CA2205307A1 - Diaminocyclobutene-3,4-diones - Google Patents

Abstract

The compound of formula (I), wherein R1 and R2 are, independent from each other, hydrogen, C1-10 straight chain alkyl, C1-10 branched alkyl, or C3-10 cyclic or bicyclic alkyl; R3 is an acyl substituent selected from the group consisting of formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms; A is selected from the group consisting of (a), wherein R4 is hydrogen, C1-6 alkyl, C1-6 perfluoroalkyl, C1-6 alkoxy, C1-6 perfluoroalkoxy, amino, C1-6 alkylamino, C2-12 dialkylamino, C1-6 alkylsulfonamido, alkylcarboxamido containing 2 to 7 carbon atoms, nitro, cyano, carboxyl; or, A
is a phenyl group of formula (b), wherein R5 and R6, independent from each other, are selected from the following: cyano, nitro, amino, C1-6 alkyl, C1-6 perfluoroalkyl, C1-6 alkoxy, C1-6 perfluoroalkoxy, C1-6 alkylamino, C2-12 dialkylamino, sulfamyl, C1-6 alkylsulfonamido, C6-12 arylsulfonamido, alkylcarboxamido containing 2 to 7 carbon atoms, arylcarboxamido containing 7 to 13 carbon atoms, C2 to C6 alkanoyl, C1-6 alkylsulfonyl, C1-6 perfluoroalkylsulfonyl, C6-12 arylsulfonyl, chloro, bromo, fluoro, iodo, 1-imidazolyl, carboxyl or hydrogen; or a pharmaceutically acceptable salt thereof, are smooth muscle relaxants.

Description

CA 0220~307 1997-0~-14 wo 96/15103 1 ~I/U~ 1.t1~5 DlAMTNOCYClOBUTENE-3. 4-DION~
B ~ of Invention The present invention relates to novel 1, 2-diamino derivatives of u~,l~utu.,c 3-4-diones having ph~tm~nlngical activity, to a process for their preparation, to ; containing them, and to their use in the treamment of disorders associated with smooth muscle contraction; via potassium channel mn~in~ inn Such disorders include, but are not limited to: urinary ;.~v~ , ,- e, 10 Il~l,~t~ iVIl, asthma, premature labor, irritable bowel syndrome, congestive heart failure, angina, and cer~bral vascular disease.
Stemp et al. disclose a class of amino substituted uy. l.~.,.,". .l;, ."~ derivatives - of chromans described as having blood pressure lowering activity and brnnrhr"lil activity in EP-426379-A2. Several series of l-amino-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-2-phenoxyalkylamino derivatives aredisclosed by Nohara et al. in US Patent 4,673,747.
The syntheses of va~iously substituted 1,2-diamino-~:ycluuu~.. ~,-3,4-diones are described in the following p~ ir~tinn~ Tietze et al., Chem Ber. 1991,124, 1215;
Tietze et al., Bioconjuga~e Chem. 1991, 2, 148; Ehrhardt et al., Chem. Ber. 1977, 110, 2506, and Neuse et al., Liebigs Ann. Chem. 1973, 619. For example, Neuse et al.
discloses 1-phenylamino-2-dimethylamino-cyclobut-1-ene-3,4-dione. The 25 UOIII~JOUIII15 of the present invention differ from the Neuse et al. compound in that they are N-acylated and they are useful as smooth muscle relaxants.
Descr;~tion of The Invention 3û In d,-,ullld,lce with the present invention, there is provided a group of ~...'''I'V'''''l~ IC~)lC:>C~ i by the formula (I):

CA 0220~307 1997-0~-14 0~0 N N
R3 R2 (1) wherein R 1 and R2 are;; ~ from each other, hydrogen, C 1 1 o st}aight chain alkyl, C1 1o b}anched alkyl, or C3-10 cyclic o} bicyclic S alkyl;
R3 is an acyl substituent selected f}om the g}oup consisting of fo}myl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alhylaulr~ yl of I to 7 carbon atoms~ aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms~
~Uylaulrull~l of 6 to 12 carbon atoms, a}ylalkanoyl of 8 to 12 carbon atoms o} alylalhylaulr~, lyl of 7 to 12 carbon aroms;
A is s~ecte~ f}om th~ group consisting of ..
.~ ~

CA 02205307 1997-0~-14 WO 9G~15103 J ~ s R4 ~ R4--~N ~ R4--~
H Sss H R,, ~J/N~--R4 R4 N~ R4 ( ~
--R4 N~ - R4 ~--R4 N~--R4 N~
wherein:
R4 is hydrogen, C1 6 alkyl, C1 6 periluoroalkyl, C1 6 alkoxy, Cl 6perfluoroalkoxy,amino, Cl 6alkylamino, C2 l2 dialkylamino,C1 6alkyl~1fon~rni~ aLkyl-~,~ bv~ ;d~ containing 2 to 7 carbon atoms, nitro, cyano, carboxyl;
or, A is a phenyl group of th~ following formula:

CA 0220~307 1997-0~-14 wo 96/15103 1 R~;

wherein:
Rs and R6, ;,-A. 1" --1- .~1 from each other, are selected from the following: cyano, nitro, amino, C1 6 alkyl, C1 6 perfluoroalkyl, Cl 6 alkoxy, C1 6 perfluoroalkoxy, Cl-6 alkylamino, C2-12 dialkylamino, sulfamyl, C1 6alkyls~lf~ m~ C6 12 aryisl~lfon:~miri(~, alkyl~,~u l,o,~ .id~, containing 2 to 7 carbon a~oms, u~l~,cub~JA~llli~ containing 7 to 13 carbon atoms, C2 6 alkanoyl, Cl-6 al~yl,ulru..~l, Cl-6 perfluoro-alhyl,ul~ l, C6 12 ~u~l~ulr~--yl, chloro, bromo, fluoro, iodo, I-imidazolyl, carboxyl or hydrogen;
or a rl. - ,. ''~..I;. ,.lly acceptable sait thereof A preferred aspect of this invention includes ..~.",1..,"".1~ of formula (1) wherein:
Rl and R2 are as stated above;
A is selected from the following:

.

CA 0220~307 1997-0~-14 wo 96/15103 ~ l >S

R4--~3 R4--~N N~
,~--R4 N~bR4 wherein: -R4 is as stated above;
or, A is a phenyl group of the following formula:
[~?,--Rs wherein:
Rs and R6, ;,.~ -r from each other, are selected from the following: cyano, nitro, amino, chlo}o, bromo, fluoro, iodo, 1-imidazolyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkanoyl . of 2 to 6 carbon atoms, carboxyl or hydrogen;
.. . . ..
or a ~ y acceptable salt thereof.

CA 0220~307 1997-0~-14 WO96/lSl03 r~ ~J,~ s The most preferred aspect of this invention includes cr~mro~ c of formula (I) wherein:
Rl and R2 are as stated above;
S A is selected from the following:
R4--~3 R4 ~ N~
N~ R4 ~ - R4 wherein:
R4 is as stated above;
or, A is a phenyl group of the fol~owing forrnula:
~ Rs 15 wherein:
Rs and R6, in~pcn~i~ont from each other, are selected from the following: cyano, nitro, amino, chloro, bromo, fluoro, iodo, 1-imidazolyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkyl of I to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms, carboxyl or hydrogen;
~a~ r~lyaccept~le~ hereof CA 02205307 1997-0~~14 PCTIUS9~/13125 wo 96115'L03 It is understood that the definition of the ~nmrol~ntlc of formula (I), when Rl,R2, R3, R4. or R5 contain a~y~ h, carbons, encompass all possible ~ vi:~ul~
and mixtures thereof which possess the activity discussed below. In particular, it s racemic ~ ,r~ ;---,c and any optical isomers which possess the 5 indicated activity. Optical isomers may be obtained in pure form by standard separation techniques or ~ specific synthesis.. The c~ v~ of this invention, throughout this ~I ~- ;ri ~li..", are c~lui~lCIILly name as 3,4-diones or 1,2-diones. The p~ ly acceptable salts of the basic comr~lnrlc of this invention are those derived from such organic and inorganic acids as: lactic, citric, 10 acetic, tartaric, succinic, maleic, malonic, hydrochloric, ~Iy~L`vblv-ll;c, l~l.o~l.l,.ll;~
nitric, su~furic, m~-lhtln~-clllfonic, and similarly known acceptable æids. Where R3, R4, or Rs is a carboxyl group, salts of the CUIIIIJVUII~iS of this invention may be for.med 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 formu~a (I). More p~lLi-,ul.,lly, the UVIIII./VUIIIlS of fortnula (I) may be prepared by reacting a compound of formula (lla):
0~0 N X
~- Ra3 (l:Ia) wherein X is a leaving group, for example, methoxy, ethoxy, isopropoxy, halogen or a similar leaving group and Al is A and Ra3 is R3, as defined ll~,lc;llb~rvl~ or a group of atoms convertible thereto, with a compound of formula (IV):

~Ra1 HN~
- Ra2 (IV) CA 0220~307 1997-0~-14 wo 96/15103 Y~ JII.51 wherein Ral and Ra2 are Rl and R2, respectively, as defined ~ ' ~ G or a group of atoms convertible thereto and, where d~lv~ Lc, converting Al into A or converting Ral into Rl or converting Ra2 into R2, followed by ~ ,yLl~iv.l if S necessary and, where desired, converting a compound having formula (I) into a ~ .1, . " . ~- ~ .., ;. ~lly acceptable salt thereof or converting a salt of a compound having fommula (I) into a compound having formula (1).
The l,VIII~U llds having formula (IIa) may be prepared by reaction of a 10 compound of formula (II):
X~O
X (II) where X is as defined above with a compound of formula (III):
Al NH2 (III) wherein Al is as defined above, followed by acylation to provide Ra3. Of course,acylation may also be conducted after reaction of the A 1 substituted compound with 20 HNRalRa2.
The reactions mentioned above may be carried out in a solvent such as ~r~tr,nitrilr methanol or ethanol at elevated or ambient t~.llly~,lalul~.
As mentioned previously, the compounds of formula (I) and their ly acceptdble salts have been found to relax smooth muscle. They are therefore useful in the treatment of disorders associated with smooth muscle cnnn~c~ir,n disorders involving excessive smooth muscle contraction of the urinary trdct (such as ;~ c), or of the gastro-intestinal tract (such as irritdble bowel30 syndrome), asthma, and hair loss. rulill~ vlc, the ~,VIII~IUUIId:~ of formula (I) are CA 0220CV307 1997-0Cv-14 wo 96115103 r ~ ., uv.v11~1~5 _9_ active as potassium channel activators which render them useful for treatment ofperipheral vascular disease, llyl/.,.tu.~iol~, congestive heart failure, stroke, anxiety, cerebral anoxia and othe~ ~1"... uA~ ; vv dlsorders.
The present invenion acculdi,l~ly provides a p~ lviU~II C~
which comprises a compound of this invention in c.. l.;.. ,,l;.. or associauion with a ,l. . ", . ~ 11y acceptable carrier. In particular, the present invention provides a ... ;r ~1 C ... ~ ;.... which comprises an effective amount of a compound of this invention and a ~,1,-.,., -- ~../;. ~11y acceptable carrier.

The ~,UIlllJo~i~iulls are preferably adapted for oral ~ n;~ However, they may be adapted for other modes of :I iminictr:ltion for example, parenteral~,l. " ...;~l . ,.l ;f~n for patients suffering from heart failure.
In order to obtain cul~Sia~ll-,y of adl~ Lion, it is preferred that a c-rlmrf.cition 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 Ihe 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 ~ of the present invenuon carl be avllli--i~t~"~d orally at a dose range of about 0.01 to 100 mglkg or preferably at a dose range of 0.1 to 10 mg/kg. Such comrl~citil~nc may be ~ d from I to 6 imes a day, more usually frvm 1 to 4 times a day.
The ~ ~ of the invention may be formulated with ~,UII~ I
excipients, such as a filler, a ~ 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 antilly~ agents, diuretics and ,~-blocking agents.
The present invention further provides a compound of the invenion for use as an actdve therapeuic substance. ('l~mro--n iC of formula (I) are of paricular use in the induction of smooth muscle relaxation.
.

CA 0220~307 1997-0~-14 wo 9611~103 ~ 2 The present inYention further provides a method of treating smooth muscle disorders in mammals including man, which comprises ~ ;..c to the afflicted mammal an effective amount of a compound or a ~ cr mrr~ci ti r n of the invention.
The fol~owing examples are presented to illustrate rather than limit the methods for production of ~cL/lc:~GllL~livc {'~ r" .-1~ of the invention.
F.~AMPLE I
10 . N-~4-Cvano-Dhenvl~-N-r3.4-dioxo-2-(1.2,2-trirnethvl . o., ~la cvclobut-l-envll ~. v, , !~ 0 4-AIl~i~wl~ ile (17.58 g, 149 mmol) was added to a solution of 3,4-diethoxy-3--,yul~u.~ , 1,2-dione (25.31 g, 149 mmol) in absolute ethanol (450 mL).
The mixtu}e was heated at reflux ovemight and the resulting suspension filtered hot to remove a small amount of a dirty yellow solid (discarded). The filtrate was gradually ~,u ' to afford several crops of 4-(3,4-dioxo-2-ethoxy-cyclobut- I-enylamino)-b~n7nnitnle, as a bright yellow solid, which were collected by filtration and combined. Yield: 29.11 g (81%): IH NMR (DMSO-d6): ~ 11.07 (s, lH), 7.81 (d, 2H), 7.56 (d, 2H), 4.79 (q, 2H), 1.46 (t, 3H).
To the product of the preceding paragraph (13.00 g, 53.7 mmol) in ethanol (360 mL) was added 2-amino-3,3-dimethylbutane (7.2 mL, 54 mmol). The mixture was heated at reflux overnight. Gradual ,_"..,,"II,.li~m of the reaction solution afforded two crops of 4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-bPn7nnitt~ as a yellow precipitate, which were collected by filtration and combined. Yield: 11.34 g (71%): IH NMR (DMSO-d6): ~ 9.89 (s, 1EI), 7.78 (d, 2H), 7.72 (d, lH), 7.60 (d, 2H), 3.96 (m, lH), 1.18 (d, 3H), 0.91 ~s, 9H).
To a solution of the product of preceding paragraph (1.20 g, 4.04 mmol) in N,N-di~ lyl~lll~ e (36 rnL) was added, in one portion, sodium hydride (as a 60% dispersion in mineral oil; û.179 g, 4.48 mmol). The frothy suspension was stirred at room ~ ulci for 15 minutes and then at 0C for an additional hour.
Propionic anhydride (0.57 mL, 4.45 mmol) was added and t~e reaction mixture was CA 0220~307 1997-0~-14 wo 96rlsl03 . ~ S

stirred at 0C fo} 15 minules and then allowed to warm to room L~ LUIG. Afte}
stirring overnight, the }eaction mixtu}e was l The resulting }esidue was taken up in methylene chloride and washed with aqueous sodium IV;~ VV~ V7 brine and wate}. 'LAhe o}ganic laye} was dried (Na2SO4) and ~ ", ~ ~l to afford a yellow 5 foam which was putified by u~ ' .y (cH3oH/cH2cl2) and ttituration (Et2O) to affo}d 0.68 g (48%) of N-(4-cyano-phenyl)-N-[3,4-dioxo-2-(122,2-trimethyl-.u~yllll;--o)-cyclobut-l-enyl]-~lu~ as a light yellow solid: mp 211-214C
; IH NMR (CDCI3): O 7.81 (d, 2H), i;50-7.42 (m, 3H), 4.28 (m, iHj, 2.18 (m, 2H),1.26 (d, 3H), 1.10 (t, 3H), 1.~0 (s, 9H). IR (KB}): 3330, 2230, 1800, 1740, 1690, 1620 cm-l; MS (m/z) 353 (M+), Elemental analysis fo} C2UH23N3o3 Calc'd: C, 67.97; H, 6.56; N, 11.89.
Found: C, 67.77; H, 6.35; N, 11.87.
EX~MPl.F. 2 N-(4-Cvano~nvhenvl~-N-r3.4-dioxv-2-(1.2.2-trim~thvl v.
CVClObut-l -envl l 1,. .., ~ F
To a solution of the ' ~.~ p}oduced in Eixample 1, second paragraph (1.20 g, 4.04 mmol) in N,N-~il.l~.lly!r " .,.~ ,5 (36 rnL) was added, in one portion, sodium hydride (as a 60% dispe}sion in mine}al oil; 0.178 g, 4.45 mmol). The frothy suspension was stirred at }oom ~ r fo} 15 minutes and then at 0C fo} an addiional hour. Benzoic anhydtide (1.01 mL, 4.46 mmol) was added and the }eaction mixtu}e was stirred at 0C for 15 minutes and then allowed to warm to room L~ Uulc. After stirring overnight, the reaction mixture was c~ The }esulting }esidue was taken up in methylene chloride and washed with aqueous sodium IviC~lvVll~liC~ brine and water. The organic laye} was dried (Na2SO4) andc~ cc~ Lcd tO affo}d a yellow foam which was purified by C~ Y
(CH30H/CH2CI2) and tritu}ation (diethyl ethe}) to affo}d 0.71 g (44%) of p}oduct as a pale yellow solid: mp 229-231C; IH NMR (CDCI3): O 7.61-7~22 (m, 9H), 7.77 (d, lH), 4.37 (m, lH), 1.28 (d, 3H), 1.02 (s, 9H). IR (KB}): 3300, 2240, 1790,1730, 1675,1610cm~l;MS(m/z)401 (M+).

CA 0220~307 1997-0~-14 Wo 96/15103 ~ JI~ S

Elernental analysis for C24H23N3O3 Calc'd: C, 71.80; H, 5.74; N, 10.47.
Found: C, ?1.49; H, 5.91; N, 10~18.
FXAMpl,E 3 N-(4-C~ N-r3.4~dioxo-2-(1.2.2-trimethvl. vu~.a )-cvclobut-l-envll-met~~~ '^ '-To a solution of the ' of Example 1, second paragraph (1.20 g, 4.04 mmol) in N,N-vi~ l r ~ (36 mL) was added, in one portion, sodium hydride (as a 60% dispersion in mincral oil; 0.178 g, 4.45 mmol). The frothy suspension was stirred at room t~ for 15 minutes and then at 0C for an additional hour. M,-th ~r~clllfonic anhydride (0.82 g, 4.71 mmol) was added and the reaction mixture was stirred at 0C for 15 minutes and then allowed to warm to room ~ U~. After stiIring overnight, the rcaction mixture was ~ ".lr~l The resulting residue was taken up in methylene chloride and washed with aqueous sodium l~h~IbVII~IL~ brine and water. The organic layer was dried (Na2SO4) and c~ d to afford a yellow foam which was purified by clll~ -dLv~
(CH30H/CH2CI2) and trituration (diethyl ether) to afford 0.71 g (47%) of product as an off-white solid: mp 190-191C; IH NMR (CDCI3): O 7.79 (d, 2H), 7.54 (d, 2H), 6.77 (d, lH), 4.29 (m, lH), 3.24 (s, 3H), 1.24 (d, 3H), 0.96 (s, 9H). IR (KBr): 3350, 2220,1800,1725, 1610 cm-l; MS (m/z) 375 (M+).
Elemental analysis for ClgH2lN3O4S :
. Calc'd: C, 57.58; H, 5.64; N, 11.19.
Found: C, 57.60; H, 5.61; N, 11.10.

- = ~ N-(4-C; ' ~-N-r3.4-dioxo-2-(1,2.2-trime~hvl-1,.~, cvclobut-l-envll-formamide To a solution of the ;"~ .".f.1; ~- of Example 1, second paragraph (1.20 g, 4.04 mmol) in N~N-dil~l~,Lllyl~vllll~llll;d~ (36 mL) was added, in one portion, sodium , hydride (as a 60% di~persion in miheral oil2 0.178 g, 4.45 mmol). The frothy CA 0220~307 1997-0~-14 096~15103 , ~/.J~I.fl~s -13- ~
suspension was stirred at ~ 1'- r. for 15 minutes and then at 0C for an additional hour. T.irlhu~ r... ;~ anhydride (0.75 mL. 4.46 mmol) was added and the reaction mixture was stirred at 0C for 15 minutes and then allowed to warm to room t~ Au~,la~ . After stirting overnight, the reaction mixture was 5 ~,, . ,l,,,~. l The resulting residue was taken up in methylene chloride and washed with aqueous sodium bi-,~bu~L~i and water. Recovered statting material, which Ul~.,iUiLdLc;d as a yellow solid during workup, was filtered away. The organic layer was dried (Na2SO4) and . ., . ,,l, ~ t ;I to afford a brown residue which was purified by Y (CH30H/CH2CI2), hTituration (diethyl ether) and recryst~lli7~tinn (EtOAc/Hex) to afford 0.12 g (9%) of product as a light yellow solid: mp 187-190C
; IH NMR (CDCI3): ~ 10.28 (s, lH), 8.33 (s, IH), 7.67 (d, 2H), 7.58 (d, 2H), 5.07 (m, IH), 1.55 (d, 3H), 1.04 (s, 9H). IR (KBr): 3400, 2220, 1800, 1740, 1690,1620 cm-l;
MS (m/z) 325 (M+).
Elemenhal analysis for ClgHIgN3O3 Calc'd: C, 66.44; H, 5.89; N, 12.91.
Found: C, 66.29; H, 5.76; N, 12.74.

Hexanoic acid (4- ' )-r3.4-dioxo-2-(1.2.2-trimethvl-L . ~JU ~ L \-cvclobut-I-envll-amide To a suspension of the illt~ ' of Example 1, second paragraph (0.70 g, 2.35 mmol) in pyridine (9 mL) was added hexanoic anhydlide (1.50 mL, 6.48 mmol).25 The mixture was stirred overnight, sttipped free of solvent and diluted with diethyl ether. A yellow solid (recovered starting material) which remained u,-di~uN~d was filtered away. The filtrate was <~ dissolved in mehhylene chloride and stirred vigorously in the presence of an equal volume of dilute aqheous sodium bi.,~l~ After 30 minutes the organic layer was removed, dried (Na2SO4) and 30 cnnre-~r~te~1 The resulting yellow film was purified by chromatography (CH30H/CH2CI2) to a~fford 0.43 g (46%~ of product as a pale yellow solid: mp 51-65C; IH NMR (CDCI3): ~ 7.81 (d, 2H), 7.48-7.38 (m, 3H), 4.28 (m, lH), 2.13 (m, 2H), 1.60 (m, 2H), 1.29-1.13 (m, iH), 0.99 (s, 9H), 0.86 (t, 3H). IR (KBr): 3340, æ30, 1800, 1725, 1610 cm-l; MS (m/z) 395 (M+).
.

CA 0220~307 1997-0~-14 3 1 ~ 25 .
- 14-- - =.
Elemental analysis for C23H2gN3O3 Calc'd: C, 69.85; H, 7.39; N, 10.62.
Found: C. 69.69; H, 7.35; N, 10.50.
E~AMP~E 6 N-(4-Cv~ o-Dhenvl)-N-r3.4-dioxo-2-~1.22-trimethvl- ' ~~-cvclobut-l-envll-i~o~
To a solution of iso-butyric anhydride (0.42 mL, 2.53 mmol) in pyridine (9 r~L) was added the '~ of Example 1, second paragraph (0 75 g, 2.52 mmol).
After stirring overnight additional anhydride (3.8 mL, 22.9 mmol) was added and stirring was continued for a second day. The mixture was stripped free of solvent and diluted with diethyl ether. A yellow solid (recovered starting material) which 15 remained undissolved was filtered away. The filtrate was c..~ d and the resuling yellow oil was purified by ~ , . ' y (CH30H/CH2CI2) and trituration (diethyl ether) to afford 0.47 g ~51%) of product as a pale yellow solid: mp 175-176C; iH NMR (CDCI3): i~ 7.81 (d, 2H), 7.47 (d, 2H), 7.42 (d, IH), 4.28 (m, IH), 2.52 (m, lH), 1.27 (d, 3H), 1.10 ~m, 6H~, 1.00 (s, 9H~. IR (KBr): 3330, 2230, 1800, 1730, 1680, 1610 cm~l; MS (m/z) 367 (M.
Elemental analysis for C2lH2sN3o3 Calc'd: C, 68.64; H, 6.86; N, 11.44.
Found: C, 68.34; H, 6.75; N, 11.26.
EXAMPL1~7 N-(4-Cv~no-Dhen vl~ -N-r3~4-dioxo-2-( 1 .2.~-trimeth vl -ù . o u cvclobut-l-envll-3-nhenvl-a~
To a suspension of the ;- ~ of Example 1, second paragraph (0.50 g, 168 mmol) in pyridine (6 mL) was added cinnamic anhydride (0.94 g, 3.38 mmol).
After sirring overnight, the mixture was ~.~Il. . .,I,. ~ ,i The resulting residue was taken up in methylene chloride and washed with aqueous sodium bi~ Ull.~ and water. The organic layer was dried (Na2SO4) and c..n. . .I~ to afford a yellow CA 0220~307 1997-0~-14 W0 96115103 ~ ~ PCI/US95/13125 gum which was purified by chromatography (CH3OH/CH2CI2) and trituration (diethyl ether) to afford 0.24 g (47%) of product as an off-white solid: mp 235-237C; IH NMR (CDCI3): ~ 7.80-7.61 (m, 3H), 7.50-7.32 (m, 8H), 6.21 (d, lH), 4.32 (m, lH), 1.29 (d, 3H), 1.03 (s, 9H). IR (KBr): 3330, æ20, 1800,1730, 1620, 160û cm-l; MS (m/z) 427 (M+).
Elemental analysis for C26H25N303.(0,06 CH~C12).(0.13 Et2) Calc'd: C, 72.19; H, 6.02; N, 9.50.
Found: C, 72.23; H, 5.96; N, 9.58.
EXAl\IPLE 8 N- (4-Cvano-rvhenyl)-N-r3.4-dioxo-2-~1~2.2-trimethvl-~.uv~'a )-cvclobut-l-~ L., l-carbamic acid ethvl ester To a stirred solution of trimethylacetic acid (0.38 g, 3.72 mmol) in tetrahydrofuran ~5 mL) at 0C was added, in order, N,N-diisul,lu~,y~ ku~ (0.65 NlL, 3.73 mmol) and (after 10 minutes) ethyl chlulurullllalt (0.36 mL, 3.77 mmol).
The resulting suspension of Llilll~Lllylàl_~,lyl ethyl carbonate was stirred for 30 mNnutes before use in the following step.
To a solution of the i~rnl~-rli~t~- of Example 1, second paracraph (1.00 g, 3.36 mmo~) in N,N-vi~ ylr ~ l;A~ (30 mL) was added, in one portion, sodium hydride (as a 60% dispersion in mineral oil; 0.150 g, 3.75 mmol). The frothy sl~cr~nC;~n was stirred at room t~ UI~: for 15 minutes and at 0C for an 25 additional hour. The mixed anhydride Cl~Cr.~nCi~n prepared in the preceding paragraph was added all at once. After stirring at room U,lll,U~,lG~Ul~ overnight, additional sodium hydlide (0.134 g, 3.35 mmol) was added and stir~ing was continued for a second night. The reaction solution was ~ l and the resulting residue . ~ was taken up in methylene chloride and washed with aqueous sodium lvic~b~ and 30 water. UNreacted staring material, which ~ iLdLt-d as a yellow solid during workup, was filtered away. The organic layer was dried (Na2SO4) and . ~~
to afford a brown gum which was purified by ul~ y (CH30H/CH2CI2) and ttituration (diethyl ether) to afford 0.20 g (16%) of N-(4-cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-1,1u~,~1c--lil-o)-cyclobut-1-enyl]-carbamic acid ethyl ester as a white wo 96/15103 solid: mp 158-l5gC; IH NMR (DMso-d6): ô 8.18 (d, 2H), 7.88 (d, 2H), 7.59 (d, 2H), 4.35-4.07 (m, 3H), 1.23 (t, 3H), 1.19 (d, 3H), 0.91 (s, 9H). IR (KBr): 3340, 2230, 1800, 1720, 1620 cm-l; MS (m/z) 369 (M.
Elemental analysis for C20H23N34 8 ' ' Calc'd: C, 65.03; H, 6.28; N, 11.37.
Found: C, 64.97; H, 6.19; N, 11.17.
F.xAMPLl~ 9 N-(4-C~ l)-N-r3.4-dioxo-2~ trimethvl-~,JV~ c~-cvclobut-l-envll-z -rt:-mide The i~ of Example 1, second paragraph (1.0 g, 3.36 mmol), acetic anhydride (0.95 mL, 10.0 mmol), and pyridine (10 mL) were mixed and allowed to 15 stand at room i~ lLu~ for 24 hours. The reaction mixture was filtered, and the solid was washed with ethyl acetate yielding 0.84 g (76%) of a yellow solid: mp 284-286C (dec); IH NMR (CDC13): o 7.82 (d, 2H), 7.47 (d, 2H), 7.38 (br d, lH), 4.27(dq, lH), 2.02 (s, 3H), 1.25 (d, 3H), 0.99 (s, 9H). IR (KBr): 3358, 2978, 2236,1804, 1739, 1685, 1614 cm~l; MS (m/z) 339 (M+).
Elemental analysis for ClgH2lN3O3 Calc'd: C, 67.24; H, 6.24; N, 12.38 Found: C. 67.15; H, 6.19; N, 12.38 (R)-~-~-N-(4-Cvano-Dhenvl)-N-r3~4-dioxo-2-~1,2~2-trimethvl .,. vv r' cvclobut-l -envll-a~ ~ ' 4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile (1 g, 4.1 mmol) and a solution of (R)-1,2,2-Li~ la,~ le (8.2 mmol) in ethanol (50 mL) were stirred at room l~ UI~ for 24 hours. The resulting yellow slurry was filtered and rinsed with ethyl acetate to yield 0.92 g (75%) of (+)-(R)-4-r3,4-dioxo-2-(1,2,2-~nm~hyl-propylamirlo)-cyclobo~ I-enylaminol bonppni~ril~ s a yell~ solld:

CA 0220~307 1997-0~-14 wo 96115103 r~

spectral data was identical to the product of Example 1, paragraph 2, except with [a] "
= + 12 (DMSO, c 0.009).
(R)-(-)-N-(4-Cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-,uluu~la.lli,,o)-5 cyclobut-1-enyl]-acetamude was prepared according to the procedure described in - Example 9. From the, ~ . " .. .1l~ - of the preceding paragraph (0.22g, 0.74 mmol) and acetic anhydride (0.21 mL, 2.2 mmol) in pyridine (2.2 mL) there was obtained 0.1 g (40%) of a yellow solid: spectral data was identical to the product of Example 9, except with [a]Z' - - 264 (DMSO, c 0.009).
~XAMI~LE 1 1 N-(4-cvano-ohellv~ -r3~4-dioxo-2-i:~vu~uu~ 5 r cYclobut-~-~nvll a~ d~
4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-b~n7n,ni~il~ (1 g, 4.1 mmol) and i~u,ulu,uyLIlll;llc (5 g, 84.6 mmol) in ~e-l-ni~ril~ (125 mL) were stirred at room ~ Lul~ fo} 24 hours. The resulting yellow slurry was filtered to give 0.78 g (31%) of 4-[3,4-dioxo-2-isuulu,uyL~l.l;l,o)-cyclobut-l-enylamino]-b~n7~ni-ril~ as a yellow solid: mp 290-292C (dec); IH NMR (DMSO-d6): o 9.89 (br s, lH), 7.77 (d u.~ ,u,u;llg a br d, 3H), 7.58 (d, 2H), 4.19 (m, lH), 1.25 (d, 6H). IR (KBr): 3200, 3178, 2239,1794,1665,1608,1576,1524 cm-l; MS (m/z) 255 (M+).
Elemental analysis for C14HI3N3O~
Calc'd: C, 65.87; H, 5.13; N, 16.46 Found: C, 65.39; H, 4.92; N, 16.41 N-(4-Cyano-phenyl)-N-[3,4-dioxo-2-;~u,ulu,uyL~ i,,o)-cyclobut-l-enyl]-acetamide was prepared according to the procedure described in Example 9. From the reactant of the preceding paragraph (0.15 g, 0.59 mrnol) and acetic anhydride (0.28 - rnL, 2.9 mmol) in pyridine (1.8 mL) there was obtained 0.1 g (57%) of pale yellow crystals: mp 187-1 88C; IH NMR (CDC13): o 7.82 (d. 2H), 7.45 (d, 2H), 7.22 (br d, - lH), 4.57 (m, IH), 2.00 (s, 3H), 1.33 (d, 6H). IR (KBr): 3339, 2980, 2239, 1760, 1'34, 1695, 1620 cm-l; MS (m/z) 297 (M.

CA 0220~307 1997-0~-14 wo 96/15103 r~ s Elemental analysis for C16HIsN3O
Calc'd: C, 64.64; H, 5.08; N, 14.13 Found: C, 64.32; H,4.83; N, 14.13 S EXAMPLE l ~
N-r2-rAcetvl-~2~2.3.3.3-~ v-DroDvl)-: ~1-3.4-dio~o-cvclobut-1-envll-N-~4-.~ ~ .h ~l)-n~ mide 4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile (I g, 4.1 mmol) and 2~2~3~3~3-~ Lanuulu~u~y~al~ lc (3 mL) in ethanol were refluxed for 24 hours.The reaction mixture was filtered and the resulting solid was triturared with diethyl ether to give 1.0 g (71%) of 4-[3~4-diOxO-2-(2~2~3~3~3-~ dLlu~ alllillo)-cyclobut-l-enylamino]-b~n7Onitril~ as a yellow solid: mp 272-275C (dec); IH
NMR (DMSO-d6): o 10.15 (br s, IH), 8.19 (br s, IH), 7.81 (d, 2H), 7.79 (d, 2H), 454 (dt, 2H). IR (KBr): 3185, 2239,1804,1672,1608,1565,1548 cm-l; MS (mlz) 346 ([M+H]+)-Elemental analysis for Cl4H8FsN3o2 Calc'd: C, 48.71; H, 2.34; N, 12.17 Found: C,4g.89; H,2.11; N,12.21 The product of the preceding paragraph (0.13 g, 0.38 mmol), acefic anhydride (0.11 mL, 1.1 mmol), and pyridine (1.1 mL) were mixed and allowed to stand at room L~ alul~ for 24 hours. The reaction mixture was diluted with ethyl acetate, filtcred, and; ' under reduced pressure. The resulting residue was taken up in hot ethyl acetate and filtered hot. The solution was allowed to cool to room a~Ul~; and hexanes was added to aid in the cryst~ i7~tinn The solid was filtered and rinsed sparingly with ethyl acetate to give 0.10 g (63%) of N-{2-[acetyl-(2,2,3,3,3-p~.~Lanuul~-propyl)-amino]-3,4-dioxo-cyclobut-l-enyl}-N-(4-cyano-phenyl)-acetamide as a pale yellow solid: mp 187-195C (dec); IH NMR (CDC13):
o 7.83 (d, 2H), 7.53 (d, 2H), 4.82 (br m, 2H), 2.37 (s, 3H), 2.07 (s, 3H). IR (KBr):
3435, 2237, 1805,1772, 1734,1707, 1603 cm-l; MS (m/z) 429 (M+).

CA 0220~307 1997-0~-14 WO 96/15103 ~ lZS

Elemental analysis for Cl8Hl2FsN3o4 Calc'd: C, 50.36; H, 2.82; N, 9.79 Found: C, 50.62; H, 2.64; N, 9.86 5 EXAMPL~ 13 N-(4-C~ c ~ Vl)-N-r2-(1.2-d;~ u.~ nino)-3.4-dioxo-cvclobut-1-envll-. '. ' '~
This compound was prepared according to the procedure described in Example 11, first paragraph. 4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-b.on7~mitT~ (1 g, 4.1 mmol) and (~)-1,2-di~ yl~ ylamine (5 g, 57.4 mmol) in acetonitrile (125 mL) there was obtained after trituration with methanol 0.28 g (24%) of 4-[2-(1,2-dimethyl-~1u,uylu~ o)-3,4-dioxo-cyclobut-l e.ly' ' )-benzonitrileasa yellow solid: mp 222-224C; IH NMR (DMSQ=d6) : o 9.89 (b~r s, IH), 7.78 (d, 2H), 7.73 (d, IH), 7.59 (d, 2H), 3.98 (m, IH), 1.76 (m, IH), 1.19 (d, 3H), 0.90 (d, 3H), 0.89 (d, 3H). IR (KBr): 2980, 2240, 1799, 1660, 1600,1565,1525 cm-l; MS
(m!z) 283 (M+).
Elemental analysis for Cl6Hl7N3o2 Calc'd: C,67.83; H,6.05; N, 14.83 Found: C, 67.32; H, 5.94; N, 14.91 N-(4-Cyano-phenyl)-N-t2-(1,2-dimethyl-l,l.,~,yl~llllill~)-3~4-dioxo-cyclobut-l-enyl]-acetamide was prepared according to the procedure described in Example 9.
From the product of the preceding paragraph(0.27 g, 0.95 ml) and acetic anhydride (0.27 mL, 2.9 mmol) in pyridine (2.9 mL) there was obtained 0.17 g (55%) of white crystals: mp 258-262C (dec); IH NMR (CDC13): o 7.82 (d, 2H), 7.46 (d, 2H), 7.29(br d, lH), 4.30 (m, IH), 2.02 (s, 3H), 1.81 (m, lH), 1.27 (d, 3H), 1.00 (d, 3H), 0.99 (d, 3H). IR (KBr): 3337, 2967, 2228,1804, 1739, 1685, 1620 cm-l; MS (m/z) 325 30 (M+)-Elemental analysis for Cl~,HIgN3O3 Calc'd: C, 66.45; H, 5.87; N, 12.91 Found: C,6648; H,5.82; N,12.79 CA 0220~307 1997-0~-14 wo 96/15103 PCrNS95/l3125 E~AMPLF, 14 N-(3-C~ . tl!l ~ N-r3.4-dioxo-~-(1.2.~-trir~hvl- ' ' -)-evelohut-l-envll-~

3-A". -~ (2.06 g, 17.4 mmol) and 3,4-diethoxy-3--,y-,lol,u;~ ,-1,2-dione (2.97 g, 17.5 mmol) in absolute ethanol (50 mL) was refluxed overnight. The reaction mixture was filtered hot, then a~lowed to cool to room ~ , ,n~ The resulting precipitate was filtered to give 3.4 g of a yellow solid which was used without further ~ " This yellow solid (1 g, 4.1 mmol) and 2-amino-3,3-di~ ylb~.L~Ile (2 g, 19.8 mmol) in acetonitrile (125 mL) were stirred at room t~ Llllc for 24 hours. The reaction mixture was filtered to give 0.66 g (54%) of3-[3,4-dioxo-2-(1,2,2-trimethyl-~lu~ ll.;l,u)-cyclobut-1-enylamino]-h~n7..nirrilrac a pale yellow solid: mp 296-298C (dec); IH NMR (DMSO-d6): o 9.79 (br s, IH), 7.94 (br s, lH), 7.6? (d, lH), 7.64 (dm~ IH), 7.53 (t, lH), 7.45 (dm, IH), 3.98 (m, lH), 1.17 (d, 3H), 0.91 (s, 9H). IR (KBr): 3193, 3148, 2974, 2228, 1793, 1673, 1582, 1544 cm-l; MS (mlz) 297 (M+).
Elemental analysis for Cl7HI9N3O2 Calc'd: C, 68.67; H, 6.44; N, 14.13 Found: C, 68.73; H, 6.36; N, 14.04 N-(3-Cyano-pheny~)-N-[3,4-dioxo-2-(1,2,2-trimethyl-~1ul yLIlllil~o)-cyclobut-1-enyl]-acetamide was prepared according to the procedure deseribed in Example 9.
From the product of the preceding paragraph (0.18 g, 0.6~ mmol) and acetic anhydride (0.28 mL, 3.0 mmol) in pyridine (1.8 mL) there was obtained 0.14 g (68%) of white crystals: mp 253-254C; IH NMR (CDC13): o 7.81 (dt, IH), 7.o'9-7.58 (m,3H), 7.41 (br d, lH), 4.27 (m, lH), 2.01 (s, 3H), 1.25 (d, 3H), 0.99 (s, 9H). IR (KBr):
3337, 2965, 2237,1804,1739,1684,1619 cm-l; MS (m/z) 339 (M+).
Elemental analysis for ClgH2lN3O3 Calc'd: C, 67.24; H, 6.24; N, 12.38 Foond: C, 67.21; H,6.20; N, 12.38 i wo 96115103 1 ~"~ 5 EXAMpLF 1 S
(R)-N-~4-Cvano-Dhenvl)-N-r2~ )-3.4-dioxo-cvclobut-1-envll-a~
(Rj-4-[2-(l-Cyclohexyl-ethylamino)-3,4-dioxo-cyclobut-1-enylamino]-bf n7nnim1~ was prepared according to the procedure described in Example 10, ~rst paragraph. From 4-(3,4-dioxo-2-ethoxy-cyclobut-l-enylamino)-b~n7nninil~ (0.36 g,1.5 mmol) and (R)-(-)-l-~:y~,lol,~,AyL..llylamine (0.29 mL, 1.95 mmol) in absolute ethanol (5 mL) there was obtained after t~ituration with hot methanol 0.31 g (64%) of a yellow solid: mp 275-280C (dec); IH NMR (DMSO-d6): o 9.87 (br s, IH), 7.78 (d, 2H), 7.72 (d, IH), 7.59 (d, 2H), 3.96 ~m, IH), 1.78 1.66 (m, 4H), 1.62 (m, lH), 1.34 (m, IH), 1.24-0.90 (m including a doublet at ~ 1.20, 8H). IR (KBr): 3200, 2920, 2850, 2220, 1790,1660,1600,1560,1528 cm-l; MS (m/z) 323 (M+).
Elemental analysis for ClsH21N3O2 Calc'd: C,7057; H, 6.55; N, 12.99 Found: C, 70.19; H, 6.60; N, 13.00 This compound was prepared according to the procedure described in Example 12, second paragraph. From the product of the preceding paragraph (0.33 g, 1.02 mmol) and acetic anhydride (0.29 mL, 3.06 mmol~ in pyridine (3.1 mL) there was obtained 0.62 g (40%) of (R)-N-(4-cyano-phenyl)-N-[2-(1-cyclohexyl-ethylamino)-3,4-dioxo-cyclobut-1-enyl]-acetamide as a yellow solid: mp 194-198C;
[a]~' = - 150.96 (DMSO, c 0.0084); IH NMR (CDCl3): ~ 7.82 (d, 2H), 7.46 (d, 2H), 7.25 (br m, lH), 4.28 (m, lH), 2.02 (s, 3H), 1.87-0.94 (m including a doublet at o 1.27, 14H) IR (KBr): 3337, 2930, 2865, 2237,1803,1729,1690,1620 cm-l; MS
(m/z) 365 (M+).
-, Elemental analysis for C21H23N303 Calc'd: C,69.02; H,6.34; N,11.50 Found: C, 68.72; H, 6.10; N, 11.55 ~ = ~

CA 0220~307 1997-0~-14 Wo 96/15103 ~ 5 N-(2-1~ ' ` ' ^-3.4-dioxo-c~clobut-1-en~l)-N-~4- -' ')-a ' ' 4-[2-Butylamino-3,4-dioxo-cyclobut-1-o~ l;llo)-b~n~oni~ was prepared 5 according to the procedure described in Example 11, first paragraph. From 4-(3,4-dioxo-2-ethoxy-cyclobut-1 e-~ l;llo)-b~-n7~ni~ (I g, 4.1 mmol) and butylamine (3 g, 41.0 mmol) in acetonitrile (125 mL) there was obtained 0.64 g (58%) of a yellow solid: mp 256-258C (dec); IH NMR (DMSO-d6): o 10.00 '(br s, lH), 7.81 (br s, lH), 7.77 (d, 2H), 7.57 (d, 2H), 3.60 (br q, 2H), 1.55 (quintet, 2H), 1.34 ~sextet, 2H), 0.90 (t, 3H). IR (KBr): 3240, 2980, 2240, 1800,1670,1625, cm-l; MS (m/z) 269 (M+)-Elemental analysis for ClsHIsN3O2 Calc'd: C, 66.90; H, 5.61; N, 15.60 Found: C, 66.23; H, 5.80; ~1,15.54 N-(2-Butylamino-3,4-dioxo-cyclobut- 1 -enyl)-N-(4-cyano-phenyl)-acetamide was prepared according to the procedure described in Example 12, paragraph two.
From the product of the preceding paragraph (0.16 g, 0.59 mmol) and acetic anhydride (0.28 mL, 2.96 mmol) in pyridine (1.8 mL) there was obtained 0.05 g (27%) of white solid: mp 194-196C; IH NMR (CDC13): o 7.82 (d, 2H), 7.45 (d, 2H), 7.34 (br m, IH), 3.78 (q, 2H), 2.01 (s, 3H), 1.65 (quintet, 2H), 1.44 (sextet, 2H), Q98 (t, 3H). IR (KBr): 3315, 2957, 2228, 1796,1727, 1696,1598 cm-l; MS (m/z) 311 (M+).
Elemental analysis for Cl7HI7N3O3 Calc'd: C, 65.58; H, 5.50; N, 13.50 Found: C,65.45; H,5.63; N, 13.45 J

CA 0220~307 1997-0~-14 ~VO 96115103 J ~~ ~5 . , .

N-~ r2-(Bicvclor2.2.1lhent-2-v~ ino)-3.4-dioxo-cvclobut-l-envll-N-~4-~ r t~h ~
.
S (endo)-4-[2-(Bicyclo[2.2.1]hept-2-ylalmno)-3,4-dioxo-cyclobut-1-enylamino]-- 1 lf was prepared according to the procedure described in Example 11, first paragraph. From 4-(3,4^dioxo-2-ethoxy-cyclobut-l-e..~L"..;"o)-~ n7n-:tril~- (0.37 g, 1.5 mmol) and (~)-endo-2-.1,llilw-l~,ll,ul.,.,--e (0.17 g, 1.5 mmol) in ~r,-t~ (30 mL) there was obtained after trituration with diethyl ether 0.32 g (69%) of a yellow solid: mp 251-252C (dec); IH NMR (DMSO-d6): o 9.88 (br s, lH), 7.85 (d, lH), 7.78 (d, 2H), 7.60 (d, 2H), 4.35 (m, lH), 2.36 (m; lH), 2 23 (m, lH), 2.2 (m, lH), 1.69-1.23 (m, 6H), 0.91 (m, lH). IR (KBr): 3200, 2942, 2220, 1798,1668, 1600, 1565,1535 cm-l; MS (m/z) 307 (M.
15 Elemental analysis for Cl8HI7N32 Calc'd: C,70.34; H,5.57; N,13.67 Found: C,70.03; H, 5.38; N, 13.97 N-(endo)-[2-(Bicyclo[2.2.1]hept-2-ylamino)-3,4-dioxo-cyclobut-1-enyl]-N-(~
20 cyano-phenyl)-acetamide was prepared according to the procedure described in Example 9. From the product of the preceding paragraph (0.021 g, 0.068 mmol) andacetic anhydride (0.033 mL, 0.35 mmol) in pyridine (0.21 mL) there was obtained 0.014 g (59%) of pale yellow solid: mp 282-285~C (dec); IH NMR (CDC13): o 7.82 (d, 2H), 7.45 (d, 2H), 7.51 (br d, lH), 4.63 (m, lH), 2.48 (m, lH), 2.31 (m, lH), 2.20 (m, lH), 2.02 (s, 3H), 1.75-1.30 (m, 6H), 0.96 (m, IH). IR (KBr): 3343, 2957, 2239, 1803, 1730, 1690, 1620 cm-l; MS (m/z) 349 (M.
Elemental analysis for C20HIgN3o3 - Calc'd: C, 68.75; H, 5.48; N, 12.03 Found: C, 68.39; H, 5.39; N, 12.02 CA 0220~307 1997-0~-14 Wo 96115103 . ~ ~, ~J~JI 1~12 N-(2-tert-~ ' ' ' -3.~ )bJ~ nYl)-N-(i ~ ' " 5-~
s ,~nninnic~ i... (4.24 g, 29.4 mmol) and 3,4-diethoxy-3-~.y.,lcl,ut,~
1,2-dione (5 g, 29.4 mmol) in abso~ute ethanol (100 mL) were refluxed overnight.The reaction mixture was filtered to give 2.3 g of a solid which was used without further ~ iri~ - This solid (0.3 g, 1.12 mmol) in tert-butylamine (50 mL) was refluxed for 3 hours. The reaction mixture was ~ and triturated with diethyl ether to give 0.12 g (39%) of 3-tert-Butylamino-4-(icnql-innlin-5-ylamino)-cyclobut-3-ene-1,2-dione as a white solid 0.125 hydrate: mp 268-270C (dec); IH
NMR (DMSO-d6): ~ 9.75 (s, lH), 9.35 (s, 1~), 8.62 (d, lH), 8.19 (s, lH), 8.01 (d, lH), 7.88 (d, lH), 7.80 (d, lH), 7.68 (t, lH), 1.47 (s, 9H). IR (KBr): 3200, 1785, 1670, 1600 cm-l; MS (m/z) 295 (M+).
Elemental analysis for Cl7Hl7N3o2 0-125 H2O
Calc'd: C, 69.14; H, 5.80; N, 14.23 Found: C, 68.08; H, 5.78; N, 13.75 N-(2-oert-Butylamino-3,4-dioxo-cyclobut- l-enyl)-N-(isoquinolin-5-yl)-acetamide was prepared according to the procedure described in Example 12, second paragraph. From the product of the preceding paragraph (0.30 g, 1.0 mmol) and acetic anhydride (0.29 mL, 3.0 mmol) in pytidine (3 mL) there was obtained 0.18 g (53%) of off-white crystals: mp 210-213C; IH NMR (CDC13): o 9.41 (s, lH), 8.66 (d, lH), 8.19 (m, lH), 8.09 (br s, lH), 7.81-7.72 (m, 2H), 7.59 (d, lH), 1.89 (s, 3H), 1.56 (s, 9H). IR (KBr): 3304, 2965,1793,1679,1588 cm~l; MS (m/z) 337 (M+).
Elemental analysis for ClgHIgN3O3 Calc'd: C, 67.64; H,5.68; N, 12.46 Found: C, 67.38; H, 5.65; N, 12.41 CA 0220~307 1997-0~-14 wo 96115103 I~ s - 25 - .
EXAMPLF. l9 N-(2-tert-ButYl~mino-3.4-dioxo-cvclobut-1 -envl)-N-(l~vridin-3-vl)-acetamide 3-AI~ -idil-e (2.77 g, 29.4 mmol) and 3,4-diethoxy-3-cyclobutene-1,2-dione (5 g, 29.4 mmol) in absolute ethanol (150 rnL) were refluxed for 1 g hou}s. The eaction mixture was ~ U~lt~,~ and clllv~ Lu~ d in h~ l æetate (1/4) to give 3.15 g of a white solid. This solid (2.6 g, 11.9 mmol) in tert-butylamine (50 mL) was refluxed for 3 hours. The reaction mixture was ~ r~l and ttiturated with diethyl ether to give 1.05 g (36%) of 3-tert-butylamino4-(pyridin-3-ylamino)-cyclobut-3-ene-1,2-dione as a white solid: mp 250-252C (dec); lH NMR
(DMSO-d6): ~ 8.57 (s, lH), 8.23 (d, lH), 7.96 ~d, lH), 7.37 (m, lH), 1.43 (s, 9H).
IR (KBr): 1790, 1685,1600 cm-l; MS (mlz) 245 (M+).
Elemental analysis for C13HIsN3O~
Calc'd: C, 63.66; H, 6.16; N, 17.13 Found: C, 63.28; H, 6.22; N, 17.07 N-(2-tert-Butylamino-3,4-dioxo-cyclobut-1-enyl)-N-(pyridin-3-yl)-acetamide was prepared according to the procedure described in Exatnple 12, second paragraph.
From the product of the preceding paragraph (0.20 g, 0.82 mmol) and acetic anhydride (0.23 trlL, 2.5 mmol) in pyridine (2.5 rllL) there was obtained 0.15 g (68%) of white crystals: mp 194195C; IH NMR (CDC13): o 8.74 (d, lH), 8.62 (s, lH~, 7.83 (br s, lH), 7.70 (m, lH), 7.47 (dd, lH), 2.00 (s, 3H), 1.52 (s, 9H). IR (KBr):
3435, 3298,1799,1741,1685,1598 cm-l; MS (m/z) 288 ([M+H]+).
Elemental analysis for ClsHI7N3O3 Calc'd: C, 62.71; H,5.96; N, 14.62 Found: C, 62.78; H, 5.91; N, 14.67 CA 0220~307 1997-0~-14 Wo 96/15103 ~ J

F,XAMPLli: 20 N-r3.4-Dioxo-2-(1.2~2-' ' ' ' ~~ ~vclobut-1-envll-N-(2-nnetho~-5-ll ir~ l-uhenvl)-a~
5 2-Methoxy-5-uinuulul~ ,,iline (5.62 g, 29.4 mmol) and 3,4-diethoxy-3-.,~.,lu~s,..e-1,2-dione (5 g, 29.4 mmol) in absolute ethanol (100 mL) were refluxed for 66 hours. The reaction mixture was filtered and the precipitate was chr~r~^ ~r~rh~i in methanol/methylene chloride to give 1.88 g of a yellow solid.This solid (1.0 g, 3.2 mmol) and 2-amino-3,3-dimethylbutane (0.43 mL, 3.2 mmol) in 10 absolute ethanol (20 mL) were stirred at room t~ Ul~ for 18 hours. The reaction mixture was ~ ;l and ulllull~lu~;la~ l with methylene chlu-id~/~-l.,il-dl-ol (96:4) to give 0.91 g (78%) of 3-ethoxy-4-(2-methoxy-5-Llifluolu,---,Ll,yl-o)-cyclobut-3-ene-1,2-dione as a white solid: mp 143-155C; IH NMR
(D~SO-d6): o 9.36 (s, IH), 8.24 (d, IH), 8.19 (d, IH), 7.35 (dd, IH), 3.99 (s, 3H), 1.18 (d, 3H), 0.91 (s, 9H). IR ~KBr): 3293, 2976,1802, 1690, issl, 1543 cm-l; MS
(mlz) 370 (M+).
Elemental analysis for Cl8H2lF3N2o3 Calc'd: C, 58.37; H, 5.72; N, 7.56 Found: C, 57.98; H, 5.65; N, 7.27 N-[3,4-Dioxo-2-(1,2,2-trimelhyl-~.u~ )-cyclobut-l-enyl]-N-(2-methoxy-5-Llinuu-u"lcthyl-phenyl)-acetamide was prepared according to the procedure described in Example 12, second paragraph. From the product of the preceding paragraph (0.20 g, 0.54 mmol) and acetic anhydride (0.15 mL, 1.6 mmol)in pyridine (1.6 mL) there was obtained 0.16 g (73%) of white crystals: mp 76-79C;
IH NMR (CDC13): o 7,73 (dd, 1~), 7.53 (d, lH), 7.38 (br d, lH), 7.12 (d, lH), 4.25 (m, lH), 3.92 (s, 3H), 1.96 (s, 3H), 1.24 (d, 3H), 1.00 and 099 (two singlets, 9H). IR
(E~Br): 3326, 2974, 1799,1715, 1609 cm-l; MS (m/z) 412 (M.
Elemental analysis for C2oH23F3N2o4 Calc'd: C, 58.25; H, 5.62; N, 6.79 Found: C, 58.44; H, 5.85, N, 6.47 -- =~
CA 0220~307 1997-0~-14 wo 96/15103 ~ "~

- E~AMPLls, 21 (endo)-N-r2-(Bicvclor2~2.1lheDt-2- ' -)-3.4-dioxo-cvclobut-1-envll-N-(nvridin-4-vl)-~ ' '-4-A~ ,yyli.lill~, (2.77 g, 29.4 mmol) and 3,4-diethoxy-3-cyclobutene-1,2-dione (5 g, 2g.4 mmol) in absolute ethanol ( 100 mL) were refluxed for 4 hours. The reacrion mixture was ~ ~ " - f ~ and ~ 'f~' "i'l '` ~ in ethyl acetate to give 0.63 g of a white solid. This solid (0.33 g, 1.5 mmol) and (+)-(endo)-2-~.,...,.~---.,1,...~ -.--(0.17 g, 1.5 mmol) in acetonitrile (30 mL) was stirred at room ~ y.,..LL~ for 2410 hours. The reaction mixture was filtered and triturated with diethyl ether to give 0.35 g (36%) of ( ~)-(endo)-3-(bicyclo[2.2.1]hept-2-ylamino)-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione as a pale yellow solid 1.56 hydrate: mp 270-277C (dec);
IH NMR (DMSO-d6): o 9.81 (br s, lH), 8.41 (d, 2H), 7.88 (d, IH), 7.44 (d, 2H), 4.34 (m, lH), 2.35 (m, IH), 2.23 (m, lH), 2.10 (m, lH), 1.69-1.20 (m, 6H), 0.90 (m, lH). IR (KBr): 3365, 2957, 1799, 1691, 1630, i599, 1533 crn-l; MS (m/z) 283 (M+)-Elemental analysis for Cl6Hl7N3o2 1.S6 H~O
Calc'd: C, 61.71; H, 6.51; N, i3.49 Found: C, 61.76; H, 6.37 N, 13.27 (endo)-N-[2-(Bicyclo[2.2.1]hept-2-ylamino)-3,4-dioxo-cyclobut-1-enyl]-N-(pyridin-4-yl)-acetamide was prepared according to the procedure described in Example 12, second paragraph. From the product of the preceding paragraph (0.17 g, 0.60 mmol) and acetic anhydride (0.28 mL, 3.0 mmol) in pyridine (1.8 mL) there was obtained 0.08 g (41%) of pale yellow solid: mp 192-194C; IH NMR (CDC13): o 8.80 (dd, 2H), 7.49 (br d, lH), 7.30 (dd, 2H), 4.63 (m, lH), 2.48 (m, iH), 2.30 (m, lH), 2.19 (m, lH), 2.06 (s, 3H), 1.75-1.30 (m, 6H), 0.97 (m, lH). IR (KBr): 3348, 2954,1799,1735,1696,1621 cm-l; MS (mlz) 325 (rM+H]+).
Elemental analysis for ClgHIgN3O3 Calc'd: C, 66.45; H, 5.89; N, 12.91 Found: C, 66.02; H, 5.87; N, 12.66 CA 0220~307 1997-0~-14 WO 96/15103 ~ 5 ~XAMPL~ 7'~
N-(2-sec-But~ .4-dioxo-cvclobut-1 ~nvl) N-~4 - ~
4-[2-sec-Butylamino-3,4-dioxo-cyclobut-1-enylamino)-b, ~ was 5 prepared according to the procedure described in Example 11, first paragraph. From 4-(3,4-dioxo-2-ethoxy-cyclobut-l-enylamino)-hr"~rni~ (1 g, 4.1 mmol) and (~)-sec-l.~ lc (excess) in ~rcîonitril-- (125 mL) there was obtained 1.36 g of a yellow solid: mp 245-247C; IH NMR (DMSO-d6): o 9.89 (br s, IH), 7.78 (d, 2H), 7.73 (d, IH), 7.58 (d, 2H), 4.01 (m, lH), 1.65-1.46 (m 2H), 1.23 (d, 3H), 0.89 (t, 3H).
IR (KBr): 3217, 3185, 3000, 2228, 1798, 1664, 1609, 1527 cm~l; MS (m/z) 269 (M+)-Elemental analysis for C15HISN3O2 Calc'd: C, 66:90; H, 5.61; N, 15.60 Found: C, 66.78; H, 5.43; N, 15.61 N-(2-sec-Butylamino-3,4-dioxo-cyclobut- 1 -enyl)-N-(4-cyano-phenyl)-acetamide was prepared according to the procedure described in Example 12, second paragraph. From the product of the preceding paragraph (0.16 g, 0.52 mmol) and acetic anhydride (0.28 mL, 2.96 mmol) in pyridine (i 8 mL) there was obtained 0.14 g (78%) of yellow crystals: mp 220-225C (dec.); IH NMR (CDC13): o 7.80 (d, 2H), 7.44 (d, 2H), 7.14 (br d, lH), 4.36 (m, IH), 2.00 (s, 3H), 1.71-1.53 (m, 2H), 1.30 (d, 3H), 0.98 (s, 3H). IR (KBr): 3348, 2978 2239, 1803, 1739, 1690, 1622 cm-l; MS
(m/z)311 (M+).
Elemental analysis for Cl7HI7N3O3 Calc'd: C, 65.58; H, 5.50; N, 13.50 Found: C,65.18i H,5.31 1;,1333 CA 0220~307 1997-0~-14 WO 96115103 1 ._11 ~J~.u l~l~a EXAMP~ F 77 (R)-N-r3.4.Dioxo-2,(1.2,2~ 1 uu.l-.,lino~-cvclobut-l-envll-N-(r ''' 3-vl)-a~ !e 3~ u~lidillc (2.77 g, 29.4 mmol) and 3,4-diethoxy-3-.. y,,lul,.. t~,.le-1,2-dione (5 g, 29.4 mmol) in ~retr~nitnl~ (35 mL) were refluxed for 18 hours. The reaction mixture was c~ r.1 and ~ 1 with 2% methanol in ethyl acetate to give 2.65 g of a white solid. This solid (0.9 g, 4.1 mmol) was stirred in a solution of (R)-1,2,2-trimethyl-,u~ uyla-ll;.le (8.2 mmol) and ethanol (50 mL) at room 10 t~,lllU~14LUlC for 24 hours. The reaction mixture was filtered and rinsed with ethyl âcetate to give 0.77 g (68%) of (+)-(R)-3-(1,2,2-trimethyl-~ ",yl4.l1i-.c,)-4-(pyridin-3-ylamino)-cyclobut-3-ene-1,2-dione as a white solid: mp 283-285C; [C~]D = +2.04(DMSO, c 0.0098); IH NMR (DMSO-ds?: ~ 8.19 (brs, lH), 8.57 (d, lH), 8.22 (dd, lH), 7.96 (dm, lH), 7.66 (brd, lH), 7.37 (dd, lH), 3.98 (m, lH), 1.17 ~d, 3H), 0.91 (s, 9H). IR (KBr): 3200, 2960,1790, 1655, 1570, 1455 cm-l; MS (m/z) 2i3 (M.
Elemental analysis for CI5H19N32 Calc'd: C, 65.91; H,7.01; N, 15.37 Found: C, 65.88; H, 7.04; N, 15.56 The title compound was prepared according to the procedure described in Example 9. From the product of the preceding paragraph (0.20 g, 0.73 mmol) and acetic anhydride (0.21 mL, 2.2 mmol) in pyridine (2.2 rnL) there was obtained 0.14 g (61%) of a 0.4 hydrate of the title compound as white crystals: mp 149-151C; IHNMR (CDC13): o 8.75 (dd, lH), 8.63 (d, IH), 7.71 (dm, lH), 7.49 (dd, lH), 7.42 (brd, lH), 2.27 (m, lH), 2.01 (s, 3H), i.26 (d, 3H), 1.00 (s, 9H). IR (KBr): 3325, 2960,1800, 1740, 1690, 1620 cm-l; MS (mlz) 315 ([M+H]+).
. . = .
Elemental analysis for C17H21N303- 0.4 H2O
Calc'd: C, 63.30, H,6.81; N, 13.03 Found: C, 63.45, ~H, 6.71; N, 12. /8 ~ ' CA 02205307 1997-0~-14 wo 96115103 PCT/US95/13125 EXAMPL~ 24 (R)-N-r3.4-Dioxo-2~ -trimethvl-r ~ -cQclobut-l-en~ll-N-(Dv~idin-4-Qll-a. ~
s 4-A~ u~ylidillc (8.27 g, 87.9 mmol) and 3,4-diethoxy-3-.,y.,luL,u.. ,.l~, 1,2-dione (15 g, 88 mmol) in ~retr)nitril~ (51 mL) were refluxed for 18 hours. The reaction mixture was diluted with ethanol, filtered and ~ . A tr.1 C~
with 2% methanol in ethyl acetate afforded 2.59 g of a while solid. This solid (0.9 g, 4.1 mmol) was stirred in a solution of (R)-1,2,2-trimethyl-~lul~yLullil,c (8.2 mmol) 10 and ethanol (50 mL) at room ICIII~ ILUIC for 24 hours; The reaction mixture was filtered and nnsed with ethyl acetate to give 0.70 g (62%~ of (+~-(R)-3-(1,2,2-trimethyl-~ yl~.l.i..o)-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione as a white solid: mp 275-279C (dec); [a] ~ = +6.02 (DMSO, c 0.006~; IH NMR (DMSO-d6~: ~ 9.80 (s, lH), 8.41 (dd, 2H), 7.73 (brd, lH), 7.45 (dd, 2H), 3.97 (m, lH), 1.17 (d, 3H), 0.91 (s, 9H). IR (KBr): 3210, 3160, i800, 1670, 16lO, 1530 cm-l; MS
(m/z) 273 (M+).
Elemental ana~ysis for ClsHIsN302 ~ =~
Calc'd: C, 65.91; H, 7.01; N, 15.37 Found: C, 65.80; H, 7.01; N, 15.60 The title compound was prepared according to the procedure described in Example 9. From the product of the preceding paragraph (0.20 g, 0.73 mmol) and acetic anhydride (0.21 mL, 2.2 mmol) in pyridine (2.2 mL) there was obtained 0.08 g (35%) of the title compound as a white solid: mp 140-142C (dec); IH NMR
(CDC13): ~ 8.81 (dd, 2H), 7.32 (brd, lHj, 7.28 (dd, 2H), 4.27 (rn, IH), 2.05 (s, 3H), 1.25 (d, 3H), 0.99 (s, 9H). IR (KBr): 3340, 2980, 1790, 1720, 1690, 1610 cm-1; MS
(m/z) 315 ([M+H]+).
Elemental analysis for Cl7H2lN303 Calc'd: C, 64.74; H, 6.71; N, 13.32 Found: C, 64.46; H, 6.68; N, 13.13 CA 0220~307 1997-0~-14 ~0 96~S103 1 ~,l/u.,,.~ S

FXAMPLF 2~
(R)-N-r3.4-~ioxo-2-(1.2.2-l- i '' /1 _ . uv .'~ ~-cvclobut-l-envll-3-methvl-N-(Dvridin-4-vl)-1,u~
This compound was prepared according IO the procedure described in Example 9. From the product of the first paragraph of Example 24 (0.17 g, 0.62 mmol) and isovaleric anhydride (0.36 mL, 1.86 mmol) in pyridine (2 5 mL) there was obtained 0.08 g (36%) of the title compound as an off-white solid: mp 193-196C;IH NMR (CDC13): o 8.81 (dd, 2H), 7.36 (dm, IH), 7.27 (dd, 2H), 4.28 (m, lH), 2.20-2.02 (m, 3H), 1.26 (d, 3H), 0.99 (s, 9Hj, 0.90 (d, 3H), 0.89 (d, 3H). IR (KBr): 3310, 2950, 1795, 1720, 1700, 1610 cm-l; MS (m/z) 357 ([M+H]+).
Elemental analysis for C20H27N3O3 Calc'd: C, 67.20; H,7.61; N, 11.76 Found: C, 66.71; H,7.63; N, 11.63 EX~MPLE 26 (R)-(-)-N-r3.4-l)iûxo-2-(1.2~2-trimethvl-v. ~,u~ )-cvclobut-l-envll-N-(vvridin-4-vl).,~.~t~
This compound was prepared according to the procedure described in Example 9 From the product of the first paragraph of Example 24 (0.20 g, 0.73 mmol) and valeric anhydride (0.42 mL, 2.2 mmol) in pyridine (2.9 mL) there was obtained 0.17 g (65 3'o) of the tit~e compound as a pale yellow solid: mp 160-165C
(dec); [c~]" = -202.72 (DMSO, c 0.0076); IH NMR (CDC13): ~ 8.81 (dd, 2H), 7.38 (dm, lH), 7.28 (dd, 2H), 4.28 (m, lH), 2.18 (dt, 2H), 1.59 (m, 2H), 1.31-1.20 (m, 2H), 1.26 (d, 3H), 1.00 (s, 9H), 0.85 (t, 3H). IR (KBr): 3310, 2970, 1735, 1720,1700,1610 cm-l; MS (mlz) 357 ([M+H]+).
Elemental analysis for C2UH27N3o3 Calc'd: C,67.20; H,7.61; N,11.76 Found: C, 6693; H, 7.73; N, 11.84 CA 0220~307 1997-0~-14 .

FXAMPI,F, t7 N-(4-C -2-~lh.~l o .1~-N-r3.~-dioxo-2-(1.2.2-trimethvl-L.VU~ -cvclobut-l-envll b~
4-Amino-3-ethylhf n7fmitrilf~ (0.86 g, 5.88 mmol) and 3,4-diethoxy-3-~:yulul/u~ -1,2-dione (1.0 g, 5.88 mmol) in acetonitrile (2 mL) was heated in an oil bath at 110C for 21 hours. 3,4-Diethoxy-3-~,~, 1ul,...~".c-1,2-dione (0.5 g, 2.9 mmol) was added to the reaction mixture and the t,lllp~ Lu~c of the oil bath increased to 150C After 48 hours the reaction mixture was cooled to room t~ u.,laLuu~, then 10 diluted with ethyl acetate and filtered. The filtrate was ,ll . .I,,.l, .1 and the resulting solid was taf;en up in ethyl ace ate (5 mL) and sonicated Filtra ion gave 0.54 g (34%) of 4-(3,4-dioxo-2-ethoxy-cyclobut-1-enylamino)-3-~llyll, ,,.",i~,;lf as a light brown solid: IH NMR (DMSO-d6): ~ 10.56 (br s, IH), 7.70 (br s overlapping a doublet at o 7.69, 2H), 7.30 (d, IH), 4.71 (q, 2H), 2.74 (q, 2H), 1.37 (t, 3H), 1.15 (t, 3H~.
4-(2-ethoxy-3,4-dioxo-cyclobut-l-enylamino)-3-ethylhfn7fnirrilf (1.26 g, 4.66 mmol~ and a solution of (R)-1,2,2-LIilll,.llyl,ulu,uylfAIllil,~, (9.3 mmol) in ethanol (58 mL~ were stirred at rQom L ,III~ UIC for 24 hours. The resulting yellow solution was .."~ l,AIf l to a yellow oil, which was dissolved in acetonitrile (20 mL) and 20 stirred at room Lclllu~ lul~. The yellow solid which ~ . was filtered off andrinsed with ethyl acetate to yield 0.79 g (52f~) of (+)-(R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-~luAuylllllillo)-cyclobut-l-enylamino]-3-G~llyll. ,.,";I ;If as an off-white solid: mp 235-237C; [a] ~ = + 68.20 (DMSO, c 0.0072); IH NMR (DMSO-d6):
v 8.04 (br s, IH), 8.04 (d, IH), 7.69-757 (m, 3H), 4.05 (m, IH), 2.71 (q, 2H), 1.27-1.16 (u.~ ,u~Jill~ doublet and triplet, 6H), 0.91 (s, 9H). IR (KBr): 3278, 2959, 2æ2, 1793,1674, 1598, I576, 1522 cm-l; MS (m/z) 325 (M+).
Elemental analysis for C19H23N302 Calcd: C,70.13; H,7.12; N,12.91 Found: C, 69.82; H, 7.17; N, 12.99 : ~
A mixture of the product of the preceding paragraph (0.37 g, 1.14 g), butyric anhydride (0.47 mL, 2.87 mmol) and pyridine (10 mL) was stirred at rt overnight.The solution was stripped free of solvent and the resulting oil was taken up in CA 0220~307 1997-0~-14 33~
hexanes. The precipitate which formed was filtered off and recrystallized (EtOAc/hexanes) to afford the title compound as Q26 g ~58%) of a white solid: mp150-152C; [a]~SD -193.90 (DMSO, c 0.0098); IH NMR (DMSO-d6): o 7.93 (d, lH), 7.82 (d, lH), 7.80-7.50 (m, 2H), 4.10 ~m, IH), 2.53 (m, 2H), 2.18 (m, IH), 1.97 (m, lH), 1.53 (m, 2H), 1.20 (m, 3H), 1.14 (m, 3H), 0.93 (s, 9H), 0.80 (t, 3H). IR
(KBr): 3340, 2980, 2230,1800,1730,1690,1600 cm~l, MS (m/z) 395 (M.
Elemental analysis for C23H2gN3O3 Calc'd: C, 69.85; H,7.39; N, 10.62 Found: C, 69.70; H, 7.46; N, 10.60 -(P)-N-~4-Cvano-2-ethvl-Dhenvl)-N-r3,4-dioxo-2-~1.2,,2-trimethvl-~.uv~ )-cvclûbut-l-envll ~.ov..

(+)-(R)-4-[3,4-Dioxo-2-(1,2,2-trimethyly~ lal~ û)-cyclûbut-l-enylamino]-3-ethylhf n7--ni~ f (0.40 g, 1.23 mmol), propionic anhydride (0.47 mL, 3.67 mmol) and pyridine (3.7 rnL) were mixed and allowed to stand at room t~ lr for 24 hours. The reaction mixture was filtered to remove undissolved solid material and the 20 filtercake was rinsed with dichlvlu..~ ..f . The combined filtrate was ~ f ~ n. l and the resulting yellow gum was crystallized with hexanes (20 mL). Solvent was decanted off and the solid materlal was tritLlrated with hexanes to afford the title compound as 0.45 g (96%) of an off-white solid: IH NMR (CDC13): o 7.70 (s, lH), 7.62 (m, lH), 7.52 (m, lH), 7.37 (m, lH), 4.28 (m, lH), 2.70-2.50 (m, 2H), 2.20-2.09 (m, lH), 2.03-1.92 (m, lH), 1.30-1.24 (m, 6H), 1.09 (t, 3H), 1.00 (d, 9H). IR (KBr):
3330, 2970, 2230, 1800,1730, 1680, 1610 cm~l; MS (mlz) 381 (M+).
Elemental analysis for C22H27N3O3 Calc'd: C, 69.27; H, 7.13; N, 11.02 Found: C, 69.25; H, 7.30; N, 10.96 ~R)-(-)-N-~4-Cvano-~ I)-N-r3.4-dio%o-2-~1.2.2-trimethvl-. Ju~a ' r,l-cvclobut-l-envll-.~

CA 0220~307 1997-0~-14 Wo 96/15103 PCrtUSsS/13125 (+)-(R)4-[3,4 Dioxo-2-(1,2,2-trimethyl-~!"vp~la,l,.l,o)-cyclobut-1-enylamino]-3-GLllyli~ n~ ' (0.40 g, 1.23 mmol), crotonie anhydride (0.55 mL, 3.71 mmol) and pyridine (3.7 mL) were mixed and allowed to stand at rggm t~ ~dL~ for 24 S hours. The reaction mixture was filtered to remove ~ vl~ solid material and the filtercake was rinsed with dichlvl~,lll.,Llla-l. . The eombined filtrate was - ~and the resuling red-brown solid was triturated with hexanes to afford the titleeompound as 0.48 g (999~o) of an off-white sslid: []25D -2451 (DMSO, e 0.011);IH NMR (CDC13): o 7.70 (s, lH), 7.68-7.55 (m, 2H), 7.34 (m, lH), 7.22 (m, lH), 5.54 (m, lH), 4.28 (m, IH), 2.67-2.48 (m, 2H), 1.84 (m, 3H), 1.27 (m, 3H), 1.24 (t, 3H), 1.00 (d, 9H). IR (KBr): 3450, 3300, 2980, 2230, 1790, 1725,1675,1625 em~l;
MS (m/z) 393 (M+).
.. ..
Elemental analysis for C23H27N3O3 Calc'd: C, 70.21; H, 6.g2; N, 10.68 Found C, 69.91; H, 7.04; N, io.49 -EXA~lPLli' 30 (R)-~-)-N-(4-Cvano-2-ethvl-Dhenvl)-N-~3,4-dioxo-2-(1 .2.2-trimethvl-u.~.,.'a ~)-evelobut-1-envll-ae~ mide (+)-(R)-4~[3,4-Dioxo-2-(1,2,2-trimethyl-~1vl,yla.,~i,,o)-cyclobut-l-enylamino]-3-ethylh- n7r-nilril~ (0.36 g, 1.11 mmol), aee~ic anhydride (0.31 mL, 3.29 mmol) and pyridine (3.4 mL) were mixed and allowed to stand at room t~ dlUlC for 24 hours.25 The reaction mixture was filtered to remove undissolved solid material and the filtercake was rinsed with ethyl acetate. The combined filtrate was ~ and the resulting solid was purified by reerystalli_ation (EtOAc/CH2CI2) and trituraion (EtOAe) to afford the title compound as 0.29 g (71%) of a whi~e solid: mp 229-231C; [a]25D -224.43 (DMSO, c 0.0092); IH NMR (CDC13): o 7.72 (s, IH), 7.64 (m, lH), 7.54-7.40 (m, lH), 7.38 (m, lH), 4.37 (m, lH), 2.72-2.53~(m, 2H), 1.92 (s, 3H), 1.32-1.23 (m, 6H), 0.99 (d, 9H). IR (KBr): 3450, 3340, 2970, 2240, 1800, 1725, 1680,1610 cm-l ; MS (mlz) 367 (M+l.
Elemental analysis for C2lH2sN3O3 ~ ._ CA 0220~307 1997-0~-14 wt~ 96115103 ~ 5 Calc'd: C, 68.64; Il, 6.86; N, 11.43 Found: C, 68.31; H, 6.82; N, 11.25 ~XAMPLE 31 (R)-(-)-N-(4-C -2-ethvl-Dhglvl)-N.r3.4~ )xo-2-(1.~ ~-trimethvl-I,.v.,~'a ~)-evelobut-l-envll r. '~
(+)-(R)-4-[3,4-Dioxo-2-(1,2,2-ttimethyl-1u.vu~ lo)-cyclobut-l-enylamino]-3-c~ (0.40 g, 1.23 mmol), valeric anhydride (0.73 mL, 3.62 mmol) and 10 pyridine (3.7 mL) were mixed and allowed to stand at room ~ ,u~,.aLulc for 24 hours.
The reaction mixture was filtered to remove undissolved solid material and the filtercake was rinsed with dichlululll~ --c. The combined filtrate was ..,..- ~
and the resulting yellow gum was crystallized with hexanes (2û mL). Solvent was decanted off and the solid was rriturated with hexanes to afford the title compound as û.47 g (93%) of an off-white solid: []2~D -199.û (DMSO, c o.ûû98j; 1H NMR
(CDC13): ~ 7.71 (s, lH), 7.63 (d, lH), 7.58-7.42 (m, 1H), 7.37 (t, lH), 4.28 (m, lH), 2.69-2.50 (m, 2H), 2.17-2.05 (m, lH), 2.û1-1.90 (m, IH), 1.57 (m, 2H), 1.3û-1.2û (m, 8H), 0.99 (d, 9H), 0.85 (t, 3H). IR (KBr): 3430, 333û, 2970, 224û, 180û, 173û, 1690, 1610 cm-l; MS (m/z) 409 (M+).
Elemental analysis for C24H3lN3O3 ~=
Calc'd: C,70.39; H,7.63; N, 10.26 Found: C,70.31; H,7.8û; N,10.20 ~R)-~-)-N-~4-cvano-2-ethvl-Dhenvl)-N-r3~4-dioxo-2-(1 2.2-trimethvl-D. uu .~l~ ' .)-evelobut-l-envll-.v.~' . I'vu,~a... dE
~ (+)-(R)-4-[3,4-Dioxo-2-(1,2,2-trimethyl-~.uu~ .i..o)-cyclobut-l-enylamino~-3û 3-ethylhf~n~nnitril~ (0.50 g, 1.54 g), uy~ bu~ylic acid anhydride (0.92 g,3.86 mmol) and pyridine (15 mL) were eombined and stirred at room t~ ,U~ ulC for2 days. The mixture was filtered and stripped free of solvent. The resulting oil was crystallized with diethyl c~ll~,i/l..".~cj and the solid which formed was filtered off and recrystallized (EtOAclhexanes) to afford the title compound as 0.39 g (58%) of a CA 0220~307 1997-0~-14 Wo 9G/15103 white solid: mp 156-159C; []2~D -226.61 (DMSO, c 0.0096), IH NMR (CDC13):
o 7.72 (s, lH), 7.62 (d, IH), 7.57-7.40 (m, IH), 7.38 (m, IH), 4.28 (m, IH), 2.69-2.48 (m, 2H), 2.04-1.94 (m, IH), 1.78-1.65 (m, 3H), 1.65-1.57 (m, 3H), 1.50-1.48 (m, lH), 1.30-1.23 (m, 6H), 1.23-1.12 (m, IH), 1.07-0.87 (m, 2H), 0.99 (d, 9H). rR (KBr):3430, 3340, 2940, 2230,1800, 1730, 1690, i610 cm-l; MS (m/z) 435 (M.
Elemental analysis for C26H33N3O3 Calc'd: C, 71.70; H, 7.64; N, 9.65 Found: C,71.88; H,1.64; N,9.61 EXAMPI,I; 33 (R)-(-)-N-(3-Chloro-i-cvano-Dhenvl)-N-r3.4-dioxo-2-(l~2~-trimethvl-L~vu~la~ o)-cv~lobut-l-envll-a~
4-Amino-2-chlcl.,l,- ,,."-;~ (3.14 g, 20.6 mmol) was added to a solution of 3,1 diethoxy-3-~,y-,lol,u;~ -1,2-dione (3.5:g, 20.6 mmoij in absolute ethanol (41 mL).
The mixture was heated at reflux ovemight and the resulting suspension filoered hot.
The filtrate was ~,v~ ldt~,.l to afford a yellow solid which was suspended in ethyl acetate, filtered, and washed several times with ethyl acetateto give 1.16 g of a yellow solid. This solid (0.5 g, 1.8 mmol) was stirred in a solution of (R)-1,2,2-trimethyl-IJlV~yldl~ c (3.6 mmol) and ethanol (18 mL) at room ~ dlUlC for 24 hours. The reaction mixture was filtered and rinsed with ethyl acetate to give 0.53 g (88%) of -(R)-(+)-4-[3,4-dioxo-2-(1,2,2-trimethyl-~1v~,rid.ll;l.v)-cyclobut-l-enylamino]-2-,lllul~ ., ,. .,, i l, ;l.~ a yellow solid: mp >300C; [] 2~ = ~1.87 (DMSO, c 0.010); IH
NMR (DMSO-d6): o 10.04 (brs, lH), 7.91 (d, lH), 7.87 (d, IH), 7.76 (brd, lH), 7.40 (dd, lH), 3.98 (rn, IH), 1.18 (d, 3H), 0.91 (s, 9H). IR (KBr): 3200, 2970, 2230, 1800,1675,1575 cm-l; MS (mlz) 331 (M+).
Elemental analysis for Cl7Hl8clN3o2 Calc'd: C, 61.54; H,5.47; N, 12.66 Found: C, 61.29; H, 5.46; N, 12.is - -This compound was prepared according to the procedure described in Example 12, second pargraph. From the product of the preceding paragraph (0.27 g, CA 0220 j307 1997 ~ 0 j ~ 14 WO 96115103 F~ ~5,~ S

0.81 mmol) and æetic anhydride (0.23 mL, 2.4 mmol) in pyridine (2.5 mL) dhere was obtained 0.16 g (53%) of the tide compound as a white solid: mp 232-235C (dec);[~x]" = -307 5 ~DMSO, c 0.010); IH NMR (CDC13): ~ 7.82 (d, lEI), 7.53 (d, lH), 7.38 (dd, lH), 7.34 (brd, IH), 4.26 ~m, lH), 2.05 (s, 3H), 1.25 (d, 3H), 0.99 (s, 9H).
IR (KBr): 3330, 2980, 2220, 1795, 1745, 1625 cm~l; MS (m,'z) 374 ([M+H]+).
Elemental analysis for ClgHzoClN3O3 Calc'd: C,61.04; H,5.39; N,11.24 ~;ound: C,60.83; H,5.31; N,ll.10 The smooth muscle relaxing activity of the . ..".~ ,fl~ of this invention was f ct~hlichf d in accordance with standard ~ ;. ,.lly accepted test procedures with IC~ C~ iV~ cnmro -nf1c as follows:
Sprague-Dawley rats (150-200 g) are rendered ~-~-f ~ ifJI c by C2 f ~ and then euthanized by cervical ~i Qlnf~tinn The bladder is removed into warm (37 deg.C) physiological salt solution (PSS) of the following ~ ,n~
(mM): NaCI, 118.4; KCI, 4.7; CaCI2, 2.5; MgSO4, 4.7; H2O, 1.2; NaHCO3, 24.9;
KH2PO4, 1.2; glucose, 11.1; EDTA, 0.023; gassed with 95% 2; 2/5% CO2; pH 7.4.
The bladder is opened and then cut into strips 1-2 mm in widdh and 7-10 mm in lengdh. The strips are ~ - lly suspended in a 10 mL tissue bath under an initialresting tension of 1.5 g. The sttips 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 ~ which usually exhibit small ~ c-",~ s 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 ætivity. Following a further 30 min period of recovery an additional 15 mM KCI are introdu~ ed into dhe tissue bath. This increase in KCI ~ results in a large increase in dhe amplitude of ~ (and initiation of f ~ ., .s in previously quiescent strips) ~ s~ upon a small increase in basal tone.
Following ct~hili7~lfinn of this enhanced level of contractile activity, i~ ."~lincreases in the; nn of test compound or vehicle are introduced into the tissue bath. Contractile activity is measured for each compound or vehicle during the last minute of ~ 30 minute cha lenge.

CA 02205307 1997-0~-14 W0961151~3 r~ ,JilJl~S
-38- ~ =
The isometric force developed by the bladder st~ips is measured using a in~l required to elicit 50% inhibilion of pre-drug contractile acivity (ICso ,Ui.~.l) is calculated from this ~,"~ -response curve. The maximum 5 percentage inhibition of contractile acivity evoked by a test compound is slso recorded for ~ c of test compound less than or equal to 30 The results of this study are shown in Table 1.

= ' -- .
-CA 0220~307 1997-0~-14 wo 96rlsl03 ~ ~.lIU ,3~ 5 ~ Table I
Inhibition of ('cmtr~rt~r~n~ in Isolated Rat Bladder Smns S
Compound n ICs~
Example 1 2 0.50iO.0 Example 2 2 0.29_0.04 Example 5 2 0.35+0.1 Example 6 4 0.$7 0.2 Example 7 2 0.37+0.08 Exarnple 9 4 0.23+0.05 Example 10 2 0.31+0.05 Example 11 2 9.7+4.1 Ex~mple 13 2 0.2~0.1 Example 14 2 3.2+0.92 Exa~mple 16 2 1.24_0.54 Example 17 2 1.84+0.36 Example 21 1 10.6 Ex~mple 23 3 - 7.2il.6 Example 24 2 2.5_0.2 Example 25 3 10.8+1.6 Example 26 4 4.9+1.2 Example 27 2 0.17iO.004 Example 28 4 0.22+0.2 Example 29 2 0.27+0.02 Example 30 4 0.35+0.1 Example 31 3 0.61_0.2 Example 32 2 0.63+0.065 Example 33 2 0.19 0.01 Hence, the C'~ J~ of this inven~ion have a IJlUl~UUll~,~d effect on smooth muscle conttactility and are useful in the treatmcnt of urinary i"~ ~,..1;". .1~ e, irlitable -CA 0220~307 1997-05-14 WO 9611S103 I ~ 125 bladder and bowel di~ease, asthma, I~ , stroke, and similar diseases as mentioned above, which are amenable to treatment with potassium channel activating by ~ orally, parenterally, or by aspiration to a patient in need :

Claims (2)

What is claimed is:

A compound of the formula:
(I) wherein:
R1 and R2 are, independent from each other, hydrogen, C1-10 straight chain alkyl, C1-10 branched alkyl, or C3-10 cyclic or bicyclic alkyl;
R3 is an acyl substituent selected from the group consisting of formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms;
A is selected from the group consisting of:

wherein:
R4 is hydrogen, C1-6 alkyl, C1-6 perfluoroalkyl, C1-6 alkoxy, C1-6 perfluoroalkoxy, amino, C1-6 alkylamino, C2-12 dialkylamino, C1-6 alkylsulfonamido, alkylcarboxamido containing 2 to 7 carbon atoms, nitro, cyano, carboxyl;

or, A is a phenyl group of the following formula:

wherein:
R5 and R6, independent from each other, are selected from the following: cyano, nitro, amino, C1-6 alkyl, C1-6 perfluoroalkyl, C1-6 alkoxy, C1-6 perfluoroalkoxy, C1-6 alkylamino, C2-12 dialkylamino, sulfamyl, C1-6 alkylsulfonamido, C6-12 arylsulfonamido, alkylcarboxamido containing 2 to 7 carbon atoms, arylcarboxamido containing 7 to 13 carbon atoms, C2-6 alkanoyl, C1-6 alkylsulfonyl, C1-6 perfluoroalkylsulfonyl, C6-12 arylsulfonyl, chloro, bromo, fluoro, iodo, 1-imidazolyl, carboxyl or hydrogen;
or a pharmaceutically acceptable salt thereof.

A compound of Claim 1 in which A is selected from the following:

wherein:
R4 is as defined in Claim 1;
or, A is a phenyl group of the following formula:
wherein:
R5 and R6, independent from each other, are selected from the following: cyano, nitro, amino, chloro, bromo, fluoro, iodo, 1-imidazolyl, alkyl or 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms, carboxyl or hydrogen;
or a pharmaceutically acceptable salt thereof.

A compound of Claim 1 in which A is selected from the following:
wherein:
R4 is as defined in Claim 1;
or, A is a phenyl group of the following formula:
wherein:
R6 and R6, independent from each other, are selected from the following: cyano, nitro, amino, chloro, bromo, fluoro, iodo,

1-imidazolyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 catbon atoms, carboxyl or hydrogen;
or a pharmaceutically acceptable salt thereof.

3-Alkylamino-4-[ (substituted phenyl)amino]-cyclobut-3-ene-1,2-dione in whieh said alkyl group contains 1 to 6 carbon atoms and the phenyl group is substituted by one or two members selected from the group consisting of cyano, nitro, amino, halo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms,trifluoroalkyl of 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms, and carboxyl groups, and the amino group in 4-position of the cyclobut-3-ene-1,2-dione is substituted with a member of the group consisting of alkylcarbonyl of 2 to 6 carbon atoms, alkenylcarbonyl of 3 to 6 carbon atoms or arylcarbonyl of 7 to 12 carbon atoms.

A compound of Claim 1 which is N-(4-cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-propionamide.

A compound of Claim 1 which is N-(4-cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-benzamide.

A compound of Claim 1 which is N-(4-cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-methanesulfonamide.

A compound of Claim 1 which is N-(4-cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-formamide.

A compound of Claim 1 which is hexanoic acid N-(4-cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-amide.

A compound of Claim 1 which is N-(4-cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino-cyclobut-1-enyl]-isobutyramide.

A compound of Claim 1 which is N-(4-cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-phenyl-acrylamide.

A compound of Claim 1 which is N-(4-cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-carbamic acid ethyl ester.

A compound of Claim 1 which is N-(4-cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-acetamide.

A compound of Claim 1 which is (R)-(-)-N-(4-cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-acetamide.

A compound of Claim 1 which is N-(4-cyano-phenyl)-N-[3,4-dioxo-2-isopropylamino-cyclobut-1-enyl]-acetamide.

A compound of Claim 1 which is N-(4-cyano-phenyl)-N-[2-(1,2-dimethyl-propylamino)-3,4-dioxo-cyclobut-1-enyl]-acetamide.

A compound of Claim 1 which is N-(3-cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-acetamide.

A compound of Claim 1 which is (R)-N-(4-cyano-phenyl)-N-[2-(1-cyclohexyl-ethylamino)-3,4-dioxo-cyclobut-1-enyl]-acetamide.

A compound of Claim 1 which is N-(2-butylamino-3,4-dioxo-cyclobut-1-enyl)-N-(4-cyano-phenyl)-acetamide.

A compound of Claim 1 which is N-(endo)-[2-(bicyclo[2.2.1]hept-2-ylamino)-3,4-dioxo-cyclobut-1-enyl]-N-(4-cyano-phenyl)-acetamide.

A compound of Claim 1 which is N-(2-tert-butylamino-3,4-dioxo-cyclobut-1-enyl)-N-(isoquinolin-5-yl)-acetamide.

A compound of Claim 1 which is N-(2-tert-butylamino-3,4-dioxo-cyclobut-1-enyl)-N-(pyridin-3-yl)-acetamide.

A compound of Claim 1 which is N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-N-(2-methoxy-5-trifluoromethyl-phenyl)-acetamide.

A compound of Claim 1 which is (endo)-N-[2-(bicyclo[2.2.1]hept-2-ylamino)-3,4-dioxo-cyclobut-1-enyl]-N-(pyridin-4-yl)-acetamide.

A compound of Claim 1 which is N-(2-sec-butylamino-3,4-dioxo-cyclobut-1-enyl)-N-(4-cyano-phenyl)-acetamide.

A compound of Claim 1 which is N-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-N-(pyridin-3-yl)-acetamide.

A compound of Claim 1 which is N-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-N-(pyridin-4-yl)-acetamide.

A compound of Claim 1 which is N-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-3-methyl-N-(pyridin-4-yl)-butyramide.

A compound of Claim 1 which is N-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-N-(pyridin-4-yl)-pentylamide.

A compound of Claim 1 in which A is where R6 is alkyl of 1 to 3 carbon atoms, chloro, bromo, fluoro or iodo, or a pharmaceutically acceptable salt thereof.

A compound of Claim 1 in which A is where R6 is alkyl of 1 to 3 carbon atoms, or a pharmaceutically acceptable salt thereof.

A compound of Claim 1 in which A is where R6 is chloro, bromo, fluoro or iodo, or a pharmaceutically acceptable salt thereof.

A compound of Claim 1 which is N-(4-cyano-2-ethyl-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-butyramide or a pharmaceutically acceptable salt thereof.

A compound of Claim 1 which is N-(4-cyano-2-ethyl-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-propylamide or a pharmaceutically acceptable salt thereof.

A compound of Claim 1 which is N-(4-cyano-2-ethylphenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-crotonamide or a pharmaceuticallyacceptable salt thereof.

A compound of Claim 1 which is N-(4-cyano-2-ethyl-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-acetamide or a pharmaceutically acceptable salt thereof.

A compound of Claim 1 which is N-(4-cyano-2-ethyl-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-pentanamide or a pharmaceutically acceptable salt thereof.

A compound of Claim 1 which is N-(4-cyano-2-ethyl-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof.

A compound of Claim 1 which is N-(3-chloro-4-cyano-phenyl)-N-[3,4 dioxo-

2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-acetamide or a pharmaceuticallyacceptable salt thereof.

A method for reducing the adverse effects of smooth muscle contractions which comprises administering, orally or parenterally, to a patient in need thereof, a compound of the formula:

(I) wherein:
R1 and R2 are, independently from each other, hydrogen, C1-10 straight chain alkyl, C1-10 branched alkyl, or C3-10 cyclic or bicyclic alkyl;
R3 is an acyl substituent selected from the group consisting of formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms;
A is selected from the group consisting of:

wherein:
R4 is hydrogen, C1-6 alkyl, C1-6 perfluoroalkyl, C1-6 alkoxy, C1-6 perfluoroalkoxy, amino, C1-6 alkylamino, C2-12 dialkylamino, C1-6 alkylsulfonamido, alkylcarboxamido containing 2 to 7 carbon atoms, nitro, cyano, carboxyl;

or, A is a phenyl group of the following formula:

wherein:
R5 and R6, independent from each other, are selected from the following: cyano, nitro, amino, C1-6 alkyl, C1-6 perfluoroalkyl, C1-6 alkoxy, C1-6 perfluoroalkoxy, C1-6 alkylamino, C2-12 dialkylamino, sulfamyl, C1-6 alkylsulfonamido, C6-12 arylsulfonamido, alkylcarboxamido containing 2 to 7 carbon atoms, arylcarboxamido containing 7 to 13 carbon atoms, C2 to 6 alkanoyl, C1-6 alkylsulfone, C1-6 perfluoroalkylsulfone, C6-12 arylsulfone, chloro, bromo, fluoro, iodo, 1-imidazolyl, carboxyl or hydrogen;
or a pharmaceutically acceptable salt thereof.

The method of Claim 10 in which the smooth muscle adversely contracting causes urinary incontinence.

The method of Claim 10 in which the smooth muscle adversely contracting causes irritable bowel syndrome.

A pharmaceutical composition comprising a compound as claimed in any one of Claims 1 to 39, in combination or association with a pharmaceutically acceptable carrier.

A process for preparation of a compound as claimed in Claim 1, which comprises reaction of a compound having the formula (IIa):
(IIa) wherein X is a leaving group, for example, methoxy, ethoxy, isopropoxy, halogen or a similar leaving group and A1 is A and Ra3 is R3, as defined hereinbefore or a group of atoms convertible thereto, with a compound of formula (IV):

(IV) wherein Ra1 and Ra2 are R1 and R2, respectively, as defined hereinbefore or a group of atoms convertible thereto and, where appropriate, converting A1 into A or converting Ra1 into R1 or converting Ra2 into R2, followed by reacylation if necessary and, where desired, converting a compound having formula (I) into a pharmaceutically acceptable salt thereof or converting a salt of a compound having formula (I) into a compound having formula (I).