CA2350888A1 - 4-3-substituted-amino-cyclobut-3-ene-1,2-diones and use for influencing smooth muscle contraction - Google Patents

Abstract

4-Substituted-3-substituted-amino-cyclobut-3-ene-1,2-diones having Formula (I): wherein R1, R2, R3, R4, R5, A and W are as defined in the specification which compounds relaxes smooth muscles.

Description

$ TITLE:4-3-SUBSTITUTED-AMINQ-CYCLOBUT-3-~NE-1,2-DIONES AND USE FOR
INFLUENCING

1. Field of the Invention The present invention relates to a novel series of 4-substituted-3-substituted-amino-cyclobut-3-ene-1,2-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, and cerebral vascular disease.

2. Description of the Prior Art Modulation of potassium channels remains at the forefront of current approaches for controlling resting cell membrane potential and affecting cell excitability. A
wide variety of discrete potassium channels exist and these have been thoroughly classified according to structure, function, pharmacological properties, and gating mechanisms in several recent reviews: Rudy, B. ~.P»roscience 1988, 25, 729-749; Atwal, K., Medicinal Research Reviews 1992, 12, 569-591; Gopalakrishnan, M. et al., Drua Development Research 1993, 28, 95-127; Primeau, J. et al., Current pharmaceutical Desian 1995, 1, 391-406;
Edwards, G, et al., ~. O in. Inve Druas 1996, 5(11), 1453-1464. Therapeutic potential for potassium channel modulators in cardiovascular disorders, metabolic disorders, central nervous system disorders, bronchial asthma, and irritable bladder is being vastly explored.
A series of N-aryl and N-heteroaryl-1,2-diamino-cyclobutene-3,4-diones disclosed by Butera et al., in U.S.
Patent Nos. 5,354,763; 5,397,790; 5,401,753; 5,403,853;
5,403,854; 5,466,712; 5,506,252 and 5,532,245 and additionally by Antane et al., in U.S. Patent Nos.
5,464,867 and 5,512,585 have the ability to hyperpolarize smooth muscle tissue via activation of the ATP-dependent potassium channel (KATp). Also disclosed is the potential utility of the N-aryl and N-heteroaryl-1,2-diaminocyclobutene-3,4-diones as useful agents for the treatment of cardiovascular disorders, metabolic disorders, central nervous system disorders, bronchial asthma, and irritable bladder.
A series of 1,2-diamino derivatives of cyclobutene-3,4-diones disclosed by Butera et al., in U.S. Patent No.
5,763,474 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 which are amenable to treatment with potassium channel activating compounds.
Kinney et al., in U.S. Patent No. 5,240;946 discloses 3,4-diamino-3-cyclobutene-1,2-diones as NMDA antagonists.
Algieri et al., in U.S. Patent No. 4,390,701 discloses 1-(substituted-amino)-2-(amino or substituted amino)cyclobutene-3,4-diones which are histamine HZ
antagonists useful in the treatment of peptic ulcers.
Additionally, Nohara, et al., in U.S. Patent No. 4,673,747 S disclose substituted aminoalkylphenoxy derivatives which exert antagonism against histamine HZ receptors.
A series of p-substituted phenyl-cyclobutenediones are reported as substrates and intermediates for monothionation reactions by Muller et al. ~vnthesis 1997,1,50-52. Related compounds are described by Schmidt et al. synthesis 1990,7,579-582 in a paper on Meerwein-arylation of semisquaric acids and semisquaric amides. Unsubstituted phenyl-cyclobutenediones are reported as reaction products between cyclobutenediones and aziridines by Ried et al.
Liebias . Chem. 1975, 1863-1872.
In an effort to generate multiple core structure libraries by combinatorial chemistry, P. A. Tempest et al.
_J. Am. Chem. ~. 1997,119,7607-7608, using Wang resin, disclose a library of p-hydroxylated phenyl-cyclobutenediones which are prepared and cleaved from the Wang resin to afford hydroxylated phenyl-cyclobutenediones.
N-Substituted--3-amino-4-phenylcyclobutenediones are reported by J.E. Thorpe ~. Chem. Soc. (B), 1534-1535(1968) in conjunction with proton nuclear magnetic resonance spectra studies of squaramides.
A series of p-halophenylcyclobutenediones disclosed as intermediates for the preparation of stilbene analogs which are described as having utility as non-linear optical elements with good heat and light resistance are reported in EP-0761643-A2. Additionally, Pu, in U.S. Patent No.
5,106,997, and Nishikata et al., in U.S. Patent Nos.
5,616,802, 5,659,085 and 5,811,552 and in JP-A-7-309819 disclose a series of cyclobutenedione derivatives useful for the preparation of nonlinear optical elements.
A series of biphenylcyclobutenediones containing an additional heterocyclic ring as a substituent on the second phenyl ring of the bicyclic moiety and having utility as angiotensin II antagonists are reported in W09401436-A1.
Additionally, 3-aryl-3-cyclobutene-1,2-diones are reported in several synthetic methodology papers: L. S.

Liebeskind et al. ~7. Qrg Chem. 1993,58(13), 3543-3549; L.
Sun et al., 7. Qrg. Chem. 1995, 60(25), 8194-8203.
The 4-substituted-3-disubstituted-amino-cyclobut-3-ene-1,2-diones described herein are useful in the treatment of disorders associated with smooth muscle contraction, via potassium channel modulation.
SL~ARy OF THE T1~1F:NTTnN
Accordingly, the present invention discloses compounds represented by Formula (I):

N

R~

n wherein:
R1, R2, and R3, are, independently hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms (optionally substituted with halogen), cycloalkyl of 3 to 10 carbon atoms, -ORS , amino, alkylamino of 1 to 10 carbon atoms, -S03H, -SOZNH2, -SONH2, -NHSOZR~, -HN-C-R~
-SOzR~ , carboxyl, aryl of 6 to 12 carbon atoms or aroyl of 7 to 12 carbon atoms;
A is a moiety selected from the group consisting of a bond, -CHZ-, -CH=CH- and -CHCOR6 ;

-s-s W is selected from the group consisting of carbon and nitrogen and wherein the carbon atom may be optionally substituted with -R1 -Rz and -R3.
Rqis a alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, wherein the aryl group is optionally substituted with alkyl of 1 to 10 carbon atoms, nitro, halogen, cyano, -ORS, O
I I
-C-ORS , is trifluoromethyl or trifluoromethoxy;
Rsis hydrogen, alkyl of 1 to 10 carbon atoms, forrnyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon at oms , O
-C-ORS , -SOZR~, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkylsulfonyl 2s of 7 to 12 carbon atoms;
Rbis alkyl of 1 to 10 carbon or aryl of 6 to 12 carbon atoms;
R~ is alkyl of 1 to 10 carbon atoms (optionally substituted with halogen);
aroyl is benzoyl and naphthoyl which is optionally substituted with one to three substituents each 3s independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF3 , and phenyl ;

aryl is naphthyl, phenyl or phenyl optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms;
with the following provisos that A is not a bond and W is not a carbon bearing a hydrogen;
a) when R1 and Rz are H; R3 is selected from the group consisting of H, 4-methyl, 4-chloro, 4-nitro and 4-methoxy; and Rqand Rsare simultaneously methyl or ethyl;
b) when R1 , RZ , R3 and RS are H; and R4 is butyl;
c) when Rl , RZ and RS are H; R3 is 4~-halo (chloro, bromo, fluoro, or iodo) and RQ is alkyl of 1 to 4 carbon atoms;
and d) when Rlis selected from the group consisting of H, 2-methyl, 2-ethyl and 2-methoxy; RZ and RS are H; R3 is 4-dimethylamino and Rqis 2-propyl;
or pharmaceutically acceptable salts thereof.
Preferred groups of compounds of Formula (I) of this invention are those in the subgroups:
a) compounds having the general formula:
R~-wherein R1 , R;Z , R3 , RQ , and R5. ara as hereinbefore defined;
b) compounds having the general formula:

_'j_ R1_ wherein Rl , RZ , R3 , R9 , and R5 are as hereinbefore defined and W is a carbon bearing a hydrogen;
c) compounds having the general formula:
R~-wherein R1 , RZ , R3 , RQ , and RS are as hereinbefore defined;
d) compounds having the general forumla:
/Ra I

R;
i5 _g_ wherein R1 , Rz , R3 , R4 , and RS are as hereinbefore defined and W is a carbon bearing a hydrogen;
e) compounds having the general formula:
R
wherein R1 , RZ , R3 , Rq , and RS are as hereinbefore defined;
f) compounds having the general forumla:
R
wherein R1 , R,, , R3 , Rq , RS and R6 are as hereinbefore and W is a carbon bearing a hydrogen;
g) compounds having the general formula:

_g_ /Ra N
R~w ~'' CORE I

Rs wherein R1 , RZ , R3 , R4 , R5 and R6 are as hereinbefore defined.
More preferred compounds of Formula (I) of this invention are those in the subgroups:
a) compounds having the general formula:
wherein:
R1 , RZ , R3 , R4 , and RS are hereinbefore defined and W is a carbon bearing a hydrogen; and b) compounds having the general formula:

R

wherein:
RI , RZ , R9 and R5 are hereinbefore defined, R3 is alkoxy of 1 to 10 carbon atoms and W is a carbon bearing a hydrogen Specifically preferred compounds of this invention according to general Formula (I) are the following compounds or pharmaceutically acceptable salts thereof:
3-(1,1-Dimethyl-2-phenyl-ethylamino)--4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione;
3-(1,1-Dimethyl-propylamino)-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione;
3-(Isopropyl-methyl-amino)-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione;
3-(4-Methoxy-phenyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione;
3-(4-Methoxy-phenyl)-4-[2-(3-trifluoromethyl-phenyl)-ethylamino]-cyclobut-3-ene-1,2-dione;
(-)-3-(4-Methoxy-phenyl)-1-4-((R)-1-phenyl-ethylamino)-cyclobut-3-ene-1,2-dione;
3-(4-Methoxy-phenyl)-4-(2-phenyl-propylamino)-cyclobut-3-ene-1,2-dione;
3-[2-(4-tert-Butyl-phenyl)-ethylamino]-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione;
4-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]benzonitrile;
3-(4-Trifluoromethyl-phenyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione;
4-(4-Trifluoromethyl-phenyl)-3-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione;
3-(1,1-Dimethyl-propylamino)-4-(pyridin-3-yl)-cyclobut-3-ene-1,2-dione hydrochloride;
3-[2-Oxo-1-(4-trifluoromethyl-phenyl)-propyl]-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione;
3-(4-Bromo-phenyl)-4-(1;2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione;

3-(4-Methoxy-benzyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione one-quarter hydrate;
{2-[1-(4-Methoxy-phenyl)-2-oxo-propyl)]-3,4-dioxo-cyclobut-1-enyl}-(1,2,2-trimethyl-propyl)-carbamic acid tert-butyl ester;
3-(1,1-Dimethyl-2-phenyl-ethylamino)-4-(3-methoxy-phenyl)-cyclobut-3-ene-1,2-dione;
3-[(E)-2-(4-Bromo-phenyl)-vinyl]-4-(1.,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione; and 4-{(E)-2-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-vinyl}-benzonitrile.
In particular, this invention also provides a method of treating or inhibiting disorders associated with smooth muscle contraction, via potassium channel modulation in warm-blooded animals in need thereof, which comprises administering to said warm-blooded animals preferably mammals, most preferably humans, an effective amount of a campound of general Formula (II) or a pharmaceutically acceptable salt thereof.

R ~-R
(II) Wherein:
R1 , RZ , and R3 , are, independently, hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms (optionally substituted with halogen), cycloalkyl of 3 to WO 00/34230 PC'f/US99/28618 10 carbon atoms, -ORS , amino, alkylamino of 1 to 10 carbon atoms, -SO3H, -SOZNH2, -SONHz, -NHSOZR~, -HI~-C-R~
-SOZR~ , carboxyl, aryl of 6 to 12 carbon atoms or aroyl of 7 to 22 carbon atoms;
A is a moiety selected from the group consisting of a bond , -CHZ - , -CH=CH - and -CHCOR6 ;
W is selected from the group consisting of carbon and nitrogen and wherein the carbon atom may be optionally substituted with -R1 , -RZ and -R3 ;
R9 is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms wherein the aryl group is optionally substituted with alkyl of 1 to 10 carbon atoms, nitro, halogen, cyano, -OR,, O
I I
-C-ORS , trifluoromethyl or trifluoromethoxy;
RSis hydrogen, alkyl of 1 to 10 carbon atoms, formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, O
-C-ORS , -SOzR,, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms;
Rbis alkyl of 1 to 10 carbon atoms, or aryl of 6 to 12 carbon atoms;

R~is alkyl of 1 to 10 carbon atoms (optionally substituted with halogen);
aroyl is benzoyl and naphthoyl which is optionally substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of. 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF3 , and phenyl ;
aryl is naphthyl, phenyl or phenyl optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms; or pharmaceutically acceptable salts thereof.
Preferred groups of compounds of Formula (II) of this invention for the method of treating disorders associated with smooth muscle contraction, via potassium channel modulation including pharmaceutically acceptable salts thereof are those in the subgroups:
a) compounds having the general formula:
I
~5 wherein R1 , RZ , R3 , R9 , and RS are as hereinbefore defined for Formula (II);
b) compounds having the general. formula:

R~

N /Ra ..J R5 wherein R1 , Rz , R3 , R9 , and RS are as hereinbefore defined for Formula (II) and W is a carbon bearing a hydrogen;
c) compounds having the general formula:
Rr.

wherein R1 , R2 , R3 , Rq , and RS are as hereinbefore defined for Formula (II);
d) compounds having the general. forumla:

wherein R1 , Rz , R3 , Rg , and R5 are as hereinbefore defined for Formula (II) and W is a carbon bearing a hydrogen;
e) compounds having the general formula:
/ Ra Ri NW, R
IS
wherein R1 , R2 , R3 , Rq , and RS are as hereinbefore defined for Formula (II);
f) compounds having the general formula:
R

R~
R~
2 Rs wherein R1 , Rz , R3 , R9 , RS and R6 are as hereinbefore defined for Formula (II) and W is a carbon bearing a hydrogen;
g) compounds having the general formula:

~3 IS
wherein R1 , RZ , R3 , RQ , R5 and R6 are as hereinbefore defined for Formula (II).
Preferred compounds of Formula (II) of this invention for the method of treating disorders associated with smooth muscle contraction, via potassium channel modulation including pharmaceutically acceptable salts thereof are those in the subgroups:
a) compounds having the general formula:

~R4 I
t5 wherein:
R1 , RZ , R3 , R4 , and RS are hereinbefore defined for Formula (II) and W is a carbon bearing a hydrogen; and b) compounds having the general formula:

I
Is wherein:
R1 , RZ , R4 arid RS are hereinbefore defined for Formula (II), R3 is alkoxy of 1 to 10 carbon atoms and W is a carbon bearing a hydrogen.
For the compounds of Formulae (I) and (II) defined above and referred to herein, unless otherwise noted, the following terms are defined:
Halogen, or halo as used herein means chloro, fluoro, bromo and iodo.
Alkyl as used herein means a branched or straight chain having from 1 to 10 carbon atoms and more preferably from 1 to 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
Cycloalkyl as used herein means a saturated ring having from 3 to 10 carbon atoms and more preferably from 3 to 6 carbon atoms. Exemplary cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Aryl as used herein means a homocyclic aromatic radical, whether or not fused, having 6 to 12 carbon atoms.
Preferred aryl groups include phenyl, alpha-naphthyl and beta-naphthyl and the like optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkyl amino of 1 to 10 carbon atoms.
Aroyl as used herein refers to -C(O)aryl where aryl is as previously defined. Examples include benzoyl and naphthoyl optionally substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF3 and phenyl.
Aralkyl as used herein means an aryl-alkyl group in which the aryl and alkyl group are previously defined.
Exemplary aralkyl groups include benzyl and phenethyl.
Alkenyl as used herein means a branched or straight chain having from 2 to 12 carbon atoms and more preferably from 2 to 6 carbon atoms, the chain containing at least one carbon-carbon double bond. Alkenyl, may be used synonymously with the term olefin and includes alkylidenes.
Exemplary alkenyl groups include ethylene, propylene and isobutylene.

Alkanoyl as used herein refers to -C(O)alkyl where alkyl is as previously defined.
Alkenoyl as used herein refers to -C(0)alkenyl where alkenyl as previously defined.
Alkoxy as used herein means an -0-alkyl group in which the alkyl group is as previously described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.
Arylalkanoyl as used herein refers to a carbonyl group or radical directly bonded to an alkyl group of 1 to 10 carbon atoms which is terminally substituted by an aryl group as previously defined, for example phenylacetic acid.
The aryl group is optionally substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, CF3, and phenyl and substituted phenyl where the substituents are selected from halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and -CF3.
Arylalkenoyl as used herein refers to a carbonyl group or radical directly bonded to an alkenyl group of 2 to 12 carbon atoms which is terminally substituted by an aryl group as previously defined. The aryl group is optionally substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF3, and phenyl and substituted phenyl where the substituents are selected from halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and -CF3.

Arylsulfonyl as used herein refers to the radical -S02aryl where aryl is as previously defined Arylalkylsulfonyl as used herein refers to the radical aryla1ky102S- where arylalkyl is as previously defined.
ring.
Phenyl as used herein refers to a 6-membered aromatic Where terms are used in combination, the definition for each individual part of the combination applies unless defined otherwise. For instance, aralkyl refers to an aryl group, and alkyl refers to the alkyl group as defined above.
The range of carbon atoms defines the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituent groups.
Among the specifically preferred compounds of this invention according to general Formula (II) are the specifically preferred compounds of Formula (I) or pharmaceutically acceptable salts thereof for the method of treating disorders associated with smooth muscle contraction via potassium channel modulation.
It is understood by those practicing the art that the definition of compounds of Formulae (I) and (II) when R1, RZ , R3 , R9 , R5 , R6 and W contain asymmetric carbons, encompass all possible stereoisomers, mixtures and regioisomers thereof which possess the activity discussed below. Such regioisomers may be obtained pure by standard separation methods known to those skilled in the art. In particular, the definition encompasses any optical isomers and diastereomers as well as the racemic and resolved enantiomerically pure R and S stereoisomers as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof, which possess the activity discussed below. Optical isomers may be obtained in pure form by standard separation techniques or enantiomer specific synthesis. It is understood that this invention encompasses all crystalline forms of compounds of Formulae (I) and (II). 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, fumaric, succinic, malefic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic and similarly known acceptable acids . Where R1 , R2 , R3 , Rq , RS , or R6 contains a carboxyl group, salts of the compounds in this invention may be formed with bases such as alkali metals (Na, K, Li) or alkaline earth metals (Ca or Mg).
The present invention accordingly provides a pharmaceutical composition which comprises a compound of Formula (II) 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.
DESCRIPTION OF THE I,~]I ~TION
The compounds of the present invention may be prepared according to one or more of the general processes outlined below.
Compounds of Formulae (I) and (II), wherein A is a bond and W, R1 , RZ , R3 , R4 and R5 are hereinbefore defined may be synthesized as shown in Scheme I by the cross-coupling reaction of 3-isopropoxy-4-(tri-n-butylstannyl)-3-cyclobutene-1,2-dione _1 [J. Org. Chem. 1990, 55, 5359-5364]
with an appropriate aryl halide 2_ or :3-pyridyl-halide (W=N) , where X is a halogen and R1 , Rz and R3 are hereinbefore defined in a polar solvent such as dimethylformamide (DMF) and the like in the presence of a Pd(O) reagent such as benzylchlorobis(triphenyl-phosphine) palladium (II) and the like in the presence of cuprous iodide to give a substituted-cyclobut~-3-ene-1,2-dione intermediate ~ where W and R1 , RZ and R3 are hereinbefore defined.
SCHEME I
X
O
J Rs Bu 3 ' b LI'd(O)1/DME Hs Ra ~\RS R
Rs EtOH / O
Vinyligous Amide ~ of Formulae (I) and (II) where A is a bond The resulting substituted-cyclobut-3-ene-1,2-dione intermediate ~ where W and R1, RZand R3are hereinbefore defined can then be converted by treatment with the appropriately substituted amine 4 where R9and Rsare hereinbefore defined in a polar solvent such as ethanol and the like, forming a direct bond, to give vinyligous amide ,~
of Formulae ( I ) and ( II ) where R1 , RZ , R3 , R4 , RS and W are hereinbefore defined.

Compounds of Formulae (I) and (II) wherein A = -CHCORband Rbis as described above may be synthesized as shown in Scheme II by reaction of ketone $ where W, R1, RZ
R3 and Rbare hereinbefore defined with diethoxysquaric acid 7 in the presence of a strong base, such as, but not limited to, potassium bis(trimethylsi:lyl)amide in a solvent such as tetrahydrofuran (THF) or diethyl ether and the like to give ether intermediate $ where W, R1 , Rz , R3 and R6 are hereinbefore defined which could then be converted into compounds of Formulae (I) and (II) by treatment with the appropriately substituted amine 4 in a polar solvent such as ethanol and the like to give compounds of Formulae (I) and ( II ) where A is a moiety -CHCOR6 and W, R1 , RZ , R3 , R9 RSand Rbare hereinbefore defined.
R~

R ~ KI~T(TMS~
/' Rs R~' ~Ra HN 4 R~
~R

EtOH / D
Formulae (I) or (II) A = -CHCOR6 Compounds of Formulae (I) and (II) wherein A is the moiety -CHZ- may be synthesized as shown in Scheme III by a WO 00/34230 PCT/US99/28b18 transhalogenation and carbon-carbon bond forming sequence (H. Finkelstein, Ber. 1910, 43, 1528; Stille, J.K., J. Am.
Chem. Soc. 1984, 106, 6417) wherein the benzylic iodide coupling partner analogous to ~Q, is formed in situ in the presence of cuprous iodide and concomitantly reacted with stannane 1_. This procedure which is generally applicable to compounds of formula ~Q, wherein the group Z is either chloride or bromide, avoids the undesirable decomposition endemic to benzylic iodides to give benzyl squarate 11 where W, R1 , R2 , and R3 are hereinbefore defined.
Treatment of benzyl squarate 11 with substituted amine 4 where R4and RSare hereinbefore defined gives disubstituted amine squarate ,~? of Formulae (I) and (II) where A is -CH2-and where W, R1 , Rz , R3 , RQ , and RS are hereinbefore defined.
SCHE~VI_E III
Rt BnPd(PPh3~,Cl R' I Z Cul,NaI,DMF \ O
I
RT
R' where Z=C1, Br Bu S

~R4 HN
~R5 EtOH / O
Formulae (I) and (II) A= -CH2-Compounds of Formulae (I) and (II) wherein A is -CH=CH- may be synthesized as shown in Scheme IV via iodomethylenation of aldehyde ~, where R1, R2, R3 and W are hereinbefore defined, in the presence of iodoform and chrominum (II) chloride in the absence of light at room temperature(RT) and using the conditions as described by Takai, K., J. Am. Chem. Soc. 1986, 1~$, 7408, giving vinyl iodide ~ where R,, Rz, R3 and W are hereinbefore defined.
Using the conditions as described by W.F. Goure et al, J.
Am. Chem. Soc., 1984, 106, 6417, vinyl iodide ~,4_ is reacted with stannane 1 in the presence of a Yd(O) reagent such as benzylchlorobis(triphenylphosphine) palladium (II) and the like in the presence of cuprous iodide to give styrenylcyclobutendione ethyl ester ~ where W, R1, R2, and R3 are hereinbefore defined. Further treatment of styrenylcyclobutendione ethyl ester ~, with substituted amine 4 where Rq and R5 are hereinbefore defined in a polar solvent such as ethanol and the like to give disubstituted aminosquarate ,~ of Formulae (I) and (II) where A is -CH=CH- and where W, R1, Rz, R3, R4 and RS are hereinbefore defined.

SCHEME IV
R~
CrCI ,CHI ,THF
Rz I -- 2 3 CHO RT, NO LIGHT R2 n BnPd(PPh3~C1 CuI,DMF,RT
RT
Bu S O"' -~Ra 4 HN~

EtOH / D R
As mentioned previously, the compounds of Formula (I) and (II) and their pharmaceutically acceptable salts have been shown in this disclosure to relax smooth muscle. They are therefore useful in the treatment of disorders 10 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 15 Formula (I) and (II) are active as potassium channel activators which render them useful for treatment of Formula (I) and (II) A= -CH=CH-peripheral vascular. disease, congestive heart failure, stroke, anxiety, cerebral anoxia and other neurodegenerative disorders. Moreover, compounds of Formula (I) and (II) mediate their biological effects by activating the large-conductance calcium-sensitive potassium channel (Bk~a) or maxiK
Compounds of the present invention are characterized by their potent smooth muscle relaxing properties in vitro. The compounds of this invention exert their smooth muscle relaxatory activity via activation of potassium channels. In addition, the compounds of the present invention are unique in that they possess intrinsic selectivity for bladder tissue over vascular tissue as demonstrated by bladder/aorta ICSO ratios (Table 1).
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 also 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 50 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 to 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 (3-blocking agents.
The present invention further provides a compound of the invention for use as an active therapeutic substance.
Compounds of Formulae (I) and (II) 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-(1,1-Dimethyl-2-~nvl-ethvlamino)-4-(4-methoxv-bhenvl) cvclobut-3-ene-1,2-dione Sten 1 Preparation of 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione To a solution of 3-isopropoxy-4-(tri-n-butyl-stannyl) 3-cyclobutene-1,2-dione (J. Org. Chem. 1990, 55, 5359-5364) (8.00 g, 18.65 mmol) in N,N-dimethyl-formamide (40 mL) was added 4-iodoanisole (4.85 g, 20.72 mmol). The flask was purged with nitrogen and cooled to 0°C. Benzylchloro-bis-(triphenylphosphine)palladium (II) (0.942 g, 1.24 mmol) and cuprous iodide (0.355 g, 1.87 mmol) were added and the mixture was stirred at room temperature overnight.

5 Diethylether (200 mL) was added and the mixture was washed successively with saturated aqueous ammonium chloride, 10~
aqueous potassium fluoride and saturated brine. The organic phase was filtered through a plug of silica. The filtrate was dried (MgS04) and concentrated to give crude 10 product which was dissolved in hot ethyl acetate, decolorized (charcoal) and filtered. The filtrate was treated with hexane and allowed to cool. 3-Isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione preci-pitated as a light yellow solid (2.46 g, 54~): 'H NMR (DMSO-db)8 15 7.89(d,2H), 7.15(d,2H), 5.45(hept,lH), 3.82(s,3H), 1.48(d,6H).
Preparation of 3-(1,1-Dimethyl-2-phenyl-ethylamino)-4-20 (4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione To a solution of 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) in ethanol (3 mL) was added 1,1-dimethyl-2-phenyl-ethylamine (0.182 g, 1.22 mmol). The mixture was stirred at 70°C overnight then 25 filtered hot through a pad of silica gel. The filtrate was concentrated and the resulting residue was recrystallized from ethyl acetate/hexanes to give 0.170 g (830) of the title product as a tan solid: m.p. 150-151°C; 1H NMR (DMSO-db)8 8.28(s,lH), 8.00(m,2H), 7.28(m,2H), 7.26(m,lH), 30 7.13(m,2H), 7.09(m,2H), 3.82(s,3H), 3.10(s,2H), 1.42(s,6H);
IR (KBr) 3420, 2950, 1775, 1715, 1650, 1570, 1410, 1252, 1200, 1045, 850, 740, 700, 602, 530 ciril; MS (m/z) 335 [M'].
Elemental analysis for CZIHzINO3:
35 Calc'd: C,75.20; H,6.31; N,4.18.
Found: C,74.35; H,6.41; N,3.90.

Example 2 3-(1 1-Dimethvl-progvlamino)-4-(4-methoxv-phenyh_)~cyclobut-3-ene-1.2-dione In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione 10 (0.150 g, 0.609 mmol) and tert-amyl amine (0.48 mL, 4.11 mmol) were converted to the title compound (0.14 g, 84~) m.p. : 133-135°C; 1H NMR (DMSO-db)8 8..28 (br s,1H) , 8.04(m,2H), 7.11(m,2H), 3.83(s,3H), 1.80(q,2H), 1.42(s,6H), U.85(t,3H); IR (KBr) 2980, 1765, 1725, 1600, 1423, 1310, 15 1260, 1175, 1030, 850 ciri'; MS (m/z) 273 [M'] .
Elemental analysis for C16H19N03 Calc'd: C,70.31; H,7.00; N,5.12.
Found: C,69.79; H,6.92; N,5.05.
~xam8le 3 3-(TSOTJ~"ODV~-methyl-amin2)-4-(4-methoxv-~henvl)-cvclobut-3 en~-1,2-dione In a manner similar to Example 1, Step 2; 3-25 isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and methyl-isopropylamine (0.07 mL, 0.670 mmol) in acetonitrile (3 mL) were converted to the title compound (0.10 g, 630) m.p.: 109-115°C; 'H NMR (DMSO-db)8 7.60(m,2H), 7.07(m,2H), 4.91(m,lH), 3.81(s,3H), 1.23 (br d, 6H) ; MS (m/z) 259 [M+] .
Elemental analysis for C15H1~N03:
Calc'd: C,69.48; H,6.61; N,5.40.
Found: C,69.23; H,6.64; N,5.55.

Example 4 3-(4-Metho.~r-phenyl)-4-(1,2,2-trimethyl-~~ogylamino)-~,vclobut-3-ene-1,2-dione In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.300 g, 1.22 mmol) and 2-amino-3,3-dimethylbutane (0.18 mL, 1.34 mmol) in acetonitrile (7 mL) were converted to the title compound (0.28 g, 80~) m.p.: 179-181°C; 'H NMR (DMSO-db)8 8.56(br d,lH), 8.06(ABq,2H), 7.09(ABq,2H), 4.31(m,lH), 3.83(s,3H), 1.24(d,3H), 0.91(s,9H); IR (KBr) 3200, 2980, 1780, 1720, 1620, 1420, 1310, 1270, 1190, 1120, 1040, 840 Cm 1; MS (m/Z) 287 [M'] .
Elemental analysis for C17Ha1NO3:
Calc'd: C,71.06; H,7.37; N,4.87.
Found: C,70.41; H,7.41; N,4.90.
Exa ple 5 3-(4-Methox~phenvl)-4-(2-(3-trifluoromethvl-~henvl) ethylaminol-cvclobut-3-ene-1,2-dione In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and 3-trifluoromethylphenethyl-amine (0.23 g, 1.22 mmol) in ethanol (3 mL) were converted to the title compound (0.155 g, 68~) m.p.: 220.2-222.3°C; 1H NMR
(DMSO-db)8 9.05(br t,lH), 7.95(ABq,2H), 7.60-7.45(m,4H), 7.08(ABq,2H), 3.94(br t,2H), 3.83(s,3H), 3.04(t,3H); IR
(KBr) 3210, 3170, =L775, 1780, 1575, 1360, 1325, 1175, 1125, 1070, 1020, 840, 800, 695 cml; MS (m/z) 375 [M'].
Elemental analysis for CzoHISNO3F3:
Calc'd: C,64.00; H,4.30; N,3.73.
Found: C,64.00; H,4.25; N,3.72.

Example 6 ( ) 3 ( 4 Methoxvr p~yl ) -4- ( (R) -1-b2he~y1-eth~lamino) -~~~lnhmt-3-ene-1,2-dione In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (150 g, 0.609 mmol) and (R)-(+)-a-methyl-benzylamine (180 ~.L, 0.914 mmol) in ethanol (1 mL) were converted to the title compound (120 mg, 64~) m.p.: 158.7-160.1°C; 'H NMR
(DMSO-db)8 9.28(d,lH), 8.04(ABq,2H), 7.35(m,SH), 7.10(ABq,2H), 3.83(s,3H), 1.64(d,3H); IR (KBr) 3260, 3060, 3030, 2970, 1770, 1720, 1600, 1560, 1520, 1440, 1410, 1380, 1340, 1310, 1260, 1220, 1180, 1120, 1100, 1025, 825, 700 cm 1; MS (m/z) 307 [M+] , [a]25p-185.42° (c0.1049,THF) .
Elemental analysis for C~9H1.,N03:
Calc'd: C,74.25; H,5.58; N,4.56.
Found: C,73.99; H,5.56; N,4.44.
~xa le 7 ~ (4 Methoxv nhenvl)-4-(2-phenvl-groyvlamino)-cvclobut-3-ene-1,2-dione In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and 2-methyl-2-phenyl-ethylamine (0.165 g, 1.22 mmol) in ethanol (2 mL) were converted to the title compound (0,130 g, 66~) m.p.: 215.4-216.2°C; 1H
NMR (DMSO-db)8 9.07(br t,lH), 7.95(ABq,2H), 7.30-7.:18(m,5H), 7.08(ABq,2H), 3.90-3.72(m,2H), 3.82(s,3H), 3.09(m,lH), 1.26(d,3H); IR(KBr) 3160, 2960, 1775, 1730, 1560, 1430, 1300, 1250, 1170, 1100, 1020, 840 ciril; MS (m/z) 322 [M+H'] .

Elemental analysis for CZOH19NO3 Calc'd: C,74.75; H,5.96; N,4.36.
Found: C,75.06; H,6.02; N,4.37.
Exams 1 a 8 3 f2 (4 tert Butvl phenyl) ethvlaminol-4-(4-methoxv-phenv~)-cvc~ob~t-3-ene-1.2-dione In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and 4-tert-butyl-phenethylamine (0.216 g, 1.22 mmol) in ethanol (2 mL) were converted to the title compound (0.180 g, 81~) m.p.: 258.1-260.2°C; 'H
NMR (DMSO-d6)8 9.07(br t,lH), 7.97(ABq,2H), 7.29(ABq,2H), 7.14(d,2H), 7.09(d,2H), 3.87(m,2H), 3.83(s,3H), 2.84(t,2H), 1.23(s,9H); TR(KBr) 3160, 2950, 1775, 1720, 1580, 1425, 1350, 1300, 1250, 1180, 1020, 840 ciril; MS (m/z) 364 [M+H'].
Elemental analysis for CZ3Hz5NO3:
Calc'd: C,76.01; H,6.93; N,3.85.
Found: C,76.17; H,7.01; N,3.84.
Example 9 4-f3 4-Dioxo-2-(1 2 2-trimethvl=propvlamino)-cvclobut-1-enyllb~nzonitrile Step 1) Preparation of 3-isopropoxy-4-(4-cyano-phenyl)-cyclobut-3-ene-1,2-dione To a solution of 3-isopropoxy-4-(tri-n-butyl-stannyl)-3-cyclobutene-1,2-dione (6.00 g, 13.99 mmol) in N,N-dimethylformamide (20 mL) was added 4-iodobenzonitrile (3.52 g, 15.38 mmol). The flask was purged with nitrogen and cooled to 0°C.
Benzylchlorobis(triphenylphosphine)palladium (II) (0.636 g, 0.838 mmol) and cuprous iodide (0.240 g, 1.26 mmol) were added and the mixture was stirred at room temperature for 2 hours. Diethyl ether (200 mL) was added and the mixture was washed successively with saturated aqueous ammonium chloride, 10~ aqueous potassium fluoride and saturated brine. The organic phase was filtered through a plug of silica. The filtrate was dried (MgSOq) and concentrated to give crude product which was dissolved in hot ethyl acetate, decolorized (charcoal) and filtered. The filtrate was treated with hexane. Several crops of 3-isopropoxy-4-(4-cyano-phenyl)-cyclobut-3-ene-1,2-dione were collected.
The second crop 0.27 g (7~) was of sufficient purity to take on to the next step.
Step 2 Preparation of 4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-benzonitrile To a solution of 3-isopropoxy-4-(4-cyano-phenyl)-cyclobut-3-ene-1,2-dione (0.27 g, 1.12 mmol) in acetonitrile (6 mL) was added 2-amino-3,3-dimethylbutane (0.23 mL, 1.68 mmol). The mixture was stirred at room temperature overnight then filtered. The solid was recrystallized from ethyl acetate/hexanes to give 0.160 g (50~) of the title product as a white solid: m.p. 192-194°C; 1H NMR (DMSO-db)8 9.01(br d,lH), 8.19(ABq,2H), 8.01(ABq,2H), 4.29(m,lH), 1.25(d,3H), 0.92(s,9H); IR(KBr) 3160, 2950, 2220, 1760, 1600, 1440, 1160, 1100, 850 ciri'; MS
(m/z) 282 [M '] .
Elemental analysis for C1~H18NZO2:
Calc'd: C,72.32; H,6.43; N,9.92.
Found: C,71.20; H,6.29; N,9.84.
Example 10 3-(4-TrifluoromethYl-bhenvl)-4-(1 2,2-trimethvl-piogy~a_m~no)-cvclobut-3-ene-1,2- ion Step 1) Preparation of 3-isopropoxy-4-(4-trifluoro-methyl-phenyl)-cyclobut-3-ene-1,2-dione In a manner similar to Example 9, Step 1, 3-isopropoxy-4-(tri-n--butylstannyl)-3-cyclobutene-1,2-dione (3.00 g, 6.99 mmol), 4-trifluoromethyl-iodobenzene (2.09 g, 7.69 mmol), benzylchlorobis(triphenylphos-phine)palladium (II) (0.318 g, 0.419 mmol) and cuprous iodide (0.12 g, 0.629 mmol) were reacted together to give 0.98 g (45~) of 3-isopropoxy-4-(4-trifluoromethyl-phenyl)-cyclobut-3-ene-1,2-dione which was of sufficient purity to use in the next step.
Stefl 2 Preparation of 3-(4-trifluoromethyl-phenyl)-4-(1,2,2-trimethylpropylamino)-cyclobut-3-ene-1,2-dione In a manner similar to Example 9, Step 2, 3-isopropoxy-4-(4-trifluoromethyl-phenyl)-cyclobut-3-ene-1,2-dione (0.40 g, 1.408 mmol) and 2-amino-3,3-dimethylbutane (0.28 mL, 2.11 mmol) were converted to the title compound.
Recrystallization from hot ethyl acetate afforded 0.18 g (39~) of compound as a white solid: m.p. 191-193°C; 'H NMR
(DMSO-db)8 8.97(br d,lH), 8.22(ABq,2H), 7.88(ABq,2H), 4.30(m,lH), 1.26(d,3H), 0.92(s,9H); IR (KBr) 3450, 3180, 2970, 1775, 1740, 1600, 1420, 1370, 1170, 1110, 1060, 850 cm'; MS (m/z) 325 (M'] .
Elemental analysis for C1.,H18NOZF3:
Calc'd: C,62.76; H,5.58; N,4.31.
Found: C,62.48; H,5.60; N,4.22.
Example 11 4-(4-Trifluoromethvl-t~henvl>-3-(1,1-dim~~h~l-nroovlamino) cyclobut-3-ene-1,2-dione In a manner similar to Example 1, Step 2, 3-isopropoxy-4-(4-trifluoromethyl-phenyl)-cyclobut-3-ene-1,2-dione (0.30 g, 1.056 mmol) and tert-amylamine (0.86 mL, 7.39 mmol) were converted to the title compound.
Recrystallization from hot ethyl acetate afforded 0.250 g (76~) of compound as a tan solid: m.p. 115.4-119°C (dec);
'H NMR (DMSO-db)8 8.60(br s,lH), 8.15(ABq,2H), 7.86(ABq,2H), 1.81(q,2H), 1.43(s,6H), 0.88(s,3H); IR (KBr) 3170, 2980, 1770, 1720, 1580, 1310, 1170, 1125, 1060, 1010, 850 ciri'; MS
(m/z ) 311 [M +] .
Elemental analysis for C16H16N~2F3 Calc'd: C,61.73; H,5.18; N,4.50.
Found: C,61.76; H,4.95; N,4.18.
Ex~7~l a 12 ~-(1,1-Dimethvl-pro~ylamino)-4-(,gvridin-3-yl)-cvcl bo ut-3=
ene-1,2-dione hydrochloride Preparation of 3-isopropoxy-4-(3-pyridyl)-cyclobut-3-ene-~1, 2-dione In a manner similar to Example 9, Step 1, 3-isopropoxy-4-(tri-n-butylstannyl)-3-cyclobutene-1,2-dione (1.90 g, 4.43 mmol), 3-iodopyridine (1.00 g, 4.87 mmol), benzylchlorobis(triphenylphosphine)palladium (II)(0.201 g, 0.267 mmol), and cuprous iodide (0.076 g, 0.399 mmol) were reacted together to give the title compound which was of sufficient purity to use in the next step: 'H NMR (DMSO-d6)8 9.07(m,lH), 8.75(m,lH), 8.20(br d,lH), 7.65(m,lH), 5.50(sept,lH), 1.50(d,6H).
Steu 2 Preparation of 3-(1,1-Dimethyl-propylamino)-4-(pyridin-3-yl)-cyclobut-3-ene-1,2-dione hydrochloride In a manner similar to Example 9, Step 2, 3-isopropoxy-4-(3-pyridyl)-cyclobut-3-ene-1,2-dione (0.20 g, 0.92 mmol) and tert-amylamine (0.75 mL, 6.45 mmol) were converted to the title compound as the free base.
Treatment with ethereal HCl afforded the hydrochloride salt as a light tan solid: m.p. 152-155.9°C (dec); 'H NMR

(DMSO-db)8 9.20(br s,lH), 8.73(m,2H), 8.47(m,lH), 7.69(m,lH), 4.6(br s,lH,plus H20), 1.82(q,2H), 1.43(s,6H), 0.88(t,3H); IR (KBr) 3475, 2970, 2470, 2050, 1770, 1590 cm 1; MS (m/z) 244 [M'] .
Elemental analysis for C14H1~NZOZC1:
Calc~d: C,59.89; H,6.10; N,9.98.
Found: C,58.58; H,5.78; N,9.57.
Examples 13-20 are prepared in a two-step procedure using the conditions described in Examples 1 or 9 using the appropriate aryl iodide, 3-isopropoxy-4-(tri-n-butylstannyl)-3-cyclobutene-1,2-dione, and the appropriate amine.
Exampla 3-(1,1-Dimethyl-propylamino)-4-(3,4-dimethoxy-phenyl)-cyclobut-3-ene-1,2-dione.
Example 14 3-(1,1-Dimethyl-2-phenyl-ethylamino)-4-(3,4-dimethoxy-phenyl)-cyclobut-3-ene-1,2-dione.
Example 15 3-(1,1-Dimethyl-propylamino)-4-(3-bromo-4,5-dimethoxy-phenyl)-cyclobut-3-ene-1,2-dione.
Example 16 3-(1,1-Dimethyl-2-phenyl-ethylamino)-4-(3-bromo-4,5-dimethoxy-phenyl)-ryclobut-3-ene-1,2-dione.
Example 17 3-(1,1-Dimethyl-propylamino)-4-(3-bromo-4,6-dimethoxy-phenyl) -cyclobut-3--ene-1, 2-dione.

Example 18 3-(1,1-Dimethyl-2-phenyl-ethylamino)-4-(3-bromo-4,6-dimethoxy-phenyl)-cyclobut-3-ene-1,2-dione.
Exa gle 19 3-(1,1-Dimethyl-propylamino)-4-(2-bromo-4,6-dimethoxy-phenyl)-cyclobut-3-ene-1,2-dione.
Example 20 3-(1,1-Dimethyl-2-phenyl-ethylamino)-4-(2-bromo-4,6-dimethoxy-phenyl)-cyclobut-3-ene-1,2-dione.
Examp 1 a 21 3-f2-Oxo-1-(4-trifluoromethyl-phenyl)-g_ro~yll-4-(1 2,2 tr;methyl-progylamino)-cvclobut-3-ene-1,2-dione SteQ 1 Preparation of 3-[2-Oxo-1-(4-trifluoromethyl-phenyl)-propyl]-4-ethoxy-cyclobut-3-ene-1,2-dione.
A solution of 1-[(4-trifluoromethyl)phenyl]-2-propanone (J. Med. Chem. 1967, 10 (6), 1008-14)(1.86 g, 9.208 mmol) in tetrahydrofuran (10 mL) was added dropwise (under nitrogen) to a cooled (-78°C) solution of potassium bis(trimethyl-silyl)amide (19.3 mL; 0.5 M in toluene, 9.67 mmol) in tetrahydrofuran/diethyl ether (1:1 ratio, 80 mL).
The mixture stirred at -78°C for 15 min. and was then stirred at room temperature for 2.5 hours. The enolate solution was cooled to -78°C and added by cannula to a cooled (-78°C) flask containing diethyl squarate (1.50 mL, 10.13 mmol) in THF/diethyl ether (1:1 ratio, 20 mL). The reaction was stirred for 15 min. at -78°C and was then allowed to warm to room temperature over a 1 hour period.
The reaction was concentrated to give a residue which was partitioned between 0.1 N HC1 and ethyl acetate. The organic phase was washed with brine, dried (MgS04) and concentrated to give crude product. Purification by flash column chromatography (2:1 hexanes/ethyl acetate) followed by trituration with petroleum ether afforded 1.18 g (39~) of title compound as a light yellow solid: 1H NMR (DMSO-d6)8 11.51(s,lH), 7.60(ABq,2H), 7.24(ABq,2H), 4.59(q,2H), 1.89(s,3H), 1.19(t,3H).
Preparation of 3-[Oxo-1-(4-trifluoromethyl-phenyl)-propyl]-4-(1,1,1-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione.
3-[2-Oxo-1-(4-trifluoromethyl-phenyl)-propyl]-4-ethoxy-cyclobut-3-ene-1,2-dione (0.350 g, 1.07 mmol) and 2-amino-3,3-dimethylbutane (0.13 mL, 0.998 mmol) were stirred together in ethanol (6 mL) at room temperature overnight.
Diethyl ether (25 mL) was added and the precipitated product was collected by filtration. It was stirred in diethyl ether/petroleum ether overnight, filtered and dried in vacuo to afford 0.15 g (37~) of desired product ('H NMR
in CDC13 suggested the presence of both the keto and enol forms in about an 8:1 ratio) as an off-white solid: m.p.
178.2-179.8°C; . 1H NMR (CDC13) b 11.74(s,lH), 7.73(ABq,2H), 7.39(ABq,2H), 3.92(m,lH), 1.86(s,3H), 0.93(d,3H), 0.69(s,9H); IR (KBr1 3310, 2970, 2600, 1775, 1710, 1560, 1395, 1260, 1160, 1125, 850 crnl; MS (m/z) 381 [M'].
Elemental analysis for CZOH22NO2F3:
Calc'd: C,62.98; H,5.81; N,3.67.
Found: C,62.67; H,5.72; N,3.56.
Example 22 ~-l4-Bromo-phenyl)-4-(',2,2-trim~~~yl-~ropylamino)-cyclobut-3-ene-1,2-dione To a heterogeneous mixture of 3-(4-bromo-phenyl)-4-isopropoxycyclobut-3-ene-1,2-dione (290 mg, 0.983 mmol) [prepared according to the method indicated in Step 1 of Example 1] in anhydrous isopropyl alcohol (6.0 mL) was added 2-amino-3,3-dimethylbutane (263 ~.L, 1.96 mmol) at room temperature, resulting in the formation of a yellow suspension. After 24 hours, the reaction mixture was diluted with isopropyl alcohol, filtered, washed with an excess of isopropyl alcohol, then dried under high vacuum at 65°C, affording a light yellow solid (225 mg, 68~): m.p.
210.6-211.3°C; 1H NMR (DMSO-db)8 8.81(d,lH), 8.00((ABq,2H), 7.75(ABq,2H), 4.29(dq,lH), 1.25(d,3H), 0.91(s,9H); IR (KBr) 3160, 3050, 2980, 1770, 1730, 1630, 1590, 1480, 1430, 1400, 1220, 1170, 1120, 1010, 840, 810, 750, 710 cni'; MS (m/z) 335/337 [M'] .
Elemental analysis for C16H18BrNO2:
Calc~d: C,57.16; H,5.40; N,4.17.
Found: C,57.03; H,5.34; N,4.22.
Example 23 3~4-Methoxv-benzyl)-4-(1,2,2-trimethyl-propvlamino~
~yclobut-3-ene-1,2-dione one-cxuarter hydrate Step 1) Preparation of 3-(4-Methoxy-benzyl)-4-isopropoxycyclobut-3-ene-1,2-dione To a heterogeneous mixture of copper iodide (178 mg, 0.932 mmol) and sodium iodide (2.09 g, 14.0 mmol) in anhydrous N,N-dimethylformamide (5.0 mL) was added 4-methoxybenzyl chloride. The reaction mixture, which had exothermed, was stirred for 30 min. at room temperature, whereupon a solution of 3-isopropoxy-4-(tri-n-butyl-stannyl)-3-cyclobut-3-ene-1,2-dione (4.00 g, 9.32 mmol) in DMF (5.0 mL) was added, followed by addition of the benzylchlorobis(triphenylphosphine)palladium (II) catalyst (530 mg, 0.699 mmol). The yellow reaction mixture turned reddish in color and finally to a greenish black. Upon stirring at room temperature for 2 hours, the mixture was diluted with ethyl acetate (250 mL), then washed consecutively with saturated ammonium chloride (3 x 100 mL), 10o potassium fluoride (3 x 100 mL) and brine (100 mL). The organic phase was dried over NaZSOq/activated carbon and submitted to flash chromatography (elution with 40~ ether-petroleum ether), affording a golden brown oil (1.04 g, 43~): 'H NMR (CDC13) 8 7.20(ABq,2H), 6.85(ABq,2H), 5.38(hept,lH), 3.83(s,2H), 3.79(s,3H), 1.43(d,6H).
Preparation of 3-(4-Methoxy-benzyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione one-quarter hydrate In a manner similar to Example 9, Step 2, the above indicated intermediate (350 mg, 1.34 mmol) in anhydrous isopropyl alcohol (7.0 mL) was treated with 2-amino-3,3-dimethyl-butane (272 mg, 2.69 mmol) at room temperature, affarding 124 mg (31~) of the title compound ('H NMR in DMSO-db suggested the presence of amide rotamers in a ratio of approximately 3:1): m.p. 137.4-138.1°C; ; 1H IVMR (DMSO-db)8 8.63(d,lH), 7.16(ABq,2H), 6.87(ABq,2H), 3.90(m,lH), 3.70(s,2H), 1.15(d,3H), 0.84(s,9H); IR (KBr) 3460, 3160, 2980, 2930, 1780, 1730, 1610, 1560, 1510, 1495, 1445, 1430, 1420, 1245, 1190, 1150, 1080, 1030, 775 cnil; MS (m/z) 301 [M'~ .
Elemental analysis for C18H23NO3~0.25 HzO:
Calc'd: C,70.68; H,7.74; N,4.58.
Found: C,70.43; H,7.77; N,4.55.

Example 24 ~~-fl-(4-Methoxv-phenyl)-2-oxo ~rogYl)1-3 ~-dioxo-cyclobut-1 -envy - ( 1 2 ~-trimetrkyl-~rogyl ) -carbam~c acid tert-butyl ester Preparation of 1-ethoxy-2-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione To a homogeneous solution of diethyl squarate (5.00 mL, 33.8 mmol) in anhydrous diethyl ether (250 mL) was added 2-amino-3,3-dimethylbutane (6.80 mL, 50.4 mmol) at room temperature. The resultant mixture was stirred for 1 hour, whereupon all volatiles were removed in vacuo. The residue was triturated with diethyl ether-petroleum ether, filtered and then dried under high vacuum affording 7.29 g (95~) of an off-white solid which was used without further purification.
Preparation of 1-ethoxy-3,4-dioxo-cyclobut-1-enyl-(1,2,2-trimethyl-propyl)-carbamic acid tert-butyl ester To a solution of the above intermediate (7.25 g, 32.2 mmol.) in methylene chloride (85 mL) at room temperature was added sequentially triethylamine (4.49 mL, 32.21 mmol), di-ter~-butyl dicarbanate (14.75 g, 67.6 mmol), and 4-dimethylamino-pyridine. The resultant opaque solution became yellow and homogeneous, and the ensuing reaction proceeded with gas evolution. All volatiles were removed by rotary evaparation and the residue was dried in vacuo, then submitted to flash chromatography (elution with 20~
ether-petroleum ether), affording 9.63 g (93~) of a light yellow oil.

Steu 3 Preparation of {2-[1-(4-Methoxy-phenyl)-2-oxo-propyl)]-3,4-dioxo-cyclobut-1-enyl}-(1,2,2-trimethyl-propyl)-carbamic acid tert-butyl ester In a manner similar to Step 1 of Example 21, was added potassium bis(trimethylsilyl)amide (2.6 mL, 1.30 mmol, 0.5 M in toluene) to a 1:1 mixture of anhydrous diethyl ether (3.5 mL) and anhydrous tetrahydrofuran (3.5 mL). The resultant mixture was cooled to -78°C, whereupon 4-methoxyphenylacetone (0.20 mL, 1.30 mmol), was added. The resultant mixture was warmed to room temperature for 2.5 hours, then cooled to -78°C and cannula transferred to a solution of the above intermediate from Step 2 (456 mg, 1.43 mmol) in diethyl ether (1.2 mL) at -78°C. Upon completed addition, the reaction mixture was warmed to room temperature, stirred for 48 hours, whereupon it was concentrated via rotary evaporation. The residue was then partitioned between methylene chloride (2 x 100 mL) and brine (100 mL). The combined organic phases were dried over Mg2SOq/activated carbon, filtered through a short pad of silica gel (elution with ether), concentrated, then filtered and concentrated to give 310 mg (35~) of the hydroscopic title compound via reiterative crystallization ('H NMR in DMSO-db suggested the presence of keto-enol tautomers in a ratio of approximately 4:1): m.p. 137.4-138.1°C; 1H NMR (DMSO-db)8 11.03(s,lH), 7.07(ABq,2H), 6.88(ABq,2H), 4.65(m,lH), 3.74(s,3H), 2.03(s,3H), 1.40(br s,l2H), 0.96(br s,9H); IR (KBr) 3440, 3080, 2980, 1795, 1755, 1620, 1570, 1525, 1475, 1435, 1370, 1275, 1260, 1155, 1140, 1025, 850, 800, 770 cml; MS (m/z) 444 [(M+H) +]/466 ( M+Na ) ' ] .

WO 00/34230 PCT/US99/286i8 Elemental analysis for CZSHa3NOs Calc'd: C,67.70; H,7.50; N,3.16.
Found: C,66.58; H,7.43; N,3.07.
Example 25 3-(1 1-Dimethyl-2-phenvl-ethylamino)-4-(3 methoxv 8h~ny1) r_vc-_I obut-3-ene-1 - ~-dione Sten 1 Preparation of 3-isopropoxy-4-(3-methoxy-phenyl)-cyclobut-3-ene-1,2-dione The title intermediate was prepared using 3-isopropoxy-4-(tri-n-butylstannyl)-3-cyclobut-3-ene-1,2-dione and 3-iodoanisole in a manner similar to the cited literature method jJ. Org. Chem. 1990, 55, 5359-5364], providing 1.336 g (26~) of a tan solid.
Preparation of 3-(1,1-Dimethyl-2-phenyl-ethylamino)-4-(3-methoxy-phenyl)-cyclobut-3-ene-1,2-dione In a manner similar to Step 2 of Example 9 was prepared the title compound via addition of 1,1-dimethyl-2-phenyl-ethylamine (384 ~.L, 2.44 mmol) to a heterogeneous mixture of the above intermediate (300 mg, 1.22 mmol) in anhydrous ethyl alcohol (5.0 mL). Isolation followed by dxying in vacuo afforded 171 mg (42~) of a white solid:
m.p. 115.8-116.3°C; 'H NMR (DMSO-d6)8 8.47(s,lH), 7.51(m,3H), 7.08(ddd,lH), 3.81(s,3H), 1.80(q,2H), 0.86(q,3H); IR (KBr) 3430, 3150, 2980, 2930, 1770, 1725, 1580, 1460, 1410, 1295, 1225, 1160, 1050, 1025, 875, 770 crri'; MS (m/z) 273 [M'] .
Elemental analysis for C16H19N03:
Calc'd: C,70.31; H,7.01; N,5.13.
Found: C,70.09; H,7.05; N,5.08.

Example 26 3-f(E)-2-(4-Bromo-phenvl)-vinyll-4-(1 2 2-trimethyl-p~pylamino)-cvclobut-3-ene-1,2-dione Stev 1 Preparation of (E)-1-iodo-2-(4-bromophenyl) ethylene To a heterogeneous mixture of chromium (II) chloride (3.98 g, 32.4 mmol) in tetrahydrofuran (40 mL) at 0°C was added via syringe pump over 1 hour (in the total absence of light) 4-bromo-benzaldehyde (1.00 g, 5.40 mmol) and iodoform (4.25 g, 1Ø8 mmol) combined as a homogeneous solution in tetrahydrofuran (20 mL). The cold bath was removed, whereupon a quantitative reaction as indicated occurred within 1 hour. The reaction mixture was diluted with 1:1 ether-hexanes (200 mL) then filtered through a short pad of silica gel, concentrated to a solid tainted with residual iodoform.
Sten 2 Preparation of 4-isopropoxy-3-[(E)-2-(4-bromophenyl)-vinyl]-cyclobut-3-ene-1,2-dione In a manner similar to Step 1 of Example 1 was prepared 298 mg (17~) of the title intermediate.
Stefl 3 Preparation of 3-[(E)-2-(4-bromophenyl)-vinyl]-4 (1.,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione In a manner similar to Step 2 of Example 25 was reacted the above :indicated intermediate (288 mg, 0.898 mmol) and 2-amino-3,3-dimethylbutane (241 ~.L, 1.80 mmol) in anhydrous ethyl alcohol (3.50 mL), affording the title compound (127 mg, 39%) as a hygroscopic yellow solid (1H
NMR (DMSO-db)8 8.87(d,lH), 7.71(m,5H), 7.46(d,lH), 4.02(dq,lH), 1.19(d,3H), 0.90(s,9H); IR (KBr) 3310, 2970, 1760, 1705, 1575, 1480, 1430, 1300, 1220, 1160, 1070, 1005, 975, 875, 820, 800 crnl; MS (m/z) 361/363 [M+].

Elemental analysis for CIBHZOBrN02:
Calc'd: 0,59.68; H,5.56; N,3.87.
Found: 0,59.55; H,5.38; N,3.72.
Example 27 4-d(E)-2-f3 4-Dioxo-2-(1 2 2-trimethyl-x~ropyla_m;no) cvc~obut-1-enyll-vinyl -benzonitrile The title compound was prepared 'via cyano-debromination (Tschaen, Synth. Comm. 1994, 24, 887) of the title compound of Example 26. To a mixture of 3-[(E)-2-(4-bromo-phenyl)-vinyl.]-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione (400 mg, 1.10 mmol) and zinc (II) cyanide (77.8 mg, 01.662 mmol) in DMF (1.20 mL) was added tetrakis(triphenylphosphine) palladium (0)(76.6 mg, 0.0662) under an atmosphere of Argon. The reaction mixture was heated to 100°C, stirred 18 hours, then worked up by dilution with toluene (150 mL), followed by consecutive extraction with ammonium hydroxide (3 x 50 mL) and brine (50 mL). The organic phase was further diluted with ethyl acetate (300 mL), dried over MgS04, filtered through a short pad of diatomaceous earth, and then concentrated onto silica gel. Submission to flash chromatography (multiple gradient elution with ether-petroleum ether) afforded a yellow solid which was triturated with ether-hexanes.
Drying under high vacuum at 60°C yielded the title compound (248 mg, 73$) as a hydroscopic yellow solid (1H NMR in DMSO-db suggested the presence of amide rotamers in a ratio of approximately 4:1): m.p. 240.2-241.0°C; 1H NMR (DMSO-d6)8 8.96(d,lH), 7.83(m,4H), 7.64(d,lH), 7.48(d,lH), 4.03(dq,lH), 1.20(d,3H), 0.90(s,9H); IR (KBr) 3450, 3250, 3290, 2960, 1770, 1725, 1620, 1600, 1500, 1480, 1440, 1405, 1170, 1140, 1080, 980, 825, 755; MS (m/z) 309 [(M+H) +], 331 [ ( M+Na ) + ] .

Elemental analysis for Cl9HZON2Oz Calc'd: 0,74.00; H,6.54; N,9.08.
Found: 0,73.59; H,6.51; N,8.83.
The smooth muscle (bladder) 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 COz asphyxiation and then euthanized by cervical dislocation. The bladder is removed into warm (37°C) physiological salt solution (PSS) of the following composition (mM): NaCl, 118.4; KC1, 4.7;
CaCl2, 2.5; MgSOq, 4.7; HzO, 1.2; NaHC03, 24.9; KHZP04, 1.2;
glucose, 11.1; EDTA, 0.023; gassed with 95~ OZ; 2/5o CO2; 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 ~.4M
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 15 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 -4$-each compound or vehicle concentration during the last minute of a 30 minute challenge.
The isometric force developed by the bladder strips is measured using a concentration required to elicit 50%
inhibition of pre-drug contractile activity (ICso concentration) and is calculated from this concentra-tion-response curve. The maximum percentage inhibition of contractile activity evoked by a test compound is also recorded for concentrations of test compound less than or equal to 30 ~.~M.
The smooth muscle (aorta) relaxing activity of the compounds of this invention was established in accordance with standard pharmaceutically accepted test procedures with representative compounds as follows:
Male Sprague-Dawley rats (150-200 g) are rendered unconscious by COZ asphyxiation and then euthanized by cervical dislocation. The thoracic aorta is removed into warm (37 deg.C) physiological salt solution (PSS) of the following composition (mM):NaCl, 118.4; KC1, 4.7; CaClz, 2 . 5 ; MgS04 ~ 7H20, 1. 2 ; NaHC03 , 24 . 9 ; KHZP04, 1. 2 ; glucose, 11.1; EDTA, 0.023; gassed with 95$ O2/5~ CO2; pH 7.4. The aorta is cleaned of fat and loose adventitia and cut into rings 3-4 mm in width. The rings are subsequently suspended between two stainless steel wire tissue holders in a 10 ml tissue bath. One wire tissue holder is attached to a fixed hook while the other is attached to an isometric force transducer. Resting tension is set at 1 g. The tissues are to recover for a period of 60 mins. prior to beginning the experiment. Tissues are challenged with PSS
containing 25 mM KC1 to elicit a contracture. The tissues are then washed repeatedly with fresh PSS over a period of 30 mins. and allowed to recover to baseline tension. PSS
containing 30-35 mM KC1 is then introduced into the tissue bath to evoke a contracture that is allowed to stabilize for not less than 45 minutes. (Other stimuli such as norepine-phrine, PGF2a, histamine, angiotensin II, endothelin or PSS containing 80 mM KC1 may also be used to evoke a contracture as necessary). Increasing concentrations of test compound or vehicle are then added to the tissue bath in a cumulative fashion.
Isometric force development by the aortic rings is measured using a force transducer and recorded on a polygraph. The percentage inhibition of contractile force evoked by each concentration of a given test compound is used to generate a concentration-response curve. The concentration of test compound required to elicit 50~
inhibition of pre-drug contractile force (ICso concentration) is calculated from this dose-response curve.
[Log concentration versus response curves are approximately linear between 20~ and 80~ of the maximum response. As such, the ICso concentration of the drug is determined by linear regression analysis (where x=log concentration and y=~ inhibition) of the data points in the 20~ to 80o region of the curve]. The maximum percentage inhibition of contractile force evoked by a test compound is also recorded for concentrations of test compound c or = to 30 ~M. Data collected from 2 animals are averaged for primary screens.
The results of these studies are shown in Table I.

Table I
Ex. n Bladder Tissue n Aorta Tissue Ratio Aorta No. ICSO (~.lM) ICso (~.tM) ICSo Bladder ICS

1 2 1.20.26 2 3.250.35 2.71 2 4 2.50.49 2 37.656.05 15.1 3 4 11.99,2.4 3 46.27.8 3.85 4 4 9.51+1.8 5 24.2+6.3 2.56 5 4 1=9.75+4.4~* -- --6 2 26.90.3 -- --7 2 1=7.4+5.70 -- --8 1 11.2 -- --9 3 1=27.28.6~ -- --10 2 15.6+3.7 -- --11 2 1=34.2+6.0~ -- --12 2 1=26.0~2.2~ -- --21 3 16.26.82 -- --22 3 25.7+1.1 -- --23 2 1=10.25.6~ -- --24 1 15.9 -- --25 2 1=30.35+0.52~* -- --26 3 15.6+8~* -- --27 5 2.94,0.62 -- --*Percent ~1M
inhibition at Hence, the compounds of this invention are selective for bladder tissue and have a pronounced effect on smooth muscle contractility and are useful in the treatment of urinary incontinence, irritable bladder and bowel disease, asthma, stroke, and similar diseases as mentioned above, which are amenable to treatment with potassium channel activating compounds by administra-tion, orally, WO 00/34230 PCT/US99/28b18 S parenterally, or by aspiration to a patient in need thereof .

Claims (59)

What is claimed is:

1. A compound having the Formula (I):

wherein:
R1 , R2 , and R3 , are, independently, hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms (optionally substituted with halogen), cycloalkyl of 3 to 10 carbon atoms, -OR7 , amino, alkylamino of 1 to 10 carbon atoms, -SO3H, -SO2NH2, -SONH2, -NHSO2R7, -SO2R7 , carboxyl, aryl of 6 to 12 carbon atoms or aroyl of 7 to 12 carbon atoms;
A is a moiety selected from the group consisting of a bond, -CH2-, -CH=CH- and -CHCOR6 ;
W is selected from the group consisting of carbon and nitrogen and wherein the carbon atom may be optionally substituted with -R1 , -R2 and -R3 ;
R4 is a alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, wherein the aryl group is optionally substituted with alkyl of 1 to 10 carbon atoms, nitro, halogen cyano, -OR7, trifluoromethyl or trifluoromethoxy;
R5 is hydrogen, alkyl of 1 to 10 carbon atoms, formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, -SO2R7, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms;
R6 is alkyl of 1 to 10 carbon atoms, or aryl of 6 to 12 carbon atoms;
R7 is a alkyl of 1 to 10 carbon atoms (optionally substituted with halogen);
aroyl is benzoyl and naphthoyl optionally substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF3, and phenyl;
aryl is naphthyl, phenyl or phenyl optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms;
with the following provisos that A is not a bond and W is not a carbon bearing a hydrogen;
a) when R1 and R2 are H; R3 is selected from the group consisting of H, 4-methyl, 4-chloro, 4-nitro and 4-methoxy;
and R4 and R5 are simultaneously methyl or ethyl;

b) when R1 , R2 , R3 and R5 are H; and R4 is butyl;
c) when R1 , R2 and R5 are H; R3 is 4-halo and R4 is alkyl of 1 to 4 carbon atoms;
d) when R1 is selected from the group consisting of H, 2-methyl, 2-ethyl and 2-methoxy; R2 and R5 are H; R3 is 4-dimethylamino and R4 is 2-propyl; or pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 wherein A is a bond and W is nitrogen or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 wherein W is a carbon bearing a hydrogen and A is -CH=CH- or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1 wherein W is nitrogen and A is -CH=CH- or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1 wherein W is a carbon bearing a hydrogen and A is -CH2- or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 wherein W is nitrogen and A is -CH2- or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 wherein W is a carbon bearing a hydrogen and A is or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 wherein W is nitrogen and A is or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 wherein A is a bond, and W is a carbon bearing a hydrogen or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 1 wherein A is a bond, W is a carbon bearing a hydrogen, and R3 is alkoxy of 1 to 10 carbon atoms and or a pharmaceutically acceptable salt thereof.

11. The compound of Claim 1 which is 3-(1,1-dimethyl-2-phenyl-ethylamino)-4-(4-methoxy-phenyl)-cyclobut-3-ene 1,2-dione or a pharmaceutically acceptable salt thereof.

12. The compound of Claim 1 which is 3-(1,1-dimethyl-propylamino)-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

13. The compound of Claim 1 which is 3-(isopropyl-methyl-amino)-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

14. The compound of Claim 1 which is 3-(4-methoxy-phenyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

15. The compound of Claim 1 which is 3-(4-methoxy-phenyl)-4-[2-(3-trifluoromethyl-phenyl)-ethylamino]-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

16. The compound of Claim 1 which is (-)-3-(4-methoxy-phenyl)-4-((R)-1-phenyl-ethylamino)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

17. The compound of Claim 1 which is 3-(4-methoxy-phenyl)-4-(2-phenyl-propylamino)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

18. The compound of Claim 1 which is 3-[2-(4-tert-butyl-phenyl)ethylamino]-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

19. The compound of Claim 1 which is 4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

20. The compound of Claim 1 which is 3-(4-trifluoro-methyl-phenyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

21. The compound of Claim 1 which is 4-(4-trifluoromethyl-phenyl)-3-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

22. The compound of Claim 1 which is 3-(1,1-dimethyl-propylamino)-4-(pyridin-3-yl)-cyclobut-3-ene-1,2-dione hydrochloride or a pharmaceutically acceptable salt thereof.

23. The compound of Claim 1 which is 3-(1,1-dimethyl-propylamino)-4-(3,4-dimethoxy-phenyl)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

24. The compound of Claim 1 which is 3-(1,1-dimethyl-2-phenyl-ethylamino))-4-(3,4-dimethoxy-phenyl)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

25. The compound of Claim 1 which is 3-(1,1-dimethyl-propylamino)-4-(3-bromo-4,5-dimethoxy-phenyl)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

26. The compound of Claim 1 which is 3-(1,1-dimethyl-2-phenyl-ethylamino)-4-(3-bromo-4,5-dimethoxy-phenyl)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

27. The compound of Claim 1 which is 3-(1,1-dimethyl-propylamino)-4-(3-bromo-4,6-dimethoxy-phenyl)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

28. The compound of Claim 1 which is 3-(1,1-dimethyl-2-phenyl-ethylamino)-4-(3-bromo-4,6-dimethoxy-phenyl)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

29. The compound of Claim 1 which is 3-(1,1-dimethyl-propylamino)-4-(2-bromo-4,6-dimethoxy-phenyl)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

30. The compound of Claim 1 which is 3-(1,1-dimethyl-2-phenyl-ethylamino)-4-(2-bromo-4,6-dimethoxy-phenyl)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

31. The compound of Claim 1 which is 3-[2-oxo-1-(4-trifluoromethyl-phenyl)-propyl]-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione or a pharmaceuti-cally acceptable salt thereof.

32. The compound of Claim 1 which is 3-(4-bromo-phenyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

33. The compound of Claim 1 which is 3-(4-methoxy-benzyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione one quarter hydrate or a pharmaceutically acceptable salt thereof.

34. The compound of Claim 1 which is {2-[1-(4-methoxy-phenyl)-2-oxo-propyl)]-3,4-dioxo-cyclobut-1-enyl)-(1,2,2-trimethyl-propyl)-carbamic acid tert-butyl ester or a pharmaceutically acceptable salt thereof.

35. The compound of Claim 1 which is 3-(1,1-dimethyl-2-phenyl-ethylamino)-4-(3-methoxy-phenyl)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

36. The compound of Claim 1 which is 3-[(E)-2-(4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione or a pharmaceutically acceptable salt thereof.

37. The compound of Claim 1 which is 4-{(E)-2-(3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-vinyl}-benzonitrile or a pharmaceutically acceptable salt thereof.

38. A pharmaceutical composition for treating or inhibiting disorders associated with smooth muscle contraction, via potassium channel modulation in warm-blooded animals in need thereof, which comprises administering to said warm-blooded animals, an effective amount of a compound of general Formula (II) wherein:

R1 , R2 , and R3 , are, independently, hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms (optionally substituted with halogen), cycloalkyl of 3 to 10 carbon atoms, -OR7 , amino, alkylamino of 1 to 10 carbon atoms, -SO3H, -SO2NH2, -SONH2, -NHSO2R7, , -SO2R7 , carboxyl, aryl of 6 to 12 carbon atoms or aroyl of 7 to 12 carbon atoms;
A is a moiety selected from the group consisting of a bond , -CH2- , -CH=CH - and -CHCOR6 ;
W is selected from the group consisting of carbon and nitrogen and wherein the carbon atom may be optionally substituted with -R1 , -R2 and -R3 ;
R4 is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms wherein the aryl group is optionally substituted with alkyl of 1 to 10 carbon atoms cyano, -OR7, , trifluoromethyl or trifluoromethoxy;
R5 is hydrogen, alkyl of 1 to 10 carbon atoms, formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, , -SO2R7, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkenoyl of 8 to 12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms;
R6 is a chain alkyl of 1 to 10 carbon atoms, or aryl of 6 to 12 carbon atoms;
R7 is alkyl of 1 to 10 carbon atoms (optionally substituted with halogen);
aroyl is benzoyl and naphthoyl optionally substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF3, and phenyl;
aryl is naphthyl, phenyl or phenyl optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms;
or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

39. A pharmaceutical composition according to claim 38 wherein W is nitrogen, A is a bond or a pharmaceutically acceptable salt thereof.

40. A pharmaceutical composition according to claim 38 wherein W is a carbon bearing a hydrogen and A is -CH=CH- or a pharmaceutically acceptable salt thereof.

41. A pharmaceutical composition according to claim 38 wherein W is nitrogen and A is -CH=CH- or a pharmaceutically acceptable salt thereof.

42. A pharmaceutical composition according to claim 38 wherein W is a carbon bearing a hydrogen and A is -CH2- or a pharmaceutically acceptable salt thereof.

43. A pharmaceutical composition according to claim 38 wherein W is nitrogen and A is -CH2- or a pharmaceutically acceptable salt thereof.

44. A pharmaceutical composition according to claim 38 wherein W is a carbon bearing a hydrogen and A is or a pharmaceutically acceptable salt thereof.

45. A pharmaceutical composition according to claim 38 wherein W is nitrogen and A is or a pharmaceutically acceptable salt thereof.

46. A pharmaceutical composition according to claim 38 wherein W is a carbon bearing a hydrogen and A is a bond or a pharmaceutically acceptable salt thereof.

47. A pharmaceutical composition according to claim 38 wherein W is a carbon bearing a hydrogen, A is a bond and R3 is alkoxy of 1 to 10 carbon atoms or a pharmaceutically acceptable salt thereof.

48. A method of treating or inhibiting disorders associated with smooth muscle contraction, via potassium channel modulation in warm-blooded animals in need thereof, which comprises administering to said warm-blooded animals, an effective amount of a compound of general Formula (II):

wherein:
R1 , R2 , and R3 , are, independently, hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms (optionally substituted with halogen) cycloalkyl of 3 to 10 carbon atoms, -OR7 , amino, alkylamino of 1 to 10 carbon atoms, -SO3H, -SO2NH2, -SONH2, -NHSO2R7, , -SO2R7 , carboxyl, aryl of 6 to 12 carbon atoms or aroyl of 7 to 12 carbon atoms;
A is a moiety selected from the group consisting of a bond, -CH2-, -CH=CH- and -CHCOR6 ;
W is selected from the group consisting of carbon and nitrogen and wherein the carbon atom may be optionally substituted with -R1 , -R2 and -R3 ;
R4 is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, wherein the aryl group is optionally substituted with alkyl of 1 to 10 carbon atoms, nitro, halogen, cyano, -OR7, , trifluoromethyl or trifluoromethoxy;

R5 is hydrogen, alkyl of 1 to 10 carbon atoms, formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, , -SO2R7, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms;
R6 is alkyl of 1 to 10 carbon atoms, or aryl of 6 to 12 carbon atoms;
R7 is alkyl of 1 to 10 carbon atoms (optionally substituted with halogen);
aroyl is benzoyl and naphthoyl optionally substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF3, and phenyl;
aryl is naphthyl, phenyl or phenyl optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms;
or a pharmaceutically acceptable salt.

49. The method of Claim 48 in which the smooth muscle adversely contracting causes urinary incontinence.

50. The method of Claim 48 in which the smooth muscle adversely contracting causes irritable bowel syndrome.

51. A method according to claim 48 wherein W is nitrogen and A is a bond or a pharmaceutically acceptable salt thereof.

52. A method according to claim 48 wherein W is a carbon bearing a hydrogen and A is -CH=CH- or a pharmaceutically acceptable salt thereof.

53. A method according to claim 48 wherein W is nitrogen and A is -CH=CH- or a pharmaceutically acceptable salt thereof.

54. A method according to claim 48 wherein W is a carbon bearing a hydrogen and A is -CH2- or a pharmaceutically acceptable salt thereof.

55. A method according to claim 48 wherein W is nitrogen and A is -CH2- or a pharmaceutically acceptable salt thereof.

56. A method according to claim 48 wherein W is a carbon bearing a hydrogen and A is or a pharmaceutically acceptable salt thereof.

57. A method according to claim 48 wherein W is nitrogen and A is or a pharmaceutically acceptable salt thereof.

58. A method according to claim 48 wherein W is a carbon bearing a hydrogen and A is a bond or a pharmaceutically acceptable salt thereof.

59. A method according to claim 48 wherein W is a carbon bearing a hydrogen, A is a bond and R3 is alkoxy of 1 to 10 carbon atoms or a pharmaceutically acceptable salt thereof.