AU727217B2 - Heterocyclylmethylamino derivatives of cyclobutene-3,4- diones as potassium channel modulators - Google Patents

Description

WO 97/48682 PCT/US97/09744 HETEROCYCLYLMETHYLAMINO DERIVATIVES OF CYCLOBUTENE-3,4-DIONES AS POTAS- SIUM CHANNEL MODULATORS Background of Invention The present invention relates to novel heterocyclylmethylamino derivatives of cyclobutene 3-4-diones having pharmacological activity, to a process for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of disorders associated with smooth muscle contraction via potassium channel modulation. Such disorders include, but are not limited to: urinary incontinence, asthma, premature labor, irritable bowel syndrome, congestive heart failure, angina, cerebral vascular disease and hypertension.

Stemp et al. (EP-426379) disclose a class of amino substituted cyclobutenedione derivatives of chromans described as having blood pressure lowering activity and bronchodilatory activity. Takeno et al. report a series of diaminocyclobuten-3,4-diones in Public Patent Disclosure Bulletin No. 6-92915. Our own efforts in this area have been disclosed in the following US Patents: 5,464,867; 5,466,712; 5,403,853; 5,403,854; 5,397,790 and 5,401,753. Several series of 1amino-2-phenylalkylamino-cyclobutene-3,4-diones are reported as H-2 receptor antagonists by Algieri et al. in US Patent 4,390,701. Several related 1-amino-2phenoxyalkylamino derivatives are disclosed by Nohara et al. in US Patent 4,673,747.

Additionally, several related 1-amino-2-pyridyloxyalkylamino derivatives are disclosed by Nohara et al. in EP-177016. The compounds of Nohara et al. are reported as H-2 receptor antagonists.

A 4-pyridinylmethylamino derivative of cyclobutendione was disclosed by Chandrakumar et al. in US Patent 5,354,746 to possess analgesic activity. The compounds of the Chandrakumar series require the presence of a tricyclic dibenzoxazepine moiety. A 3-pyridinylmethylamino derivative of cyclobutendione was disclosed by Ife in EP-112704 and was reported to be an H-2 antagonist. The compounds of the Ife series require the presence of an N'-pyridyl-diamino moiety.

-2- The syntheses of variously substituted 1,2-diamino-cyclobutene-3,4-diones are described in the following publications: Tietze et al., Chem Ber. 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. 1973, 619.

The above discussion of documents, acts, compositions and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each claim of this application.

Description of The Invention In accordance with the present invention, there is provided a group of compounds represented by the formula o 0

/R,

A N N I I R3 2 (I) wherein: 3 25 R, and R 2 are, independently, hydrogen, straight chain alkyl of 1 to carbon atoms, branched chain alkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, bicycloalkyl of 4 to 10 carbon atoms or aralkyl of 7 to 20 carbon atoms, wherein the aromatic moiety of the aralkyl group may be optionally substituted with one to three straight chain alkyl of 1 to 10 carbon atoms, branched chain alkyl of 1 to 10 carbon atoms, halogen, nitro, cyano, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, R trifluoromethyl or trifluoromethoxy groups; C:\WINWORD\AUSONSPECIU33017SPE.DOC -2A-

R

3 is hydrogen, formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyi 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 arylalkylsulfonyl of 7 to 12 carbon atoms;

S.

S S

S*

S

S S S S S

S

S. *S S S

S

S

WO 97/48682 PCT/US97/09744 -3- A is selected from the group consisting of: R 4 R- N R4 R 4 t R41; (0)n

R

6 R4~i wherein: n is 0 or 1;

R

4 R5 and R6 are, independently, cyano, nitro, 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, 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 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, perfluoroalkylsulfonyl of 1 to 6 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, chloro, bromo, fluoro, iodo, 1-imidazolyl, carboxyl or hydrogen; or a pharmaceutically acceptable salt thereof.

A preferred aspect of this invention includes compounds of formula (I) wherein: R1 and R2 are as stated above;

R

3 is hydrogen; WO 97/48682 PCT/US97/09744 A is selected from the following: R4-Q--

RN

R

R5 wherein R 4 R5 and R6 are as defined above; or a pharmaceutically acceptable salt thereof.

Preferred values of R1 and R2 are, independently, hydrogen, methyl, ethyl, n- or iso-propyl, iso, sec- or tert-butyl, straight or branched chain pentyl, or phenylalkyl in which the alkyl is methylene or ethylene and in which the phenyl moiety may be optionally substituted with one to three substituents selected from methyl, ethyl, fluorine, chlorine, bromine, nitro, cyano, methoxy, ethoxy, methoxyoxycarbonyl, ethoxyoxycarbonyl, trifluoromethyl and trifluoromethoxy.

R3 is preferably hydrogen. Preferably n is 0.

Preferred values of R 4 R5 and R6 are, independently, hydrogen, cyano, nitro, amino, methyl, methoxy, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethoxy or carboxyl.

Compounds of formula of particular interest are: 3-(1,1-dimethylpropylamino)-4-[(pyridin-4-ylmethyl)-amino]-cyclobut-3-ene- 1,2dione or a pharmaceutically acceptable salt thereof; 1,-dimethylpropylamino)-4-[pyridin-3-ylmethyl)amino]cyclobut-3-ene- 1,2-dione or a pharmaceutically acceptable salt thereof; WO 97/48682 WO 9748682PCT[US97/09744 1, 1-dimethylpropylamino)-4- [(pyridin-2-ylmethyl)amino] -cyclobut-3-ene- 1 ,2-dione or a pharmaceutically acceptable salt thereof; 3-tert-butylamino-4-[(pyridin-4-ylmethyl)aminol-cyclobut-3ene 1 ,2-dione or a pharmaceutically acceptable salt thereof; 3 -tert-butylamino-4- [(pyridin-3-ylmethyl) amino] -cyclobut-3-ene- 1 ,2-dione or a pharmaceutically acceptable salt thereof; 3-tert-butylamino-4-[(pyridin-2-ylmethyl)amino]-cyclobut-3-ene- 1,2-dione or a pharmaceutically acceptable salt thereof; 3 -(isopropyl-methyl-amnino)-4-[(pyridin-4-ylmethyl)-amino] -cyclobut-3-ene- 1,2-dione or a pharmaceutically acceptable salt thereof; 3- [(5-nitro-benzofuran-2-ylmethyl)-amino-4-( 1, 2 2 -trimethylpropylamino)-cyclobut-3ene- 1 ,2-dione or a pharmaceutically acceptable salt thereof; 1,1 -dimethyl-propylamino)-4-[(5-nitro-benzofuran-2-ylmethyl)-aminoI..cyclobut-3 ene- 1,2-dione or a pharmaceutically acceptable salt thereof; 3-tert-butylamino-4-[(5-nitro-benzofuran-2-ylmethyl)-amino] -cyclobut-3-ene- 1,2-dione or a pharmaceutically acceptable salt thereof; 2- 1,1-dimethyl-propylamino)-3,4-dioxo-cyclobut-lI-enylamino] -methyl) or a pharmaceutically acceptable salt thereof; 2-f [3, 4 -dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-l1-enylamino] -methyl) benzofuran-5-carbonitrile or a pharmaceutically acceptable salt thereof; 2- [(2-tert-butylamino-3,4-dioxo-cyclobut-l1-enylamino)-methyl]-benzofuran-5carbonitrile or a pharmaceutically acceptable salt thereof; 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] (1 ,2,2-trimethyl-propylamino)-cyclobut-3-ene- 1,2dione or a pharmaceutically acceptable salt thereof; 2- [2-0 1 -dimethyl-propylamino)-3,4-dioxo-cyclobut- 1 -enylamino] -methyl) -3or a pharmaceutically acceptable salt thereof.

It is understood that the definition of the compounds of formula when R 1 R2, R3, R4, R5 or R6 contain asymmetric chiral centers, encompasses all possible stereoisomers and mixtures thereof which possess the activity discussed below. In particular, it encompasses racemic modifications and any optical isomers which possess the indicated activity. *Optical isomers may be obtained in pure form by WO 97/48682 PCT/US97/09744 -6standard separation techniques or enantiomer specific synthesis. It is understood that this invention encompasses all crystalline forms of compounds of formula The compounds of this invention, throughout this specification, are equivalently named as 3,4-diones or 1,2-diones. The pharmaceutically acceptable salts of the basic compounds of this invention are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.

Where R4, R5 or R6 contains a carboxyl group, salts of the compounds of this invention may 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 formula More particularly, the compounds of formula may be prepared by reacting a compound of formula (II):

(II)

wherein X is a suitable leaving group, for example, methoxy, ethoxy, isopropoxy, butoxy, halogen or a similar leaving group with a compound of formula (III): /Rai

HN\

Ra2 Ra 2

(III)

wherein Ral and Ra2 are R1 and R2, respectively, as defined hereinbefore or a group of atoms convertible thereto. The subsequent intermediate may then be allowed to react with a compound of formula (IV):

A

1

-CH

2

NH

2

(IV)

wherein Al is A as defined hereinbefore or a group of atoms convertible thereto. The reactions mentioned above may be carried out in a solvent such as acetonitrile, WO 97/48682 PCT/US97/09744 -7methanol, ethanol, tetrahydrofuran or dioxane at elevated or ambient temperatures.

Furthermore, the order of reaction may be reversed, that is, a compound of formula (II) may be allowed to react initially with a compound of formula The subsequent intermediate may then be allowed to react with a compound of formula (III) as described hereinbefore, to give the compounds of formula The compounds of formula and their pharmaceutically acceptable salts are smooth muscle relaxants functioning via potassium channel activation. They are therefore useful in the treatment of disorders associated with smooth muscle contraction, disorders involving excessive smooth muscle contraction of the urinary tract (such as incontinence), or of the gastro-intestinal tract (such as irritable bowel syndrome), asthma and hair loss. Furthermore, the compounds of formula are, as potassium channel activators, useful for treatment of peripheral vascular disease, hypertension, congestive heart failure, stroke, anxiety, cerebral anoxia and other neurodegenerative disorders.

The present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention in combination or association with 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 may be adapted for other modes of administration, for example, parenteral administration for patients suffering from heart failure.

In order to obtain consistency of administration, it is preferred that a composition of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules and powders in sachets or vials. Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to mg. Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 WO 97/48682 PCT/US97/09744 -8to 10 mg/kg. Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.

The compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent and the like. They are formulated in conventional manner, for example, in a manner similar to that used for known antihypertensive agents, diuretics and (3blocking agents.

The present invention further provides a compound of the invention for use as an active pharmaceutical or therapeutic substance. Compounds of formula are of particular use in the induction of smooth muscle relaxation.

The present invention further provides a method of treating smooth muscle disorders in mammals including man, which comprises administering to the afflicted 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 methods for production of representative compounds of the invention.

Example 1 3-(1.l-Dimethvlironvlamino)-4-[(Dvridin-4-vlmethvl-amino]cvclobut-3-ene-1.2-dione A solution of 3,4-dibutoxycyclobut-3-ene-1,2-dione (4.526 g, 20 mmol) and 1,1-dimethylpropylamine (1.743 g, 20 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature for 19.5 hours. The solvent was removed and the residue was chromatographed (gravity, chloroform-hexane) on neutral, activity III silica (150 g).

The white solid isolated from the appropriate eluates was recrystallized from hexane to give 4.105 g of a white product: mp 56.5-57.5 0 C (softens 55.5 0 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 -dione as a white solid: mp 56-57°C WO 97/48682 WO 978682PCTIUS97/09744 -9- (softens 55 'H NMR (DMSO-d 6 8 8.63 and 8.48 (two br s 1H, rotomers), 4.67 (in, br, 2H), 1.67 (in, br, 4H), 1.39 (in, 2H), 1.26 (in, br, 6H), 0.91 3H), 0.78 3H1).

IR (KBr): 3170, 1790, 1700 cm-1; MS 239 A solution of the above 3-butoxy-4-( 1, 1-dimethylpropylamino)-cyclobut-3ene-1,2-dione (1.197 g, 5.0 mmol) and 4-aminomethylpyridine (0.541 g) in tetrahydrofuran (10 mL) was stirred at room temperature for 23 hours. The mixture was freed of solvent and the residue was triturated with diethyl ether and dried to provide 1.154 g of a buff solid. Recrystallization (twice) of the crude product from methanol gave 0.832 g of 3-(1,1-dimethylpropylamino)-4-[(pyridin-4ylmethyl)-aminolcyclobut-3-ene- 1,2-dione as a white compound: mp 258 .0-259.5'C dec (softens 257.5'C); I'H NM R (DMSO0-d4): 8 8.56 (in, 2H), 7.86 (mn, br, 1 7.46 (s, br, 1H), 7.32 (in, 2H), 4.77 2H), 1.67 2H), 1.32 6H), 0.83 3H). IR (KBr): 3270, 1790, 1650 cm'1; MS 273 Elemental Analysis for C1 5 H,qN 3 0 2 Calcd: C, 65.91; H, 7.01; N, 15.37 Found: C, 65.55; H, 6.88; N, 15.12 20Exml2 3-(1 .1 -Dimethvln~rol~vlamino)-4-[rvridin-3-vlmethvl)aminolcyclobut-3-ene-1 .2-dione Tetrahydrofuran (10 mL), 3-butoxy-4-( 1,1-dimethylpropylamino)cyclobut-3ene-1,2-dione (1.197 g, 5.0 mmol, as prepared in Example and 3-aminoinethylpyridine (0.54 1 g) were stirred together at room temperature for 24 hours. The reaction mass was freed of solvent and the residue was triturated with diethyl ether and dried to afford 1.228 g of a cream-colored solid. Two recrystallizations of this material from methanol provided 0.887 g of 3-(1,1-dimethylpropylamino)-4- [pyridi n- 3 ymeth yl) amino] cyclobu t- 3-ene- 1, 2-dione as a white solid: mp 263.5- 264.5' C (softens 260.0'C); I'H NMR (DMSO-d 6 5 8.57 (mn, 1H), 8.52 (mn, 1H), 7.80 (mn, br, 1H), 7.76 (in, 1H), 7.41 (in, 1H), 7.39 br, 1H), 4.72 2H), 1.66 2H), 1.30 6h), 0.82 3H). IR (KBr): 3230, 1790, 1650 cm'1; MS 274 WO 97/48682 WO 9748682PCTIUS97/09744 10 Elemental Analysis for C 1 5

H

14

N

3 0 2 Calcd: C, 65.91; H, 7.01; N, 15.37 Found: C, 66.23; H, 7.08; N, 15.38 341.1 -Dinlethylnlrollvlamino)-4-[(Uvridin-2-ylmethvl)pminpl.

cyclobut-3-ene- I .2-dione A solution of 3-butoxy-4-( 1,1-dimethylpropylamino)-cyclobut-3-ene- 1,2-dione (0.622 g, 2.6 mmol, as prepared in Example 1) and 2-aminomethylpyridine (0.281 g, 2.6 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature for 22 hours.

Removal of solvent, trituration of the residue with diethyl ether and drying gave 0.656 g white solid. Recrystallization (twice) of the crude product from acetonitrile afforded 0.447 g of 3- (1,1-dimethylpropylamino)-4- [(pyridin-2-ylmethyl)amino] cyclobut-3-ene-1,2-dione as a white solid: mp 192.0-192.5" C (softens 188.50); 1H NMR (DMS0-l 6 8 8.58 (in, 1H), 8.00 (in, br, 7.82 (in, 1H), 7.58 br, 1H), 7.37 (in, 1H1), 7.33 (mn, 11H), 4.85 2H), 1.67 2H), 1.31 6H), 0.83 3H). IR (KBr): 3210, 1790, 1660 cin'; MS 273 Elemental Analysis for C1 5 H 19

N

3 0 2 Calcd: C, 65.91; H, 7.01; N, 15.37 Found: C, 65.78; H, 6.94; N, 15.48 Exaple4 3-tert-Butvlamino-4-I(nvrid in-4-lmeth vI)aminolcyclobut-3-ene- I .2-dione In a procedure similar to that described in Example 1 utilizing the appropriate starting materials, 3-tert-butylamino-4- [(pyridin-4-ylmethyl)amino] -cyclobut-3-ene- 1,2-dione was prepared as a white solid: mp 271.0-271.5'C (softens at 269.5*C).

WO 97/48682 WO 7/4682PCTIJS97/09744 11 3-tert-Butylamino-4- r(ovridin-3-vlmethvflaminolcyclobut-3-ene- 1.2-dione In a procedure similar to that described in Example 1 utilizing the appropriate starting materials, 3-tert-butylamino-4- [(pyridin-3-ylmethyl)amino] -cyclobut-3 -ene- 1,2-dione was prepared as a white solid: mp 296.0'C dec. (softens at 290.5*C).

10Exml6 3-tert-Butvlaniino-4-f (pvridin-2-ylmethyfiaminolcyclobut-3-ene-1I.2-dione In a procedure similar to that described in Example 1 utilizing the appropriate starting materials, 3 -tert- butylamino-4- (pyridin-2-ylmethyl) amino] -cyc lobut- 3-ene- 1,2-dione was prepared as a white solid: mp 236.0-236.5'C dec. (softens at 233.5*C).

3-(Isopronly-methvl-amino)-4-[(Dvridin-4-vlmethvl)-anhinolcyclobut-3-ene-1I.2-dione In a procedure similar to that described in Example 1 utilizing the appropriate starting materials, 3-(isopropyl-methyl-amino)-4- [(pyridin-4-ylmethyl)-amino] cyclobut-3-ene-1,2-dione was prepared as a white solid: mp 214.5-215.0'C dec.

(softens at 211.5*C).

WO 97/48682 PCT/US97/09744 12- Example 8 3-f(5-Nitro-benzofuran-2-vlmethvl)-amino-4-(1.2.2-trimethvlDroyvlamino)cvclobut-3-ene-1.2-dione To a suspension of NaH (3.41 g, 80%, 113.6 mmol) in dimethylformamide (400 mL) at 0°C was added acetone oxime (7.61 g, 104.1 mmol). After stirring for 1 hour at 0°C, 4-nitrofluorobenzene (10.00 mL, 94.6 mmol) was introduced via syringe and the resulting mixture was stirred for 1 hour. Brine (400 mL) was added and the resulting precipitate was collected by filtration. The product was washed with water and dried in vacuo to afford 18 g (100%) of white solid: 'H NMR (DMSO-d 6 8 8.20 2H), 7.25 2H), 2.06 (s 3H), 2.11 3H).

The above oxime adduct (10.39 g, 53.56 mmol) was heated in saturated ethanolic HCI (200 mL) at reflux. After 3 hours, the reaction mixture was cooled and concentrated to 1/4 volume. Water was added and the precipitated cyclization product was collected by filtration to afford 9.0 g of 2-methyl-5-nitrobenzofuran: 'H NMR (DMSO-d 6 S8.39 1H), 8.15 (dd, 1H), 7.45 1H), 6.49 1H), 2.48 3H).

To a stirring solution of the above benzofuran (5.00 g, 28.25 mmol) and benzoyl peroxide (0.68 g, 2.83 mmol) in carbon tetrachloride (200 mL) was added 1,3-dibromo- (4.04 g, 14.12 mmol). The mixture was irradiated with a 200 watt lamp while stirring for 1 hour, cooled and partitioned between dichloromethane/water.

The organic phase was washed with water (2 x 100 mL) and brine (2 x 100 mL), dried (MgSO 4 decolorized (charcoal), and concentrated in vacuo to afford 7.12 g of crude product. Recrystallization from ethyl acetate/hexane afforded 4.38 g of 2as an off-white solid: 'H NMR (CDC13): 8 8.49 (d, 1H), 8.25 (dd, 1H), 7.58 1H), 6.91 1H), 4.59 2H).

A mixture of the above 2-bromomethyl-5-nitrobenzofuran (1.57 g, 6.13 mmol), potassium phthalimide (1.70 g, 9.19 mmol), and 18-crown-6 (0.161 g, 0.61 mmol) was stirred in acetonitrile (15 mL) overnight at room temperature. The solvent was removed by vacuum, and the residue was partitioned between ethyl acetate and brine. The organic phase was washed with 0.1N sodium hydroxide (2 x 50 mL) then brine (2 x 50 mL), WO 97/48682 PCT/US97/09744 13dried (MgSO 4 and concentrated to afford an off-white solid. The crude product was triturated with cold ethyl acetate/diethyl ether/hexane to afford 1.47 g of phthalimide adduct as a white solid: 'H NMR (DMSO-d6): 8 8.55 1H), 8.17 (dd, 1H), 7.88 4H), 7.75 1H), 5.00 2H).

The above phthalimide adduct (1.45 g, 4.49 mmol) was treated with hydrazine hydrate (0.38 mL) in refluxing ethanol (15 mL) for 1.5 hours. The reaction was cooled to 0°C and acidified (conc. HC1) to pH=l. The mixture was filtered and the solid was washed with 6N HCI and water. The filtrate was basified with potassium carbonate and then extracted with ethylacetate. The organic phase was dried (MgS04) and concentrated to afford 0.74 g of 2-methylamino-5-nitrobenzofuran as a light yellow solid: 'H NMR (DMSO-d 6 8 8.55 1H), 8.11 (dd, 1H), 7.72 1H), 6.85 1H), 3.84 2H), 2.00 (brs, 2H).

To the 2-methylamino-5-nitrobenzofuran (0.74 g, 3.85 mmol) stirring in tetrahydrofuran (15 mL) at 0°C was added 3,4-dibutoxy-3-cyclobutene-1,2-dione (1.25 mL, 5.78 mmol) via syringe. The mixture was stirred for 5 hours at room temperature and was then concentrated in vacuo. The residue was crystallized from ethyl acetate/diethyl ether/hexanes to afford 0.83 g of adduct as an off-white solid. A second crop (0.17 g) was isolated from the mother liquor. Total yield: 75%. 'H NMR (DMSOd6): 6 9.40 and 9.20 (2 br m, 1H rotameric), 8.60 1H), 8.20 (dd, 1H), 7.80 1H), 7.04 1H), 4.88 and 4.67 (2 br m, 2H, rotameric), 4.60 2H), 1.67 2H), 1.30 (m, 2H), 0.85 3H).

3-Butoxy-4-[(5-nitro-benzofuran-2-ylmethyl)-amino]-cyclobut-3-ene-1,2-dione (0.250 g, 0.727 mmol) was dissolved in an ethanolic solution of R(+)-2-amino-3,3dimethylbutane (0.167 N, 6.0 mL, 1.00 mmol). The mixture was diluted with ethanol (1 mL) and tetrahydrofuran (1 mL). After 3 hours, an additional 6.0 mL of ethanolic amine (1.00 mmol) was added and the mixture was allowed to stir for 48 hours at room temperature. The heterogeneous mixture was diluted with 1:1 diethylether/ethyl aceate and filtered to afford 0.20 g of isomer of 3-[(5-nitro-benzofuran-2-ylmethyl)amino]-4-(1,2,2-trimethylpropylamino)-cyclobut-3-ene- 1,2-dione: mp 300 0 C; 'H NMR (DMSO-d 6 8 8.61 1H), 8.21 (dd, 1H), 7.88 (d and m, 2H), 7.35 (br d, 1H), 7.06 (s, WO 97/48682 WO 978682PCTIUS97/09744 14- 1H), 4.98 (in, 211), 3.92 (in, 111), 1.10 311), 0.86 911). IR (KBr): 3180, 2950, 1800, 1650, 1550 cm'1; MIS 371 Elemental Analysis for C 19

H

21

N

3 0 Calcd: C, 61.45; H, 5.70; N, 11.31 Found: C, 60.52; H, 5.50; N, 11.21 Example 9 3-0I -Dimeth A -nronvlamino)-4-1(5-n itro-benzfu rn-2-11meth vi').minolcyclobut-3-ene- 1.2-d ione To 3-butoxy-4-[(5-nitrobenzofuran-2-ylmethyl)-amino] -cyclobut- 3-ene- 1,2-dione (0.25 g, 0.727 mmol), as prepared in Example 8, in ethanol (5 ml-) was added tertamylamine (0.53 mL, 4.54 inmol). 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 afford 0.22 g of 3-(1,1dimethyl-propylamino)-4-[(5-nitro-benzofuran-2-ylmethyl)-anino] -cyclobut-3-ene- 1,2dione as an off-white solid: mp 283.5-287.5 'C (dec); 11- NMR (DMSO-d 6 8 8.61 (d, 111), 8.18 (dd, 1H), 7.96 (br t, 111), 7.81 111), 7.46 (br s, 1H1), 7.07 111), 4.99 (d, 2H), 1.66 211), 1.30 611), 0.82 311). IR (KBr): 3220, 2950, 1800 cm'1; MIS (m/z) 357 Elemental Analysis for C18111 9

N

3 0 Calcd: C, 60.50; H, 5.36; N, 11.76 Found: C, 59.3 1; H1, 5.15; N, 11.53 Example 3-tert-But Ila mi no-4- [(5-ni tro- ben zofuran -2-'vlmeth vi)-ami nocyclobut-3-ene-1 .2-dione To 3-butoxy-4-j[I(5- nitro- benzofuran- 2-ylImeth yl) amino] -cyclobut- 3 -ene- 1 ,2-dione (0.25 g, 0.727 inmol), as prepared in Example 8, in ethanol (5 mL) was added tert- WO 97/48682 PCT/US97/09744 butylamine (0.51 mL, 4.85 mmol). The reaction was stirred at 70 0 C for 18 hours and then at room temperature for 48 hours. Workup in a manner identical to Example 9 afforded 0.20 g of 3-tert-butylamino-4-[(5-nitro-benzofuran-2-ylmethyl)-amino]cyclobut-3-ene-1,2-dione as an off-white solid: mp 300 OC; 'H NMR (DMSO-d6): 8 8.61 1H), 8.20 (dd, 1H), 7.91 (br t, 1H), 7.81 1H), 7.59 (br s, 1H), 7.07 1H), 4.98 2H), 1.36 9H). IR (KBr): 3220, 2930, 1800, 1675 cm MS 344.3 Elemental Analysis for C1 7

HI

7

N

3 0 Calcd: C, 59.47; H, 4.99; N, 12.24 Found: C, 58.86; Hm 4.78; N, 11.88 Example 11 2-f 2-(1.1l-Dimethvl-Dronvlamino)-3.4-dioxo-cvclobut- -envlaminol-methvll- Acetone oxime (6.34 g, 86.64 mmol) was added to a suspension of sodium hydride (as a 80% dispersion in mineral oil; 2.72 g, 90.82 mmol) in N, Ndimethylformamide (400 mL) at 0OC. The frothy suspension was stirred for 1 hour as the mixture was warmed to 25"C. p-Fluorobenzonitrile (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 room temperature. After stirring overnight, the reaction mixture was poured into brine (300 mL). The resulting white precipitate was collected by filtration, washed with water, and dried in vacuo. Yield: 13.97 g (98 1 H NMR (DMSOd6): 8 7.78 2H), 7.76 2H), 2.04 3H), 2.00 3H).

To the product of the proceeding paragraph (13.97 g, 80.28 mmol) was added ethanolic hydrochloric acid (400 mL). The mixture was heated at reflux for 4 hours.

The reaction mixture was cooled and concentrated to 1/3 the volume. The reaction mixture was diluted with water, resulting in the instantaneous formation of a precipitate. The precipitate was collected by filtration, washed with water, and dried in vacuo. The crude product was purified by HPLC (10:1, hexane/ ethyl acetate).

Yield: 7.26 g (58 1 H NMR (CDC13): 5 7.79 1H), 7.47 (dd, 1H), 7.43 1H), 6.44 1H), 2.47 3H).

WO 97/48682 PCT/US97/09744 -16- To a solution of the product of the proceeding 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 to a solid. The crude product was recrystallized from ethyl acetate/ hexane. Yield: 2.40 g (59 1H NMR (DMSO-d6): 8 8.49 1H), 8.25 (dd, 1H), 7.58 1H), 6.91 1H), 4.59 2H).

To a solution of the product of the proceeding paragraph (2.63 g, 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 brine and immediately a precipitate formed. The precipitate was collected by filtration, washed with diethyl ether and dried. The organic phase was washed with 0.1 N sodium hydroxide (2x50 mL) and then brine (2x50 mL). The solution was concentrated in vacuo to afford another batch of solid. Yield: 2.50 g (76 1

H

NMR (DMSO-d6): 8 8.18 1H), 7.91 4H), 7.77 (dd, 1H), 7.74 1H), 7.07 (d, 1H), 5.00 2H).

To a solution of the product of the proceeding paragraph (2.50 g, 7.74 mmol) in ethanol (20 mL) was added hydrazine-hydrate (0.66 mL). The mixture was heated to reflux for 1.5 hours. The reaction mixture was cooled to 0°C and acidified with concentrated hydrochloric acid to pH of 1. The mixture was filtered and the filter cake was washed with 6N hydrochloric acid and then water. The filtrate was basified with potassium carbonate and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, treated with Norite®, and concentrated to afford an off white solid. Yield: 0.85 g (62 1H NMR (DMSO-d6): 8 8.17 1H), 7.78 (dd, 1H), 7.74 1H), 6.82 1H), 3.85 2H), 2.10 (br s, 2H).

To a solution of the product of the proceeding paragraph (0.84 g, 4.40 mmol) in tetrahydrofuran (15 mL) was added 3,4-diethoxy-3-cyclobutene-1,2-dione (1.13 g, WO 97/48682 PCT/US97/09744 -17- 6.60 mmol) at 0OC. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was concentrated in vacuo and the crude product was triturated with ethyl acetate/ diethyl ether/ hexane to yield an off white solid. The solid was filtered and dried to yield the desired product. Yield: 1.05 g (76 1H NMR (DMSO-d6): 8 9.41 and 9.21 (br m, 1H, rotamers), 8.22 1H), 7.81 (dd, 1H), 7.00 1H), 4.88 and 4.68 (2 br m, 2H, rotamers), 4.65 2H), 1.39 (m, 3H).

To a solution of the product of the proceeding paragraph (0.25 g, 0.79 mmol) in ethanol (17 mL) was added tert-amyl amine (0.21 g, 2.37 mmol). The reaction mixture was heated at 70'C and allowed to stir overnight. The solid which had formed was filtered and washed with ethyl acetate, diethyl ether, and hexane to afford 0.18 g of 2-([2-(1,1-dimethyl-propylamino)-3,4-dioxo-cyclobut- -enylamino]as an off white solid: mp 171.1-173.2 1

H

NMR (DMSO-d6): 8 8.19 1H), 7.96 1H), 7.81 1H), 7.74 (dd, 1H), 7.45 (s, 1H), 6.96 1H), 4.97 2H), 1.67 2H), 1.29 6H), 0.83 3H). IR (KBr): 3230, 2950, 2220, 1800 cm- 1 MS 337 Elemental analysis for C19H19N303 Calc'd: C, 67.64; H, 5.68; N, 12.46.

Found: C, 66.87; H, 5.32; N, 12.37.

Example 12 2-ff3.4-Dioxo-2-(1.2.2-trimethvl-Drovlamino)-cvclobut- -envlaninol-methyll- To a solution of the product of paragraph 6 in Example 11 0.250g, 0.79 mmol) in ethanol (2mL) was added ethanolic (R)-2-amino-3,3-dimethylbutane (0.166 N in EtOH, 9.50 mL, 1.58 mmol). The reaction mixture was heated at 70C and allowed to stir overnight. The solid which had formed was filtered and washed with ethyl acetate, diethyl ether, and hexane. The solid was dried in vacuo to 0.22 g of the (1R) isomer of 2- [3,4-dioxo-2-(12,2-trimethyl-propylamino)-cyclobutas an off white solid: mp >300; 1

H

WO 97/48682 WO 9748682PCT[US97/09744 18 NMR (DMSO-d6): 8 8.18 111), 7.80 (dd, 1H), 7.74 (dd, 1H), 7.31 (br d, 111), 6.95 111), 4.96 (in, 2H), 3.91 (br mn, 111), 1.11 3H), 0.81 9H). IR (KBr): 3170, 2950, 2250, 1850, 1650, 1560 cm- 1 MS 351 Elemental analysis for C20H21N303 Calc'd: C, 68.36; H, 6.02; N, 11.96.

Found: C, 68.00; H, 5.83; N, 12.00.

Example 13 2-r(2-tert-Butylamino-3.4-dioxo-cvclobut- I -en y~amino')-meth 111benzofu ran -5-ca rbonitrile To a solution of the product of paragraph 6 in Example 11 (0.250 g, 0.79 minol in ethanol (17 inL) was added tert-butyl amine (0.17g, 2.37 iniol). The reaction mixture was heated at 70*C and allowed to stir overnight. The solid which had formed was filtered and washed with ethyl acetate, diethyl ether, and hexane.

The solid was dried in vacuo to yield afford 0. 12 g (51 of 2-[(2-tert-butylainino- 3 ,4-dioxo-cyclobut-l1-enylainino)-inethyl] -benzofuran-5-carbonitrile as a light pink solid: mp 298.8-300.3 1 H NMR (DMSO-d6): 8 8.18 1H), 7.96 111), 7.81 (dd, 1H), 7.74 (dd, 1H), 7.57 1H), 6.95 1H), 4.96 211), 1.35 9H). IR (KBr): 3300, 2950, 2210, 1800, 1660, 1525 cm- 1 MS 323 Elemental analysis for C18H17N303 Calc'd: C, 66.86; H, 5.30; N, 13.00 Found: C, 65.64; H, 4.93; N, 12.57 Example 14 2-f 2-(1 .1-Dimetl-2-plhenvl-ethvlamino)-3.4-dioxo-cvclobut-1 -enlaminolmeth III-benzofu ran-5-ca rbonitrfle To a solution of the product of paragraph 6 in Example 11 (0.23g, 0.73 minol) in ethanol (20 inL) was added alpha, alpha-dimethylphenethylamine (0.33g, 2.19 WO 97/48682 WO 9748682PCTfUS97/09744 19 mL). The reaction mixture was heated at 7O*C and allowed to stir overnight. The solid which had formed was filtered and washed with ethyl acetate, diethyl ether, and hexane. The solid was dried in vacuo to afford 0.11 g of 2-{[2-(1,1-Dimethyl- 2-phenyl-ethylamino)-3,4-dioxo-cyclobut-l1-enylamino] -methyl) carbonitrile as an off white solid: mp 233.4-235.2*C; 1 H NMR (DMSO-d6): 8 8.20 7.89 7.81 (dd, 7.74 (dd, 111), 7.36 11H), 7.23 (in, 3H), 7.06 (d, 2H), 6.94 11H), 4.97 2H), 2.98 2H), 1.31 IR (KBr): 3300, 3000, 2200, 1800, 1660, 1590 cm- 1 MS 399 Elemental analysis for C24H21N303 Calc'd: C, 72.17; H, 5.30; N, 10.52 Found: C, 71.28; H, 5.20, N, 10.33 3-U(Pvridin-4-vlmethvl-aminol-4-(1 .2.2-trimetvli-Dlronylamino)cyclobut-3-ene-1 .2-dione In a procedure similar to that described in Example 1 utilizi ng the appropriate starting materials, 3- [(pyridin-4-ylmethyl)-amino]-4- (1 ,2,2-trimethyl-propylamino)cyclobut-3-ene-1,2-dione was prepared as a white solid: mp 282.5-283.0'C dec.

(softens at 271.5*C).

2-if2-(1.1-Dimethvl-nronvlamino)-3.4-dioxo-cyclobut-I-enlaminol-niethvll-3chloro-benzofu ran-5-ca rhonitrile The benzofuran adduct prepared in Example 11, paragraph 2 was used to synthesize 3-chloro-2-methylbenzofuran- 5-carbonitrile (Cross, P. Dickinson, R.

Parry, M. Randall, M. J. J. Med. Chem., 1986, 29, 1643-1650). Yield: 23 lH NMR (CDCl3): 8 7.81 7.55 (dd, 11H), 7.47 2.49 3H).

3-Chloro-2-bromomhethyl-benzofuran-5-carbonitrile was prepared in a manner similar to 2-bromomethyl-benzofuran-5-carbonitrile synthesized in Example 11,.

WO 97/48682 PCT/US97/09744 paragraph 3. Yield: 53%: 1 H NMR (DMSO-d6): 8 8.24 1H), 7.93 2H), 4.94 2H).

The product from the proceeding paragraph was reacted with potassium pthalamide in a manner similar to Example 11, paragraph 4 to yield the pthalimide adduct. Yield: 72%: 1 H NMR (DMSO-d6): 8 8.18 1H), 7.89 6H), 5.03 (s, 2H).

3-Chloro-2-methylamino-benzofuran-5-carbonitrile was prepared in a manner similar to Example 11, paragraph 5. Yield:63% 1 H NMR (DMSO-d6): 8 8.18 (d 1H), 7.81 (dd, 2H), 3.85 2H), 3.21 (br s, 2H).

The above amino compound was reacted with 3,4-dibutoxy-3-cyclobutene- 1,2-dione in a manner similar to Example 11, paragraph 6. Yield: 75%: 1 H NMR (DMSO-d6): 8 9.40 and 9.18 (br m, 1H, rotamers), 8.21 1H), 7.91 (dd, 2H), 4.98 and 4.75 (2 br m, 2H, rotamers), 4.61 2H), 1.63 2H), 1.35 2H), 0.87 (m, 3H).

To a solution of the product of the proceeding paragraph (0.14 g, 0.37 mmol) in ethanol (12 mL) was addedtert-amyl amine (0.065 g, 0.74 mmol). The reaction mixture was heated at 70'C and allowed to stir for 13 h. The solid which had formed was filtered and washed with ethyl acetate, diethyl ether, and hexane. the solid was dried in vacuo to yield a light orange solid. Yield: 0.11 g (74 mp 257.3-258.1 1H NMR (DMSO-d6): 8 8.22 1H), 7.93 1H), 7.90 1H), 7.87 (dd, 1H), 7.40 1H), 5.05 2H), 1.66 2H), 1.29 6H), 0.80 3H). IR (KBr): 3230, 2950, 2220, 1800 cm- 1 MS 371 Elemental analysis for C19H18C11N303 Calc'd: C, 61.38; H, 4.88; N, 11.30 Found: C, 60.75 H, 4.81; N, 11.11 WO 97/48682 PCT/US97/09744 -21- The smooth muscle relaxing activity of the compounds of this invention was established in accordance with standard pharmaceutically accepted test procedures with representative compounds as follows: Sprague-Dawley rats (150-200 g) are rendered unconscious by CO 2 asphyxiation and then euthanized by cervical dislocation. The bladder is removed into warm (37 deg.C) physiological salt solution (PSS) of the following composition NaCl, 118.4; KCI, 4.7; CaC1 2 2.5; MgSO4, 4.7; H 2 0, 1.2; NaHCO 3 24.9;

KH

2 P0 4 1.2; glucose, 11.1; EDTA, 0.023; gassed with 95% 02; 2/5% C02; pH 7.4.

The bladder is opened and then cut into strips 1-2 mm in width and 7-10 mm in length. The strips are subsequently suspended in a 10 mL tissue bath under an initial resting tension of 1.5 g. The strips are 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 prior to a challenge with 0.1 uM carbachol. The carbachol is then washed out and the tissue allowed to relax to its resting level of activity. Following a further 30 min period of recovery an additional mM KC1 are introduced into the tissue bath. This increase in KC1 concentration results in a large increase in the amplitude of spontaneous contractions (and initiation of contractions in previously quiescent strips) superimposed upon a small increase in basal tone. Following stabilization of this enhanced level of contractile activity, incremental increases in the concentration of test compound or vehicle are introduced into the tissue bath. Contractile activity is measured for each compound or vehicle concentration during the last minute of a 30 minute challenge.

The isometric force developed by the bladder strips is measured using a concentration required to elicit 50% inhibition of pre-drug contractile activity (IC 50 concentration) and is calculated from this concentration-response curve. The maximum percentage inhibition of contractile activity evoked by a test compound is also recorded for concentrations of test compound less than or equal to 30 p.M.

The results of this study are shown in Table I.

WO 97/48682 PCT/US97/09744 -22- Table I Inhibition of Contractions in Isolated Rat Bladder Strips Compound Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Example 16

IC

50

M

0.42 0.06 1.25 0.39 1.25 0.34 3.0 0.2 2.63 0.22 11.45 4.3 *1=27.3 7% 1.4% *I=22.2 7.4% *I=11.5 3.2% 1.56 0.16 3.75 1.44 4% *I=19.94 *1=31.9 6.4% 2.45 0.99 1.3 0.63 Percent inhibition at 30 p.M Percent contraction at 30 lM WO 97/48682 PCT/US97/09744 -23- In addition, we tested the ability of the compound of Example 1, as representative of the other compounds of this invention, to inhibit the hyperactivity of hypertrophied bladder (detrussor) smooth muscle in conscious female rats with hypertrophied bladders and thereby alleviate urinary incontinence according to the protocol described by Malmgrem et al., J. Urol. 142:1134, 1989.

Female Sprague-Dawley rats, ranging in weight from 190-210g are used. Up to animals are prepared each time. After development of bladder hypertrophy 4-8 animals are used per test.

Compounds are dissolved in PEG-200 and administered by gastric gavage or intraveneously in a volume of 5 ml/kg. For primary screening all drugs are administered at the arbitrary dose of 10 mg/kg p.o. to groups of 4 rats.

The animals are anesthetized with halothane. Through a midline incision the bladder and urethra are exposed and a ligature of 4-0 silk is tied around the proximal urethra in the presence of a stainless steel rod (1 mm diameter) to produce a partial occlusion. The rod is then removed. The abdominal region is closed using surgical staples and each rat receives 150,000 units of bicillin C-R. The animals are allowed six weeks to develop sufficient bladder hypertrophy. After six weeks, the ligature is removed under halothane anesthesia and a catheter (PE 60) with a cuff is placed in the dome of the bladder and secured with a purse string suture. The catheter is tunneled under the skin and exteriorized through an opening in the back of the neck.

The abdominal incision is sutured and the free end of the catheter sealed. In order to prevent infections, the rats receive an injection of bicillin C-R (150000 units/rat).

Two days later the animals are used in cystometrical evaluations. The animals are placed in the metabolic cages and the catheter is attached (using a 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 to collect and record urine volume. Animals are allowed 15-30 minutes to rest before the saline infusion (20 ml/hr for 20 minutes) is started for the first cystometry period. Two hours after the first cystometry period, the rats are dosed with the vehicle or the test compound and one hour later a second cystometry is performed.

WO 97/48682 PCT/US97/09744 -24- The following urodynamic variables are recorded: Basal bladder pressure Threshold pressure the lowest bladder pressure during cystometry bladder pressure immediately prior to micturition volume expelled peak pressure during voiding mean amplitude of bladder pressure fluctuations during filling Micturition volume Micturition pressure Spontaneous activity Presentation of results: The mean value of each variable is calculated before and after compound administration. For each compound the changes in the variables measured are compared to the values obtained before treatment and expressed as percent inhibition. The data are also subjected to 2-way analysis of variance to determine significant (p<0.05) changes in the variable measured.

The results of this study are shown in Table II Table II Inhibition of Spontaneous Contractions In Vivo Compound Example 1 of animals dose mg/kg Red -8 4 percent reduction in the total number of spontaneous contractions in the hypertrophied rat bladder model 25 Hence, the compounds of this invention have a pronounced effect on smooth muscle contractility and are useful in the treatment of urinary incontinence, irritable bladder and bowel disease, asthma, hypertension, stroke, and similar diseases as mentioned above, which are amenable to treatment with potassium channel activating compounds by administration, orally, parenterally, or by aspiration to a patient in need thereof.

Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps.

e

Claims (1)

1. 9. A is selected from the group consisting of: 9 9 9 WO 97/48682 PCT/US97/09744 -27- N N N R4- I4- R4- I N R '(O)n Rs Rs R 5 (O)n R6 Rs wherein: n is 0 or 1 R 4 R5 and R6 are, independently, cyano, nitro, 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, 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 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, perfluoroalkylsulfonyl of 1 to 6 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, chloro, bromo, fluoro, iodo, 1-imidazolyl, carboxyl or hydrogen; or a pharmaceutically acceptable salt thereof. WO 97/48682 PCT/US97/09744 -28- A compound of Claim 1 in which R 3 is hydrogen and A is selected from the following: N r 4 R 4 4 R 'N R Rs Rs Rs R6 or a pharmaceutically acceptable salt thereof. A compound of Claim 1 or 2 in which R1 and R2 are, independently, hydrogen, methyl, ethyl, n- or iso-propyl, iso, sec- or tert-butyl, straight or branched chain pentyl, or phenylalkyl in which the alkyl is methylene or ethylene and in which the phenyl moiety is optionally substituted with one to three substituents selected from methyl, ethyl, fluorine, chlorine, bromine, nitro, cyano, methoxy, ethoxy, methoxyoxycarbonyl, ethoxyoxycarbonyl, trifluoromethyl and trifluoromethoxy. A compound of Claim 1, 2 or 3 in which R 4 R5 and R6 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 which is selected from: 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-dione or a pharmaceutically acceptable salt thereof; 3-(1,1-dimethylpropylamino)-4-[(pyridin-2-ylmethyl)amino]-cyclobut-3-ene-1,2- dione or a pharmaceutically acceptable salt thereof; WO 97/48682 WO 9748682PCTIUS97/09744 29 3-tert-butylamino-4-[(pyridin-4-ylmethyl)amino]-cyclobut-3-ene- 1,2-dione or a pharmaceutically acceptable salt thereof; 3-tert-butylamino-4-[(pyridin-3-ylmethyl)amino]-cyclobut-3-ene- 1 ,2-dione or a pharmaceutically acceptable salt thereof; 3-tert-butylamino-4- [(pyridin-2-ylmethyl)amino]-cyclobut-3-ene- 1,2-dione or a pharmaceutically acceptable salt thereof; 3-(isopropyl- methyl-amino)-4- [(pyridin-4-ylmethyl) -amino] -cyclobu t-3-ene- 1,2- dione or a pharmaceutically acceptable salt thereof; 3- [(5-nitro-benzofuran-2-ylmethyl)-amino-4-( 1,2,2-trimethylpropylamino)-cyclobut- 3-ene-1,2-dione or a pharmaceutically acceptable salt thereof; 3- 1 -dimethyl-propylamino)-4- [(5-nitro-benzofuran- 2-ylmethyl)- amino)]-cyclobut- 3-ene-1,2-dione or a pharmaceutically acceptable salt thereof;, 3-tert-butylamino-4- [(5-nitro-benzofuran-2-ylmethyl)-amino] -cyclobut-3-ene- 1,2- dione or a pharmaceutically acceptable salt thereof; 2- (1,1 -dimethyl-propylamino)- 3,4-dioxo-cyclobut-l1-enylamino] -methyl)- or a pharmaceut ically acceptable salt thereof; 2- ,4-dioxo-2-( 1,2,2-trimethyl-propylamino)-cyclobut-l1-enylaminoj-methyl) or a pharmaceutically acceptable salt thereof; 2-[(2-tert-butylamino-3,4-dioxo-cyclobut- 1 carbonitrile or a pharmaceutically acceptable salt thereof; 2- 1, 1 -dimethyl-2-phenyl-ethylamino)-3,4-dioxo-cyclobut- 1 -enylamino]- methyl) -benzofuran-5-carbonitrileor a pharmaceutically acceptable salt thereof; 3- [(pyridin-4-ylmethyl)- amino] (1 ,2,2-trimethyl-propylamino)-cyclobut- 3-ene- 1,2- dione or a pharmaceutically acceptable salt thereof; 1, 1 -dimethyl-propylamino)- 3,4-dioxo-cyclobut- 1 -enylamino] -methyl) -3- or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound of formula as defined in any of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor. A method for reducing the adverse effects of smooth muscle contractions which comprises administering, orally or parenterally, to a patient in need thereof, a WO 97/48682 PCT/US97/09744 compound of formula or a pharmaceutically acceptable salt thereof, as defined in any of claims i to The method of Claim 7 in which the smooth muscle adversely contracting causes urinary incontinence. The method of Claim 7 in which the smooth muscle adversely contracting causes irritable bowel syndrome. (10) A compound of formula or a pharmaceutically acceptable salt thereof, as defined in any of claims 1 to 5 for use as an active pharmaceutical or therapeutic substance. (11) A compound of formula or a pharmaceutically acceptable salt thereof, as defined in any of claims 1 to 5 for use in reducing the adverse effects of smooth muscle contractions. (12) A compound of formula according to claim 11 in which the smooth muscle adversely contracting causes urinary incontinence. (13) A compound of formula according to claim 11 in which the smooth muscle adversely contracting causes urinary incontinence. (14) Process for the preparation of a compound of formula or a pharmaceutically acceptable salt thereof as defined in any of claims 1 to 5, which comprises reacting a compound of formula (II): (II) 0wherein X is a suitable leaving group, with a compound of formula (I0) wherein X is a suitable leaving group, with a compound of formula (III) 31 HN Ra 2 (III) wherein Ral and Ra2 are R 1 and R2 respectively, as defined above or a group of atoms convertible thereto, and reacting the product thereof with the compound of formula (IV): A 1 -CH 2 NH 2 (IV) wherein A 1 is A as hereinbefore defined or a group of atoms convertible thereto to give the compound of formula and, optionally convening to a pharmaceutically acceptable salt thereof; or alternately, reacting the compound of formula (II) as hereinbefore defined with the compound of formula (IV) as hereinbefore defined and then reacting the product thereof with the compound of formula (III) as hereinbefore defined to give the compound of formula and optionally converting to a pharmaceutically acceptable salt thereof. Use of a compound as defined in any one of Claims 1-5 in the manufacture of a pharmaceutical composition for use in reducing the adverse effects of smooth muscle contractions. (16) A compound according to Claim 1, substantially as hereinbefore described with reference to any one of the Examples. (17) Process according to Claim 14 substantially as hereinbefore described with 25 reference to any one of the Examples. DATED: 27 August 1999 S PHILLIPS ORMONDE FITZPATRICK RA Attorneys for: 30 AMERICAN HOME PRODUCTS CORPORATION