 (br d, 1 H), 7.76 (d, 2 H), 7.56 (d, 2 H), 7.42-7.27 (m, 5 H), 5.06 (m , 1H), 1.94 (m, 2h), 0.90 (t, 3H0, IR (KBr): 3200, 2220, 1790, 1670, 1600 cm "1; MS (m / z) 331 (M +).

Elemental Analysis for C20H17N3 ° 2 Cale: C, 72.49; H, 5.17; N, 12.68. Found: C, 72.17; H, 5.04; N, 12.80.

EXAMPLE 12 4- [3,4-Dioxo-2- (benzylamino) -cyclobut-1-enylaminobenzonitriol.

To the reagent of Example 1, step 1, (1.00 g, 4.13 [mu] tmol) enetanol (30 mL) was added benzylamine (0.45 mL, 4.1 mmol). The mixture was heated to reflux for 18 hours, hardly cooled and filtered under vacuum. The precipitate was triturated with hot methanol to gauge 0.78 g (62%) of the product as an anerous solid: m.p. 288-290 ° C (dec); 1 H NMR (DMSO-dg): 9.91 (s, 1 H), 8.10 (m, 1 H), 7.79 (d, 2 H), 7.75 (d, 2 H), 7.75 (d, 2 H), 7.91-7.78 (m, 5H), 4.82 (d, 2H). IR (KBr): 3190, 2220, 1790, 1660, 1575 cm "1; MS (m / z) 303 (M +).

Elemental Analysis for c? AHi3N3 ° 2 Cale: C, 17.28; H, 4.32; N, 13.85. Jan: C, 71.07; H, 4.16; N, 12.89.

EXAMPLE 13 (R) -4-. { 2- [1- (4-meti lo-feni lo) -e i the ino] -3,4-dioxo-cic lobut- 1-eni lamino) - benzonitri lo To the reagent of Example 1, step 1 (1.00 g, 4.13 mmol) in ethanol (30 mL) were added (R) -l- (p-tol i) -eti lamina (0.56 g, 4.1 mmol). The mixture was heated to reflux for 18 hours, hardly cooled and filtered under vacuum to gauge 1.02 g (75%) of the product as a yellow solid: m.p. 300 ° C; | 125Q -56.01 (DMSO); 1 H NMR (DMSO-dg): either 9.81 (s, 1H), 8.10 (m, 1H), 7.76 (d, 2H0, 7.55 (d, 2H), 7.29 (d, 2H), 7.19 (d, 2H), 5.26 (m, 1H), 1.57 (d, 3H).

IR (KBr): 3200, 2220, 1790, 1670, 1600 cm "1; MS (m / z) 331 (M +).

Elemental Analysis FOR C20H17N3 ° 2 Cale: C, 72.49; H, 5.17, 12.68 Found: C, 72.42; H, 5.07; N, 12.82.

EXAMPLE 14 (R) -4- 2- | 1- (4-Methoxy-phenyl) -ethylane-3,4-dioxo-cyclobut-1-enylamino} -benzonitri To a solution of (1R, 11R) -N- (1'-pheni leti) -1- (4"-methoxyphene) -eti lamina (1.37 g, 5.36 mmol, prepared as in J. Med Chem. 1992, 35, 2327) and ammonium formate (1-01 g, 16.0 mmol) in methanol (125 mL) were added 10% palladium on activated carbon.The suspension was refluxed for 2 h, filtered through Celite and concentrated To the reagent of Example 1, step 1, (1.00 g, 4.13 mmol) was added to the solution of the resulting residue in ethanol (30 mL) .The mixture was heated to reflux for 18 h, quenched and filtered under vacuum. The precipitate was chromatographed (CH30H / CH2C12) and recrystallized (CH30H / CH2C12) to gauge 0.21 g (15%) of the product as a yellow solid: mp 300 C; | < - | Q -46.95 (DMSO); 1H NMR (DMS0-df): &9.89 (s, 1H), 8.13 'S, 1H). 7. 77 (d, 2H), 7.56 (d, 2H), 7.34 (d, 2H), 6.95 (d, 2H), 5.23 (m, 1H), 3.73 (s, 3H), 1.57 (d, 3H). IR (KBr): 3200, 2200, 1800, 1670, 1575 cm "1; MS (m / z) 347 (M +).

Elemental Analysis for C20H17N3 ° 3 (° -03 CH ^ C 12) Cale: C, 68.75; H, 4.91; N, 12.01. Found: C, 68.40; H, 4.74; N, 11.89 EXAMPLE 15 (R) -4 ~ (3,4-Dioxo-2- [1- (4-trifluoromethoxy-phenyl) ethylamino] -cyclobut-1-enylaminot-benzonitrile.

To a solution of (IR, 1 'R) -N- (1' feni leti lo) -1- (4"-trif luoromethoxyphene) -eti lamina (1.92 g, 6.21 mmol, prepared as in J. Med Chem, 1992, 35, 2327) and ammonium formate (1.17 g, 18.6 mmol) in methanol (150 mL) were added 10% palladium on activated carbon.The suspension was refluxed for 2 hours, filtered through Celite and concentrated The reagent from Example 1, step 1 (1.00 g, 4.13 mmol) was added to a solution of the resulting residue in ethanol (35 mL) .The mixture was heated to reflux for 18 h, poorly cooled and filtered in vacuo. was combined with a second culture of solids obtained from the cooled filtrate, chromatographed (CH30H / CH2C12) and recrystallized (CH30H / CH2C12) to gauge 0.74 g (45%) of the product as a white solid: mp 281-284 ° C (dec); H25D -55.94 (DMSO); 1 H NMR (DMSO-dg): 9.94 (s, 1H), 8.22 (d, 1H), 7.78 (d, 2H), 7.60-7.51 (m, 4H), 7.40 (d, 2H), 5.33 (, 1H), 1.60 (d, 3H), IR (KBr): 3200, 2200, 1800, 167 0.1560 cm "1; MS (m / z) 401 (M +).

Elemental Analysis for C20H14F3N3 ° 3 Cale: C, 59.85; H, 3.52; N, 10.47 Jan: C, 59.94; H, 3.38; N, 10.43 EXAMPLE 16 4- [3,4-dioxo-2- (2,2,2-trifluoro-1-phenylethylamino) -cyclobut-1-ynylamino] -benzonitrile To a solution of N-2,2,2-trifluoro-1-pheni leti lo-N-1 '- (feni lo) eti lamina (1.65 g, 6.22 mmol, prepared as in J. Org. Chem. 1977, 42, 2436) and ammonium formate (1.17 g, 18.6 mmol) in ethanol (150 L) were added 10% palladium on activated carbon. The suspension was refluxed for 4 h, filtered through Celite and concentrated to a volume of approximately 10 mL. The reagent from Example 1, step 1 (1.00 g, 4.13 mmol) and ethanol (20 mL) was added and the mixture was heated to reflux for 18 hours, hardly cooled and filtered under vacuum to remove or remove a small amount of solid. The filtrate was chromatographed (CH30H / CH2C12) and the resultant yellow recrystallized from chloroform and ether to obtain 0.72 g (47%) of the product as a pale yellow solid: m.p. 206-207 ° C; 1 H NMR (DMSO-dg): 5 9.99 (s, 1H0, 8.88 (d, 1H), 7.82 (d, 2H), 7.60-7.46 (m, 9H), 5.98 (m, 1H), 3.73 (s, 3H IR (KBr): 3200, 2200, 1800, 1690, 1570 cm "1; MS (m / z) 371 (M +).

Elemental Analysis for C1gH12F3N302 Cale: C, 61.46; H, 3.26; N, 11.32 Jan: C, 61.26; H, 3.16; N, 11.23.

EXAMPLE 17 (R) -4- [3,4-dioxo-2- (1-phenyl-ethylamino) -cyclobut-1-eti the] -3-meth-1-benzonitrile Step 1) Preparation of 4- (3,4-dioxo-2-ethoxy-cyclobut-1-enylamino) -3-methylbenzonitrile 4-amino-3-methy I lbenzonitri (1.94 g, 7.14 mmol) were added to the solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (2.53 g, 14.9 mmol) in acetonitrile (5 mu) . After having refluxed the mixture for 24 hours a second portion of 3,4-diethoxy-3-cyclobutene-1,2-dione (1.15 g, 6.76 mmol) were added and continuously heated for an additional 48 hours. The reaction mixture was diluted with ethyl acetate (50 mL), vigorously stirred and filtered, free of undissolved solids. The filtrate was GC iado (CH30H / CH2C12) to aforar 0.90 g (24%) of product as a yellow solid: 1H NMR (DMSO-dg): or 10.50 (s, 1H), 7.76-7.63 (m, 2H), 7.31 (d, 1H), 4.71 (c, 2H), 2.33 (s, 3H), 1.38 (t, 3H).

Step 2) Preparation of (R) -4- [3,4-dioxo-2- (1-phenylethylamino) -cyclobut-1-enynyl] -3-methyl-benzonitriyl.

To the previous reagent (0.90 g, 3.51 mmol) in ethanol (40 mL) was added (R) - < x-meti lbenci lamina (0.45 mL, 3.49 mmol). The mixture was heated to reflux for 18 hours. The resulting clean solution was concentrated and the residue chromatographed (CH30H / CH2C12) to gauge 0.98 g (85%) of the product as a yellow solid: m.p. 110-130 ° C (dec); | p | 25D-40.91 (DMSO); 1 H NMR (DMSO-dg): & 8.95 (s, 1H), 8.58 (d, 2H), 7.70-7.28 (m, 8H), 5.36 (m, 1H), 2.33 (s, 3H), 1.61 (d, 3H). IR (KBr): 3250, 1790, 1690, 1590 cm "1; MS (m / z) 332 (MH +).

Elemental Analysis for C20H17N3 ° 2 '^ ° "10 CH2C12 ^ Cale: C, 71.03; H, 5.10; N, 12.36 Jan: C, 71.37; H, 5.09; N, 12.61.

EXAMPLE 18 (R) -4- [3,4-dioxo-2-1 (-1-phenyl-ethylamino) -cyclobut-1-enylary-3-ethyl-benzonitrile Step 1) Preparation of 4- (3,4-dioxo-2-ethoxy-cyclobut-1-enylamino) -3-ethyl-benzonitrile 4-amino-3-eti lbenzonitri I (2.00 g, 13.7 mmol) were added to a solucidnde 3,4-diethoxy-3-cyclobutene-1,2-dione (2.30 g, 13.5 mmol) in acetonitrile (5 mL). After refluxing the mixture for 24 hours, a second portion of 3,4-diethoxy-3-cyclobutene-1,2-dione (1.15 g, 6.76 mmol) was added and continuously heated for an additional 24 hours. The reaction mixture was diluted with ethyl acetate (45 mL), vigorously stirred and the filtrate free from undissolved solids. The filtrate was concentrated and the resulting residue was purified and iado GC (CH30H / CH2C12) and trituration with ester to aforar 0.86 g (24%) of product as a light yellow solid: H NMR (DMSO-dg): b * 10.57 ( s, 1H), 7.77-7.66 (m, 2H), 7.31 (d, 1H), 4.71 (c, 2H) 2.73 (c, 2H), 1.37 (t, 3H), 1.13 (t, 3H) ).

Step 2) Preparation of (R) -4- [3,4-dioxo-2- (1-phenylethylamino) -cyclobut-1-enylamino] -3-ethyl-benzonitrile To the previous reagent (0.85 g, 3.14 mmol) in ethanol (25 mL) was added (R) -x-methylbenzene (0.41 mL, 3.18 mmol). The mixture was heated to reflux for 18 hours, hardly cooled and filtered by suction. The filtrate was cooled by gradual evaporation of the solvent and the precipitate which formed was collected in two crops to gauge 0.76 g (70%) of the product as a crude solid: m.p. 206-207 ° C (dec); | 25D -45.25 (DMSO); 1 H NMR (DMSO-dg): d 9.98 (s, 1H), 8.55 (d, 2H), 7.68-7.29 (, 8H), 5.37 (, 1H), 2.69 (c, 2H), 1.61 (d, 3H) , 1.20 (t, 3H). IR (KBr): 3200.2200, 1800, 1670, 1570 cm'1; MS (m / z) 345 (M +).

Elemental Analysis for C12H19N3 ° 2 Cale: C, 73.03; H, 5.54; N, 12.17 Found; C, 72.69; H. 5.52; N, 12.18.

EXAMPLE 19 (R) -N- (4-c i ano-pheni lo) -N-l3,4-di oxo-2- (1-phenyl-eti lamino-cyclobut-1-eni lo] -acetamide To a stirred solution of the reagent of Example 1, step 2 (1.77 g, 5.58 mmol) in N, N-dimethylformamide (50 mL), sodium hydride (as a 60% dispersion) was added in one portion. mineral oil, 0.252 g, 6. 30 mmol). The frothy suspension was stirred at temp. environment for 15c minu + tos and? l.u.e "go" to,? 0OC- for an additional hour. Acetic anhydride (0.58 mL, 6.15 mmol) were added and the reaction mixture was stirred at 0 ° C for an hour and a half and then allowed to warm to rt. After an additional 1 hour of stirring, the reaction solution was concentrated. The resulting yellow solid was washed with successive portions of acetone, methylene chloride and ethyl acetate. The combined washings were concentrated and the resulting residue chromatographed to gauge 0.48 g (24%) of the product as a crude solid: m.p. 240-243 ° C; |? | 25D -94.66 (DMSO); 1 H NMR (DMSO-dg); & 8.29 (d, 1H), 7.96 (d, 2H), 7.69 (d, 2H), 7. 45-7.25 (m, 5H), 5.49 (m, IR), 2.06 (s, 3H), 1.59 (d, 3H) I IRR ((KKBBrr)) :: 3340, 2230, 1800, 1740, 1690, 1610 cm "1; MS (m / z) 359 (M +).

Elemental Analysis for C21 17N3 ° 3 (0.05 CH ^ Cl 2) Cale: C, 69.53; H, 4.74; N, 11.56 Enco .: C, 69.16; H, 4.74; N, 11.53.

The smooth muscle relaxant activity of the compounds of this invention were established in accordance with the standard pharmaceutically accepted testing procedures in the representative compounds as follows: Spregue-Dawley rats (150-200 g) were rendered meaningless by asphyxiation with C02 and then euthanized by cervical dislocation. The bladder was stirred into a warm physiological salt solution (37 ° C) of the following composition (mM): NaCl, 118.4; KCl, 4.7; CaCl2 2.5; MgSO4, 4.7; HgO, 1.2; NaHCDg, 24.9; KH ^, 1.2; glucose, 11.1; EDTA, 0.023; Gassed with 95% of 02; 2/5% C02; pH 7.4. The bladder is opened and cut into strips 1-2 mm wide and 7-10 mm long. The strips are subsequently suspended in a 10 mL bath of the tissue under an initial resting tension of 1.5 g. The strips are taken from the site 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 exhibited small spontaneous contractions, are left to recover for a period of 1 hour before a stimulus with 0.1 uM carbachol. The carbachol is then washed and the tissue left to relax at its resting activity level. Following an additional 1 hour and 30 minutes of recovery, in additional 15 M KCl, they are introduced into a tissue bath. This increase in KCl concentrations results in a large increase in the amplitude of spontaneous contractions (and inhibition of contractions in previously quiescent strips) superimposed on a small increase in basal tone. Following stabilization, of this increased level of contractile activity, this increase in the concentration of the experienced compound or vehicle is introduced into a tissue bath. The contractile activity is measured for each concentration of the compound or vehicle during the last minutes of the 30 minutes of stimulation.

The isometric force developed by those of the bladder are measured using a concentration required to obtain 50% inhibition of contractile activity before the drug (concentration of I 0) is calculated from this curve of the concentration of the response. The percentage of maximum inhibition of the contractile activity evoked by the compound tested is also recorded by the concentrations of the test compound or equal to 30 μM.

The results of this study are shown in Table I.

Table I Inhibition of the concentration in bladder scrapings of an isolated rat. Compound n Inhibition Force IC50 (%) a (x) EXAMPLE 1 6 0.056 JJM EXAMPLE 4 3 2.3 jiM EXAMPLE 5 3 38% (30 jiM) EXAMPLE 9 4 22% (30 JJM) EXAMPLE 11 4 28% (30 JM) ) Therefore, the compounds of this invention have a pronounced effect on muscle contractility and are useful in the treatment of urinary incontinence, bowel and irritable bowel disorders, asthma, hypertension, shock, and similar conditions as mentioned above. , which are receptive to treat with activating compounds of the potassium channel by administration orally or parenterally, or by aspiration to a patient in need thereof.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, everything contained in the following is claimed as property.

Claims (22)

1. Claims A compound of the formula: (I) characterized in that: R1 is hydrogen, branched or straight chain C ^ .g alkyl, cyclic or bicyclic C3 .Q alkyl, C2 to C7 alkanoyl, C13 alkylsulfonyl of 1 to 7 carbon atoms, C12 azoyl at 12 carbon atoms, arylalkinium has from 9 to 20 carbon atoms, arylsulfone has from 6 to 12 carbon atoms, aryloalkyl from 8 to 12 carbon atoms or arylalkylsulfonyl from 7 to 12 carbon atoms; R2 is hydrogen, branched or straight chain CI_IQ alkyl or cyclic and bicyclic 3-C alkyl; A is a group of the following formula: wherein: R7 and Rg, independent of each of the others, are selected from the following: cyano, nitro, amino, C-alkyl, fi (perfluoroalkyl C._g, alkoxy C. g, perfluoroalkoxy C. , C,, »mono or dialkylamino, sulfonamide, alkyl sulfonamide, g, arylsulphone ida Cg_12, alkylcarboxamide C2_g, arylcarboxy ida C7_12, alkylsulfonyl C. g, perfluoroalkyl-sulfonyl, ary1 sulfoni lo Cg_12» chlorine, bromine, fluorine, iodine, 1-imidazole, carboxyl, carboalkoxy of 2 to 7 carbon atoms, hydroxyl or hydrogen; or, A is Het where Het is selected from the following: wherein: R g is hydrogen, C 1 g alkyl, C 1 g perfluoroalkyl, C 1 g alkoxy, C 1 g g alkoxy, amino, C 2 mono or dialkylamino, C 1 -C 1 alkylsulfonamide, C 2 g alkylcarboxamide, nitro, cyano, carboxyl, chlorine, bromine, fluorine, iodine; n is an integer from 0 to 6; R and R are, independently of each other, C1-C branched or straight chain alkyl, or C, cyclic or bicyclic alkyl; perfluoroalkyl CI_IQ »hydroxyalkyl CI_IQ» alkoxyalkyl C2_10 > fluoro; or, where together they take the form of a spirocyclic ring containing a total of 3-7 carbon atoms; Re and Rg are independent of each other, are selected from the following: cyano, nitro, amino, C.sub.6 alkyl, perfluoroalkyl C. | g, alkoxy C, g, perfluoroalkoxy C, e »amino, ^ - \? mono or dialkylamino, sulfonamide, alkylsulphonamide C ^ g, arylsulphone ida cc_i2 'alkyl-carboxy ida C2_g, arylcarboxamide C7_12, alkylsulfonyl C. g, perfluoroalkylsulfonium lo C ^ g, ary1 sulfonyl lo Cg_ 12. chlorine, bromine , fluoro, iodo, 1- i idazol i lo, carboxyl, C2_7 carboalkoxy, hydroxy or hydrogen; a pharmaceutically acceptable salt thereof.
2. 2. - A compound, according to claim 1, characterized in that: it is a group of the following formula: wherein: R7 and Rg, independent of each other, are selected from the following: cyano, nitro, amino, chloro, bromo, bromo, fluoro, iodo, 1-imi -dazolyl, carboxyl, hydrogen; or A is Het, where Het is selected from the following formula: where: g is like the previous state; n = 0; R3 and R ^ are, independently of each other, hydrogen, branched or straight chain alkyl C._10, perfluoroalkyl, hydroxyl, C1-alkyl, or fluoro; R5 and Rg, independent of each of the others, are selected from the following: cyano, nitro, amino, C ^ g alkyl, perfluoroalkyl, C1-C6alkoxy, perfluoroalkoxyC, g, amino, chlorine, bromine, fluoro, iodine, carboxyl, C2-7 carboalkoxy * hydroxyl, hydrogen; or a pharmaceutically acceptable salt thereof.
3. 3. - The compound, according to claim 1, characterized in that it is 4-3,4-dioxo-2- (1-phenyl-1-ethynyl) -cyclobut-1-enylamino] -benzonitrile.
4. 4. The compound, according to claim 1, characterized in that 3- (5-bromo-pyridin-3-ylamino) -4- (1-phenyl-ethylamino) -cyclobut-3-en-1, 2- iana
5. 5. The compound, according to claim 1, characterized in that it is 3- (2-methoxy-5-trifluorolethyl-phenylamino-) - 4- (i-phenyl-ethylamino) -cyclobut-3-en-1, 2 -Diona.
6. 6. The compound, according to claim 1, characterized in that it is 3- (l-phenyl-ethylamino) 4- (pyridin-4-ylamino) -cyclobut-3-en-1,2-dione.
7. 7. The compound, according to claim 1, characterized in that it is 3- (4-trif luorome-toxi-phenylamino) -4 - (- 1-phenyl-ethylamino) -cyclobut-3-en-1,2-dione.
8. 8. - The compound, according to claim 1, characterized in that it is 4-. { 2- £ l- (4-nitro-phenyl) -ethylamino] -3,4-dioxo-cyclobut-1-enylamino-benzoni-tri lo.
9. 9. The compound, according to claim 1, characterized in that it is 3- [3,4-dioxo-2- (1-phenyl-ethyl-lamino) -cyclobut-1-enylamino] -benzonitriyl.
10. 10. The compound, according to claim 1, characterized in that it is 4- [3,4-dioxo-2- (1-met i lo-1-phenyl-ethylamino) -cyclobut-1-enylamino-benzo-nitrile.
11. 11. The compound, according to claim 1, characterized in that it is 4- [3,4-dioxo-2- (1-phen i 1 -propylamino) -cyocobut-1-enylamino-J-benzonitrile.
12. 12. The compound, according to claim 1, characterized in that it is 4- [3,4-dioxo-2- (benzylamino) -cyclobut-1-enylamino-J-benzonitrile.
13. 13. - The compound, according to claim 1, characterized in that it is 4-. { 2- 1- (4-methyl-phenyl) -ethylamino-3,4-dioxo-cyclobut-1-enylamino} benzonitri lo.
14. 14. - The compound, according to claim 1, characterized in that it is 4-. { 2- [1- (4-methoxy-phene) -ethylamino-3,4-dioxo-cyclobut-1-enylamino-benzonitrile,
15. 15. The compound, according to claim 1, characterized in that it is 4-3,4-dioxo-2- [1- (4- trifluoromethoxy-phene) -ethylamino-cyclobut-1-enylamino} -benzonitri lo.
16. 16. The compound, according to claim 1, characterized in that it is 4- £ 3,4-dioxo-2- (2, 2, 2-trifluoro-1-phenyl-etilamino) -cic lobut- 1-eni laminated } -benzonitri lo.
17. 17. The compound, according to claim 1, characterized in that it is 4- [3,4-dioxo-2- (1-pheny1-ethylamino) -cyclobut-1-enylamino-3-methyl-benzonyl-tri .
18. 18. The compound, according to claim 1, characterized in that it is 4- [3,4-dioxo-2- (1-pheny1-ethylamino) -cyclobut-1-enylamino-3-ethi-lo-benzonitrile.
19. 19. - The compound according to claim 1, characterized in that it is N- (4-cyano-phenyl) -N-3,4-dioxo-2- (1-phenyl-ethyl-indo) -cyclobut-1-enyl] - acetamide.
20. 20. - A method for reducing the adverse effects of smooth muscle contractions, characterized in that it comprises administration, orally or parenterally, to a patient in need of it, of a compound of the formula: (I) wherein: R1 is hydrogen, straight or straight chain C1-10 alkyl, cyclic or bicyclic C3_10 alkyl, C2 -C7 alkanoyl, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms , ari lalc * pnoi lo of 9 to 20 carbon atoms, ari lsulfoni lo of 6 to 12 carbon atoms, ary lalcanoi lo of 8 to 12 carbon atoms or arylalki 1 sulfonium of 7 to 12 carbon atoms; R is hydrogen, C 1, branched or straight chain C 1 alkyl, or cyclic or bicyclic 3 1 C alkyl; A is a group of the following formula: wherein: R7 and Rg, independent of each of the others, are selected from the following: cyano, nitro, amino, alkyl. g, perfluoroalkyl C, g, alkoxy c5 > perf luoroalkoxy C ^ g, amino, C < 1-12 mono- or dialkylamino, sulfonamide, alkylsulphonamide, C6_12 alkylsulfonamide, alkylcarboxamide, 2g, C7_12 arylcarboxamide, alkylsulfonyl, g, perfluoroalkyl, sulphonyl, g, arylsulfon, Cg_12, > chlorine, bromine, fluorine, iodine, 1-imidazole i, carboxyl, carboalkoxy of 2 to 7 carbon atoms, hydroxyl or hydrogen; or, A is Het where Het is selected from the following where: Rg is hydrogen, alkyl Cj_g, perfluoroalkyl C, c, alkoxy perfuoroalkoxy Cj_g, amino, C._12 mono or dialkylamino, alky1 sulfonamide alkylcarboxamide C2_g, nitro, cyano, carboxyl, chloro, bromo, fluoro, iodo; n is an integer from 0 to 6; R3 and R. are independently from each other, alkyl CI_IQ of branched or straight chain, or cyclic or bicyclic C3_12 alkyl; perf luoroalkyl C1_10 'hydroxyalkyl CI_IQ > alkoxyalkyl C2_1Q, fluoro; or, where together they take the form of a spirocyclic ring containing a total of 3-7 carbon atoms; Rg and Rg, independent of each other, are selected from the following: cyano, nitro, amino, alkyl C. g, perfluoroalkyl, c? _c »alkoxy c? G» perf luoroalkoxy C. g, amino, c? _i2 mono or dialkylamino, sulfonamide, alkylsulfonamide C ^ g, arylsulfonamide Cfi-12'alkylcarboxamide C2-6 'arylcarboxamide C7_12' alkylsulfonyl C ^ g, perfluoroalkyl 1 its 1 -phonyl C, g, ary lsulfoni lo Cg_ 12 »chloro, bromo, fluoro, iodo, 1-imidazole i, carboxyl, carboalkoxy C2_7, hydroxyl, or, hydrogen; or a salt thereof, pharmaceutically acceptable.
21. 21. - The method according to claim 20, characterized in that the contractions of the smooth muscle adversely cause urinary incontinence.
22. 22. The method, according to claim 20, characterized in that the contractions of the smooth muscle adversely cause the irritable bowel syndrome. SUMMARY OF THE INVENTION The compounds of formula (I) wherein R is hydrogen, branched or straight chain alkyl C, cyclic or bicyclic C-alkyl, alkanoyl of 2 to 7 atoms of carbon, alkylsulfonyl of 1 to 7 carbon atoms, aoryl of 7 to 12 carbon atoms, arylakenoyl of 9 to 20 carbon atoms, arylsulfonyl with 6 to 12 atoms or carbon, arylalkanoyl of 8 to 12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms; R is hydrogen, branched or straight chain alkyl C or cyclic or cyclic C-alkyl, A is a group of formula -i c (II), where R and R independent of each of the • * • - * 7 8 others, are selected from the following: cyano, nitro, amino, C-alkyl perfluoroalkyl C. alkoxy C, 1-D 1 -D l -O perfluoroalkoxy C amyno, mono- or dialkylamino C 1-6 1-12 Sulphonamide, alkylsulfonamide C, arylsulfonamide C alkylcarboxamide C, arylcarboxamide C, alkylsulfo- 2-6 7-12 nyl C perfluoroalkylsulfonyl C arylsulfonyl 1-6 C 1-6 C, chlorine, bromine, fluorine, iodine, 1-imidazole , carboxy- 6-12 alkyl, carboalkoxy of 2 to 7 carbon atoms, hydroxyl or hydrogen; or A ES Het where Het is selected from (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), ( k), (l), (m), (n), (o), (pP, where R is hydrogen, Cf alkyl, perfluoroalkyl C. ... 1-6