U.S. patent application number 10/098140 was filed with the patent office on 2002-11-28 for 4-substituted-3-substituted-amino-cyclobut-3-ene-1,2-diones and analogs thereof as novel potassium channel openers.
This patent application is currently assigned to American Home Products Corporation. Invention is credited to Butera, John Anthony, Jenkins, Douglas John, Lennox, Joseph Richard.
Application Number | 20020177613 10/098140 |
Document ID | / |
Family ID | 26833393 |
Filed Date | 2002-11-28 |
United States Patent
Application |
20020177613 |
Kind Code |
A1 |
Butera, John Anthony ; et
al. |
November 28, 2002 |
4-substituted-3-substituted-amino-cyclobut-3-ene-1,2-diones and
analogs thereof as novel potassium channel openers
Abstract
4-Substituted-3-substituted-amino-cyclobut-3-ene-1,2-diones
having the Formula (I): 1 wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, A and W are as defined in the specification which
compounds relaxes smooth muscles.
Inventors: |
Butera, John Anthony;
(Clarksburg, NJ) ; Lennox, Joseph Richard;
(Cardiff by the Sea, CA) ; Jenkins, Douglas John;
(Wilmington, NC) |
Correspondence
Address: |
WYETH
FIVE GIRALDA FARMS
MADISON
NJ
07940
US
|
Assignee: |
American Home Products
Corporation
Madison
NJ
07940
|
Family ID: |
26833393 |
Appl. No.: |
10/098140 |
Filed: |
March 12, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10098140 |
Mar 12, 2002 |
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09713061 |
Nov 15, 2000 |
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6376555 |
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09713061 |
Nov 15, 2000 |
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09454051 |
Dec 3, 1999 |
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60135498 |
Dec 4, 1998 |
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Current U.S.
Class: |
514/344 ;
514/345; 514/346; 514/525; 514/646; 546/286; 546/290; 546/291;
558/418; 564/307 |
Current CPC
Class: |
C07C 225/20 20130101;
C07C 2601/04 20170501; C07C 271/24 20130101; C07D 213/50 20130101;
C07C 255/58 20130101 |
Class at
Publication: |
514/344 ;
514/345; 514/346; 514/525; 514/646; 558/418; 564/307; 546/286;
546/290; 546/291 |
International
Class: |
A61K 031/44; A61K
031/277; C07D 213/63; C07D 213/70; A61K 031/135 |
Claims
What is claimed is:
1. A compound having the Formula (I): 32wherein: R.sub.1, R.sub.2,
and R.sub.3, are, independently, hydrogen, halogen, nitro, cyano,
alkyl of 1 to 10 carbon atoms (optionally substituted with
halogen), cycloalkyl of 3 to 10 carbon atoms, --OR.sub.7, amino,
alkylamino of 1 to 10 carbon atoms, --SO.sub.3H,
--SO.sub.2NH.sub.2, --SONH.sub.2, --NHSO.sub.2R.sub.7,
33--SO.sub.2R.sub.7, 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, --CH.sub.2--, --CH.dbd.CH-- and
--CHCOR.sub.6; W is selected from the group consisting of carbon
and nitrogen and wherein the carbon atom may be optionally
substituted with -R.sub.1, -R.sub.2 and -R.sub.3; R.sub.4 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, --OR.sub.7, 34trifluoromethyl or trifluoromethoxy;
R.sub.5 is hydrogen, alkyl of 1 to 10 carbon atoms, formyl,
alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms,
35--SO.sub.2R.sub.7, 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; R.sub.6 is alkyl of 1 to 10 carbon atoms, or aryl
of 6 to 12 carbon atoms; R.sub.7 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, --CF.sub.3,
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 R.sub.1
and R.sub.2 are H; R.sub.3 is selected from the group consisting of
H, 4-methyl, 4-chloro, 4-nitro and 4-methoxy; and R.sub.4 and
R.sub.5 are simultaneously methyl or ethyl; b) when R.sub.1,
R.sub.2, R.sub.3 and R.sub.5 are H; and R.sub.4 is butyl; c) when
R.sub.1, R.sub.2 and R.sub.5 are H; R.sub.3 is 4-halo and R.sub.4
is alkyl of 1 to 4 carbon atoms; d) when R.sub.1 is selected from
the group consisting of H, 2-methyl, 2-ethyl and 2-methoxy; R.sub.2
and R.sub.5 are H; R.sub.3 is 4-dimethylamino and R.sub.4 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.dbd.CH-- or a pharmaceutically acceptable
salt thereof.
4. A compound according to claim 1 wherein W is nitrogen and A is
--CH.dbd.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 --CH.sub.2-- or a pharmaceutically acceptable
salt thereof.
6. A compound according to claim 1 wherein W is nitrogen and A is
--CH.sub.2-- or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 1 wherein W is a carbon bearing a
hydrogen and A is 36or a pharmaceutically acceptable salt
thereof.
8. A compound according to claim 1 wherein W is nitrogen and A is
37or 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 R.sub.3 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 of a pharmaceutically
acceptable salt thereof.
12. The compound of claim 1 which is
3-(1,1-dimethyl-propylamino)-4-(4-met-
hoxy-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-metho-
xy-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-trimeth-
yl-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-trifluor-
omethyl-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-phe-
nyl-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-prop-
ylamino)-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-propy-
lamino)-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-d-
imethyl-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-(pyrid-
in-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-d-
imethoxy-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-bro-
mo-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-bro-
mo-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-bro-
mo-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 pharmaceutically 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-trimeth-
yl-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-propylam-
ino)-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-trimethy-
l-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) 38wherein: R.sub.1,
R.sub.2, and R.sub.3, are, independently, hydrogen, halogen, nitro,
cyano, alkyl of 1 to 10 carbon atoms (optionally substituted with
halogen), cycloalkyl of 3 to 10 carbon atoms, --OR.sub.7, amino,
alkylamino of 1 to 10 carbon atoms, --SO.sub.3H, --SO.sub.2N.sub.2,
--SONH.sub.2, --NHSO.sub.2R.sub.7, 39--SO.sub.2R.sub.7, 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,
--CH.sub.2--, --CH.dbd.CH-- and --CHCOR.sub.6; W is selected from
the group consisting of carbon and nitrogen and wherein the carbon
atom may be optionally substituted with -R.sub.1, -R.sub.2 and
-R.sub.3; R.sub.4 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, --OR.sub.7, 40trifluoromethyl or trifluoromethoxy;
R.sub.5 is hydrogen, alkyl of 1 to 10 carbon atoms, formyl,
alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms,
41--SO.sub.2R.sub.7, 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; R.sub.6 is a chain alkyl of 1 to 10 carbon atoms,
or aryl of 6 to 12 carbon atoms; R.sub.7 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, --CF.sub.3,
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.dbd.CH-- or a
pharmaceutically acceptable salt thereof.
41. A pharmaceutical composition according to claim 38 wherein W is
nitrogen and A is --CH.dbd.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 --CH.sub.2-- or a
pharmaceutically acceptable salt thereof.
43. A pharmaceutical composition according to claim 38 wherein W is
nitrogen and A is --CH.sub.2-- 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 42or a pharmaceutically
acceptable salt thereof.
45. A pharmaceutical composition according to claim 38 wherein W is
nitrogen and A is 43or 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 R.sub.3 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); 44wherein: R.sub.1, R.sub.2, and R.sub.3,
are, independently, hydrogen, halogen, nitro, cyano, alkyl of 1 to
10 carbon atoms (optionally substituted with halogen) cycloalkyl of
3 to 10 carbon atoms, --OR.sub.7, amino, alkylamino of 1 to 10
carbon atoms, --SO.sub.3H, --SO.sub.2NH.sub.2, --SONH.sub.2,
--NHSO.sub.2R.sub.7, 45--SO.sub.2R.sub.7, 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, --CH.sub.2--,
--CH.dbd.CH-- and --CHCOR.sub.6; W is selected from the group
consisting of carbon and nitrogen and wherein the carbon atom may
be optionally substituted with -R.sub.1,-R.sub.2and -R.sub.3;
R.sub.4 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.sub.7, 46trifluoromethyl or
trifluoromethoxy; R.sub.5 is hydrogen, alkyl of 1 to 10 carbon
atoms, formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7
carbon atoms, 47--SO.sub.2R.sub.7, 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; R.sub.6 is alkyl of 1 to
10 carbon atoms, or aryl of 6 to 12 carbon atoms; R.sub.7 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, --CF.sub.3, 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.dbd.CH-- or a pharmaceutically acceptable
salt thereof.
53. A method according to claim 48 wherein W is nitrogen and A is
--CH.dbd.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 --CH.sub.2-- or a pharmaceutically acceptable
salt thereof.
55. A method according to claim 48 wherein W is nitrogen and A is
--CH.sub.2-- or a pharmaceutically acceptable salt thereof.
56. A method according to claim 48 wherein W is a carbon bearing a
hydrogen and A is 48or a pharmaceutically acceptable salt
thereof.
57. A method according to claim 48 wherein W is nitrogen and A is
49or 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 R.sub.3 is alkoxy of 1 to 10 carbon atoms
or a pharmaceutically acceptable salt thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Provisiodal
Application No. 60/135,498, which was converted from U.S. patent
application Ser. No. 09/206,012, filed Dec. 4, 1998 pursuant to a
petition filed under 37 C.F.R. 1.53 (c)(2) filed Feb. 16, 1999
BACKGROUND OF INVENTION
[0002] 1. Field of the Invention
[0003] 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.
[0004] 2. Description of the Prior Art
[0005] 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. Neuroscience
1988, 25, 729-749; Atwal, K., Medicinal Research Reviews 1992, 12,
569-591; Gopalakrishnan, M. et al., Drug Development Research 1993,
28, 95-127; Primeau, J. et al., Current Pharmaceutical Design 1995,
1, 391-406; Edwards, G. et al., Exp. Opin. Invest. Drugs 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.
[0006] A series of N-aryl and
N-heteroaryl-1,2-di,amino-cyclobutene-3,4-di- ones disclosed by
Butera et al., in U.S. Pat. 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. Pat. Nos. 5,464,867 and
5,512,585 have the ability to hyperpolarize smooth muscle tissue
via activation of the ATP-dependent potassium channel (K.sub.ATP).
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.
[0007] A series of 1,2-diamino derivatives of
cyclobutene-3,4-diones disclosed by Butera et al., in U.S. Pat. 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.
[0008] Kinney et al., in U.S. Pat. No. 5,240,946 discloses
3,4-diamino-3-cyclobutene-1,2-diones as NMDA antagonists.
[0009] Algieri et al., in U.S. Pat. No. 4,390,701 discloses
1-(substituted-amino)-2-(amino or substituted
amino)cyclobutene-3,4-dione- s which are histamine H.sub.2
antagonists useful in the treatment of peptic ulcers. Additionally,
Nohara, et al., in U.S. Pat. No. 4,673,747 disclose substituted
aminoalkylphenoxy derivatives which exert antagonism against
histamine H.sub.2 receptors.
[0010] A series of p-substituted phenyl-cyclobutenediones are
reported as substrates and intermediates for monothionation
reactions by Muller et al. Synthesis 1997,1,50-52. Related
compounds are described by Schmidt et al. Synthesis 1990,7,579-582
in a paper on Meerwein-arylation of semisguaric acids and
semisquaric amides. Unsubstituted phenyl-cyclobutenediones are
reported as reaction products between cyclobutenediones and
aziridines by Ried et al. Liebiags Ann. Chem. 1975,.1863-1872.
[0011] In an effort to generate multiple core structure libraries
by combinatorial chemistry, P. A. Tempest et al. J. Am. Chem. Soc.
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.
[0012] -N-Substituted-3-amino-4-phenylcyclobutenediones are
reported by J. E. Thorpe J. Chem. Soc. (B), 1534-1535(1968) in
conjunction with proton nuclear magnetic resonance spectra studies
of squaramides.
[0013] A series of p-halophenylcyclobutene diones 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. Pat. No. 5,106,997, and Nishikata et al.,
in U.S. Pat. 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.
[0014] 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 WO9401436-A1.
[0015] Additionally, 3-acyl-3-cyclobutene-1,2-diones are reported
in several synthetic methodology papers: L. S. Liebeskind et al. J.
Org. Chem. 1993,58(13), 3543-3549; L. Sun et al., J. Org. Chem.
1995, 60(25), 8194-8203.
[0016] 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.
SUMMARY OF THE INVENTION
[0017] Accordingly, the present invention discloses compounds
represented by Formula (I): 2
[0018] wherein:
[0019] R.sub.1, R.sub.2, and R.sub.3, are, independently hydrogen,
halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms (optionally
substituted with halogen), cycloalkyl of 3 to 10 carbon atoms,
--OR.sub.7, amino, alkylamino of 1 to 10 carbon atoms, SO.sub.3H,
--SO.sub.2NH.sub.2, --SONH.sub.2, --NHSO.sub.2R.sub.7, 3
[0020] --SO.sub.2R.sub.7, carboxyl, aryl of 6 to 12 carbon atoms or
aroyl of 7 to 12 carbon atoms;
[0021] A is a moiety selected from the group consisting of a bond,
--CH.sub.2--, --CH.dbd.CH-- and --CHCOR.sub.6;
[0022] W is selected from the group consisting of carbon and
nitrogen and wherein the carbon atom may be optionally substituted
with -R.sub.1 -R.sub.2 and -R.sub.3.
[0023] R.sub.4 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, --OR.sub.7, 4
[0024] trifluoromethyl or trifluoromethoxy;
[0025] R.sub.5 is hydrogen, alkyl of 1 to 10 carbon atoms, formyl,
alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms,
5
[0026] --SO.sub.2R.sub.7, 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;
[0027] R.sub.6 is alkyl of 1 to 10 carbon or aryl of 6 to 12 carbon
atoms;
[0028] R.sub.7 is alkyl of 1 to 10 carbon atoms (optionally
substituted with halogen);
[0029] 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, --CF.sub.3, and phenyl;
[0030] 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;
[0031] with the following provisos that A is not a bond and W is
not a carbon bearing a hydrogen;
[0032] a) when R.sub.1 and R.sub.2 are H; R.sub.3 is selected from
the group consisting of H, 4-methyl, 4-chloro, 4-nitro and
4-methoxy; and R.sub.4 and R.sub.5 are simultaneously methyl or
ethyl;
[0033] b) when R.sub.1, R.sub.2, R.sub.3 and R.sub.5 are H; and
R.sub.4 is butyl;
[0034] c) when R.sub.1, R.sub.2 and R.sub.5 are H; R.sub.3 is
4-halo (chloro, bromo, fluoro, or iodo) and R.sub.4 is alkyl of 1
to 4 carbon atoms; and
[0035] d) when R.sub.1 is selected from the group consisting of H,
2-methyl, 2-ethyl and 2-methoxy; R.sub.2 and R.sub.5 are H; R.sub.3
is 4-dimethylamino and R.sub.4 is 2-propyl;
[0036] or pharmaceutically acceptable salts thereof.
[0037] Preferred groups of compounds of Formula (I) of this
invention are those in the subgroups:
[0038] a) compounds having the general formula: 6
[0039] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
as hereinbefore defined;
[0040] b) compounds having the general formula: 7
[0041] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
as hereinbefore defined and W is a carbon bearing a hydrogen;
[0042] c) compounds having the general formula: 8
[0043] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
as hereinbefore defined;
[0044] d) compounds having the general formula: 9
[0045] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
as hereinbefore defined and W is a carbon bearing a hydrogen;
[0046] e) compounds having the general formula: 10
[0047] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
as hereinbefore defined;
[0048] f) compounds having the general formula: 11
[0049] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and
R.sub.6 are as hereinbefore and W is a carbon bearing a
hydrogen;
[0050] g) compounds having the general formula: 12
[0051] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and
R.sub.6 are as hereinbefore defined.
[0052] More preferred compounds of Formula (I) of this invention
are those in the subgroups:
[0053] a) compounds having the general formula: 13
[0054] wherein:
[0055] R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
hereinbefore defined and W is a carbon bearing a hydrogen; and
[0056] b) compounds having the general formula: 14
[0057] wherein:
[0058] R.sub.1, R.sub.2, R.sub.4 and R.sub.5 are hereinbefore
defined, R.sub.3 is alkoxy of 1 to 10 carbon atoms and W is a
carbon bearing a hydrogen
[0059] Specifically preferred compounds of this invention according
to general Formula (I) are the following compounds or
pharmaceutically acceptable salts thereof:
[0060]
3-(1,1-Dimethyl-2-phenyl-ethylamino)-4-(4-methoxy-phenyl)-cyclobut--
3-ene-1,2-dione;
[0061]
3-(1,1-Dimethyl-propylamino)-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,-
2-dione;
[0062]
3-(Isopropyl-methyl-amino)-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2--
dione;
[0063]
3-(4-Methoxy-phenyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-
-1,2-dione;
[0064]
3-(4-Methoxy-phenyl)-4-[2-(3-trifluoromethyl-phenyl)-ethylamino]-cy-
clobut-3-ene-1,2-dione;
[0065]
(-)-3-(4-Methoxy-phenyl)-1-4-((R)-1-phenyl-ethylamino)-cyclobut-3-e-
ne-1,2-dione;
[0066]
3-(4-Methoxy-phenyl)-4-(2-phenyl-propylamino)-cyclobut-3-ene-1,2-di-
one;
[0067]
3-[2-(4-tert-Butyl-phenyl)-ethylamino]-4-(4-methoxy-phenyl)-cyclobu-
t-3-ene-1,2-dione;
[0068]
4-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]benzon-
itrile;
[0069]
3-(4-Trifluoromethyl-phenyl)-4-(1,2,2-trimethyl-propylamino)-cyclob-
ut-3-ene-1,2-dione;
[0070]
4-(4-Trifluoromethyl-phenyl)-3-(1,1-dimethyl-propylamino)-cyclobut--
3-ene-1,2-dione;
[0071]
3-(1,1-Dimethyl-propylamino)-4-(pyridin-3-yl)-cyclobut-3-ene-1,2-di-
one hydrochloride;
[0072]
3-[2-Oxo-1-(4-trifluoromethyl-phenyl)-propyl]-4-(1,2,2-trimethyl-pr-
opylamino)-cyclobut-3-ene-1,2-dione;
[0073]
3-(4-Bromo-phenyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1-
,2-dione;
[0074]
3-(4-Methoxy-benzyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-
-1,2-dione one-quarter hydrate;
[0075]
{2-([1-(4-Methoxy-phenyl)-2-oxo-propyl)]-3,4-dioxo-cyclobut-1-enyl}-
-(1,2,2-trimethyl-propyl)-carbamic acid tert-butyl ester;
[0076]
3-(1,1-Dimethyl-2-phenyl-ethylamino)-4-(3-methoxy-phenyl)-cyclobut--
3-ene-1,2-dione;
[0077]
3-[(E)-2-(4-Bromo-phenyl)-vinyl]-4-(1,2,2-trimethyl-propylamino)-cy-
clobut-3-ene-1,2-dione; and
[0078]
4-{(E)-2-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl-
]-vinyl}-benzonitrile.
[0079] 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 compound of general Formula (II) or a
pharmaceutically acceptable salt thereof. 15
[0080] Wherein:
[0081] R.sub.1, R.sub.2, and R.sub.3, are, independently, hydrogen,
halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms (optionally
substituted with halogen), cycloalkyl of 3 to 10 carbon atoms,
--OR.sub.1, amino, alkylamino of 1 to 10 carbon atoms, --SO.sub.3H,
--SO.sub.2NH.sub.2, --SONH.sub.2, --NHSO.sub.2R.sub.7, 16
[0082] --SO.sub.2R.sub.7, carboxyl, aryl of 6 to 12 carbon atoms or
aroyl of 7 to 12 carbon atoms;
[0083] A is a moiety selected from the group consisting of a bond,
--CH.sub.2--, --CH.dbd.CH-- and --CHCOR.sub.6;
[0084] W is selected from the group consisting of carbon and
nitrogen and wherein the carbon atom may be optionally substituted
with -R.sub.1, -R.sub.2 and -R.sub.3;
[0085] R.sub.4 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.sub.7, 17
[0086] trifluoromethyl or trifluoromethoxy;
[0087] R.sub.5 is hydrogen, alkyl of 1 to 10 carbon atoms, formyl,
alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms,
18
[0088] --SO.sub.2R.sub.7, 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;
[0089] R.sub.6 is alkyl of 1 to 10 carbon atoms, or aryl of 6 to 12
carbon atoms;
[0090] R.sub.7 is alkyl of 1 to 10 carbon atoms (optionally
substituted with halogen);
[0091] 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 to10 carbon atoms, --CF.sub.3, and phenyl;
[0092] 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.
[0093] 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:
[0094] a) compounds having the general formula: 19
[0095] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
as hereinbefore defined for Formula (II);
[0096] b) compounds having the general formula: 20
[0097] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
as hereinbefore defined for Formula (II) and W is a carbon bearing
a hydrogen;
[0098] c) compounds having the general formula: 21
[0099] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
as hereinbefore defined for Formula (II);
[0100] d) compounds having the general formula: 22
[0101] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are
as hereinbefore defined for Formula (II) and W is a carbon bearing
a hydrogen;
[0102] e) compounds having the general formula: 23
[0103] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
as hereinbefore defined for Formula (II);
[0104] f) compounds having the general formula: 24
[0105] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and
R.sub.6 are as hereinbefore defined for Formula (II) and W is a
carbon bearing a hydrogen;
[0106] g) compounds having the general formula: 25
[0107] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and
R.sub.6 are as hereinbefore defined for Formula (II).
[0108] 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:
[0109] a) compounds having the general formula: 26
[0110] wherein:
[0111] R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
hereinbefore defined for Formula (II) and W is a carbon bearing a
hydrogen; and
[0112] b) compounds having the general formula: 27
[0113] wherein:
[0114] R.sub.1, R.sub.2, R.sub.4 and R.sub.5 are hereinbefore
defined for Formula (II), R.sub.3 is alkoxy of 1 to 10 carbon atoms
and W is a carbon bearing a hydrogen.
[0115] For the compounds of Formulae (I) and (II) defined above and
referred to herein, unless otherwise noted, the following terms are
defined:
[0116] Halogen, or halo as used herein means chloro, fluoro, bromo
and iodo.
[0117] 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.
[0118] 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.
[0119] 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.
[0120] 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, --CF.sub.3 and
phenyl.
[0121] 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.
[0122] 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.
[0123] Alkanoyl as used herein refers to --C(O)alkyl where alkyl is
as previously defined.
[0124] Alkenoyl as used herein refers to --C(O)alkenyl where
alkenyl as previously defined.
[0125] Alkoxy as used herein means an --O-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.
[0126] 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, CF.sub.3, 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 --CF.sub.3.
[0127] 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, --CF.sub.3, 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 --CF.sub.3.
[0128] Arylsulfonyl as used herein refers to the radical
--SO.sub.2aryl where aryl is as previously defined
[0129] Arylalkylsulfonyl as used herein refers to the radical
arylalkyl O.sub.2S-- where arylalkyl is as previously defined.
[0130] Phenyl as used herein refers to a 6-membered aromatic
ring.
[0131] 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.
[0132] The range of carbon atoms defines the number of carbons in
the carbon backbone and does not include carbon atoms occurring in
substituent groups.
[0133] 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.
[0134] It is understood by those practicing the art that the
definition of compounds of Formulae (I) and (II) when R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 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,
maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric,
sulfuric, methanesulfonic and similarly known acceptable acids.
Where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, or R.sub.6
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).
[0135] 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 INVENTION
[0136] The compounds of the present invention may be prepared
according to one or more of the general processes outlined
below.
[0137] Compounds of Formulae (I) and (II), wherein A is a bond and
W, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 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.dbd.N), where X is a halogen and R.sub.1,
R.sub.2 and R.sub.3 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 3 where
W and R.sub.1, R.sub.2 and R.sub.3 are herfeinbefore defined.
28
[0138] The resulting substituted-cyclobut-3-ene-1,2-dione
intermediate 3 where W and R.sub.1, R.sub.2 and R.sub.3 are
hereinbefore defined can then be converted by treatment with the
appropriately substituted amine 4 where R.sub.4 and R.sub.5 are
hereinbefore defined in a polar solvent such as ethanol and the
like, forming a direct bond, to give vinyligous amide 5 of Formulae
(I) and (II) where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and
W are hereinbefore defined.
[0139] Compounds of Formulae (I) and (II) wherein A=--CHCOR.sub.6
and R.sub.6 is as described above may be synthesized as shown in
Scheme II by reaction of ketone 6 where W, R.sub.1, R.sub.2,
R.sub.3 and R.sub.6 are hereinbefore defined with diethoxysquaric
acid 7 in the presence of a strong base, such as, but not limited
to, potassium bis(trimethylsilyl)amide in a solvent such as
tetrahydrofuran (THF) or diethyl ether and the like to give ether
intermediate 8 where W, R.sub.1, R.sub.2, R.sub.3 and R.sub.6 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
--CHCOR.sub.6 and W, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
and R.sub.6 are hereinbefore defined. 29
[0140] Compounds of Formulae (I) and (II) wherein A is the moiety
--CH.sub.2-- may be synthesized as shown in Scheme III by a
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 10 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 10, wherein the group
Z is either chloride or bromide, avoids the undesirable
decomposition endemic to benzylic iodides to give benzyl squarate
11 where W, R.sub.1, R.sub.2, and R.sub.3 are hereinbefore defined.
4 Treatment of benzyl squarate 11 with substituted amine 4 where
R.sub.4 and R.sub.5 are hereinbefore defined gives disubstituted
amine squarate 12 of Formulae (I) and (II) where A is --CH.sub.2--
and where W, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
hereinbefore defined. 30
[0141] Compounds of Formulae (I) and (II) wherein A is
--CH.dbd.CH-- may be synthesized as shown in Scheme IV via
iodomethylenation of aldehyde 13 where R.sub.1, R.sub.2, R.sub.3
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.,
T. Am. Chem. Soc. 1986, 108, 7408, giving vinyl iodide 14 where
R.sub.1, R.sub.2, R.sub.3 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 14 is reacted with stannane 1 in the
presence of a Pd(O) reagent such as
benzylchlorobis(triphenylphosphine) palladium,(II) and the like in
the presence of cuprous iodide to give styrenylcyclobutendione
ethyl ester 15 where W, R.sub.1, R.sub.2, and R.sub.3 are
hereinbefore defined. Further treatment of styrenylcyclobutendione
ethyl ester 15 with substituted amine 4 where R.sub.4 and R.sub.5
are hereinbefore defined in a polar solvent such as ethanol and the
like to give disubstituted aminosquarate 16 of Formulae (I) and
(II) where A is --CH.dbd.CH-- and where W, R.sub.1, R.sub.2,
R.sub.3, R.sub.4 and R.sub.5 are hereinbefore defined. 31
[0142] 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 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), asthmas
and hair loss. Furthermore, the compounds of Formula (I) and (II)
are active as potassium channel activators which render them useful
for treatment of 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.sub.ca)
or maxiK
[0143] 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 IC.sub.50 ratios (Table 1).
[0144] 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.
[0145] 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.
[0146] 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.
[0147] 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
.beta.-blocking agents.
[0148] 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.
[0149] 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.
[0150] 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-phenyl-ethylamino)-4-(4-methoxy-phenyl)-cyclobut-3-ene-1-
,2-dione
[0151] Step 1
[0152] Preparation of
3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2- -dione
[0153] 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.degree. 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.
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
(MgSO.sub.4) and concentrated to give crude 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-ph- enyl)-cyclobut-3-ene-1,2-dione
precipitated as a light yellow solid (2.46 g, 54%); .sup.1H NMR
(DMSO-d.sub.6) .delta.7.89(d,2H), 7.15(d,2H), 5.45(hept,1H),
3.82(s,3H), 1.48(d,6H).
[0154] Step 2
[0155] Preparation of
3-(1,1-Dimethyl-2-phenyl-ethylamino)-4-(4-methoxy-ph-
enyl)-cyclobut-3-ene-1,2-dione
[0156] 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.degree. C. overnight then 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 (83%) of the title product as a tan solid: m.p. 150-151.degree.
C.; .sup.1H NMR (DMSO-d.sub.6) .delta.8.28(s,1H), 8.00(m,2H),
7.28(m,2H), 7.26(m,1H), 7.13(m,2H), 7.09(m,2H), 3.82(8,3H),
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 cm.sup.-1; MS
(m/z) 335 [M.sup.+].
[0157] Elemental analysis for C.sub.21H.sub.21NO.sub.3:
1 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-Dimethyl-propylamino)-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione
[0158] 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 tert-amyl amine (0.48 mL, 4.11 mmol) were
converted to the title compound (0.14 g, 84%) m.p.: 133-135.degree.
C.; .sup.1H NMR (DMSO-d.sub.6).delta.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), 0.85(t,3H); IR
(KBr) 2980, 1765, 1725, 1600, 1423, 1310, 1260, 1175, 1030, 850
cm.sup.-1; MS (m/z) 273 [M.sup.+].
[0159] Elemental analysis for C.sub.16H.sub.19NO.sub.3:
2 Calc'd: C, 70.31; H, 7.00; N, 5.12. Found: C, 69.79; H, 6.92; N,
5.05.
EXAMPLE 3
3-(Isopropyl-methyl-amino)-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione
[0160] 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 methyl-isopropylamine (0.07 mL, 0.670 mmol) in
acetonitrile (3 mL) were converted to the title compound (0.10 g,
63%) m.p.: 109-115.degree. C.; .sup.1H NMR (DMSO-d.sub.6)
.delta.7.60(m,2H), 7.07(m,2H), 4.91(m,1H), 3.81(s,3H), 1.23(br
d,6H); MS (m/z) 259 [M.sup.+].
[0161] Elemental analysis for C.sub.15H.sub.17NO.sub.3:
3 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-Methoxy-phenyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-di-
one
[0162] 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.degree. C.; .sup.1H NMR (DMSO-d.sub.6)
.delta.8.56(br d,1H), 8.06(ABq,2H), 7.09(ABq,2H), 4.31(m,1H),
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.sup.-1; MS
(m/z) 287 [M.sup.+].
[0163] Elemental analysis for C.sub.17H.sub.21NO.sub.3:
4 Calc'd: C, 71.06; H, 7.37; N, 4.87. Found: C, 70.41; H, 7.41; N,
4.90.
EXAMPLE 5
3-(4-Methoxy-phenyl)-4-[2-(3-trifluoromethyl-phenyl)-ethylamino]-cyclobut--
3-ene-1,2-dione
[0164] 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.degree. C.; .sup.1H NMR
(DMSO-d.sub.6).delta.9.05(br t,1H), 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, 1775, 1780, 1575, 1360, 1325, 1175, 1125, 1070, 1020, 840,
800, 695 cm.sup.-1; MS (m/z) 375 [M.sup.+].
[0165] Elemental analysis for C.sub.20H.sub.16NO.sub.3F.sub.3:
5 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-Methoxy-phenyl)-4-((R)-1-phenyl-ethylamino)-cyclobut-3-ene-1,2-di-
one
[0166] 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)-(+)-.alpha.-methyl-benzylamine (180 .mu.L,
0.914 mmol) in ethanol (1 mL) were converted to the title compound
(120 mg, 64%) m.p.: 158.7-160.1.degree. C.; .sup.1H NMR
(DMSO-d.sub.6).delta.9.28(d,1H), 8.04(ABq,2H), 7.35(m,5H),
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.sup.-1; MS (m/z)
307 [M.sup.+],
[0167] [.alpha.].sub.D.sup.25-185.42.degree. (c0.1049,THF)
[0168] Elemental analysis for C.sub.19H.sub.17NO.sub.3:
6 Calc'd: C, 74.25; H, 5.58; N, 4.56. Found: C, 73.99; H, 5.56; N,
4.44.
EXAMPLE 7
3-(4-Methoxy-phenyl)-4-(2-phenyl-propylamino)-cyclobut-3-ene-1,2-dione
[0169] 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.degree. C.; .sup.1H NMR
(DMSO-d.sub.6).delta.9.07(br t,1H), 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,1H), 1.26(d,3H);
IR(KBr) 3160, 2960, 1775, 1730, 1560, 1430, 1300, 1250, 1170, 1100,
1020, 840 cm.sup.-1; MS (m/z) 322 [M+H.sup.+].
[0170] Elemental analysis for C.sub.20H.sub.19NO.sub.3:
7 Calc'd: C, 74.75; H, 5.96; N, 4.36. Found: C, 75.06; H, 6.02; N,
4.37.
EXAMPLE 8
3-[2-(4-tert-Butyl-phenyl)-ethylamino]-4-(4-methoxy-phenyl)-cyclobut-3-ene-
-1,2-dione
[0171] 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.degree. C.; .sup.1H NMR
(DMSO-d.sub.6).delta.9.07(br t,1H), 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); IR(KBr) 3160, 2950, 1775, 1720, 1580, 1425, 1350, 1300,
1250, 1180, 1020, 840 cm.sup.-1; MS (m/z) 364 [M+H.sup.+].
[0172] Elemental analysis for C.sub.23H.sub.25NO.sub.3:
8 Calc'd: C, 76.01; H, 6.93; N, 3.85. Found: C, 76.17; H, 7.01; N,
3.84.
EXAMPLE 9
4-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]benzonitrile
[0173] Step 1) Preparation of
3-isopropoxy-4-(4-cyano-phenyl)-cyclobut-3-e- ne-1,2-dione
[0174] 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.degree. C.
Benzylchlorobis(triphenyiphosphine)pa- lladium (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 (MgSO.sub.4) 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.
[0175] Step 2
[0176] Preparation of
4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobu-
t-1-enyl]-benzonitrile
[0177] 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.degree. C.;
.sup.1H NMR (DMSO-d.sub.6).delta.9.01(br d, 1H), 8.19(ABq,2H),
8.01(ABq,2H), 4.29(m,1H), 1.25(d,3H), 0.92(s,9H); IR(KBr) 3160,
2950, 2220, 1760, 1600, 1440, 1160, 1100, 850 cm.sup.-1; MS (m/z)
282 [M.sup.+].
[0178] Elemental analysis for C.sub.17H.sub.18N.sub.2O.sub.2:
9 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-phenyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-en-
e-1,2-dione
[0179] Step 1) Preparation of
3-isopropoxy-4-(4-trifluoro-methyl-phenyl)-c-
yclobut-3-ene-1,2-dione
[0180] In a manner similar to Example 9, Step 1,
3-isopropoxy-4-(tri-n-but- ylstannyl)-3-cyclobutene-1,2-dione (3.00
g, 6.99 mmol), 4-trifluoromethyl-iodobenzene (2.09 g, 7.69 mmol),
benzylchlorobis(triphenylphosphine)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.
[0181] Step 2
[0182] Preparation of
3-(4-trifluoromethyl-phenyl)-4-(1,2,2-trimethylpropy-
lamino)-cyclobut-3-ene-1,2-dione
[0183] In a manner similar to Example 9, Step 2,
3-isopropoxy-4-(4-trifluo-
romethyl-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.degree. C.; .sup.1H NMR (DMSO-d.sub.6).delta.8.97(brd,1H),
8.22(ABq,2H), 7.88(ABq,2H), 4.30(m,1H), 1.26(d,3H), 0.92(s,9H); IR
(KBr) 3450, 3180, 2970, 1775, 1740, 1600, 1420, 1370, 1170, 1110,
1060, 850 cm.sup.-1; MS (m/z) 325 [M.sup.+];
[0184] Elemental analysis for C.sub.17H.sub.18NO.sub.2F.sub.3:
10 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-Trifluoromethyl-phenyl)-3-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1-
,2-dione
[0185] In a manner similar to Example 1, Step 2,
3-isopropoxy-4-(4-trifluo-
romethyl-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.degree. C. (dec);
.sup.1H NMR (DMSO-d.sub.6) .delta.8.60(br s, 1H), 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
cm.sup.-1; MS (m/z) 311 [M.sup.+].
[0186] Elemental analysis for C.sub.16H.sub.16NO.sub.2F.sub.3:
11 Calc'd: C, 61.73; H, 5.18; N, 4.50. Found: C, 61.76; H, 4.95; N,
4.18.
EXAMPLE 12
3-(1,1-Dimethyl-propylamino)-4-(pyridin-3-yl)-cyclobut-3-ene-1,2-dione
hydrochloride
[0187] Step 1
[0188] Preparation of
3-isopropoxy-4-(3-pyridyl)-cyclobut-3-ene-1,2-dione
[0189] In a manner similar to Example 9, Step 1,
3-isopropoxy-4-(tri-n-but- ylstannyl)-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: .sup.1H NMR (DMSO-d.sub.7).delta.9.07(m,1-
H), 8.75(m,1H), 8.20(br d,1H), 7.65(m,1H), 5.50(sept,1H),
1.50(d,6H).
[0190] Step 2
[0191] Preparation of
3-(1,1-Dimethyl-propylamino)-4-(pyridin-3-yl)-cyclob-
ut-3-ene-1,2-dione hydrochloride
[0192] 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.degree. C. (dec); .sup.1H NMR
(DMSO-d.sub.6).delta.9.20(br s,1H), 8.73(m,2H), 8.47(m,1H),
7.69(m,1H), 4.6(br s,1H,plus H.sub.2O), 1.82(q,2H), 1.43(s,6H),
0.88(t,3H); IR (KBr) 3475, 2970, 2470, 2050, 1770, 1590 cm.sup.-1;
MS (m/z) 244 [M.sup.+].
[0193] Elemental analysis for C.sub.14H.sub.17N.sub.2O.sub.2Cl
:
12 Calc'd: C, 59.89; H, 6.10; N, 9.98. Found: C, 58.58; H, 5.78; N,
9.57.
[0194] 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-butylstannyi)-3-cyclobutene-1,2-dione, and
the appropriate amine.
EXAMPLE 13
[0195]
3-(1,1-Dimethyl-propylamino)-4-(3,4-dimethoxy-phenyl)-cyclobut-3-en-
e-1,2-dione.
EXAMPLE 14
[0196]
3-(1,1-Dimethyl-2-phenyl-ethylamino)-4-(3,4-dimethoxy-phenyl)-cyclo-
but-3-ene-1,2-dione.
EXAMPLE 15
[0197]
3-(1,1-Dimethyl-propylamino)-4-(3-bromo-4,5-dimethoxy-phenyl)-cyclo-
but-3-ene-1,2-dione.
EXAMPLE 16
[0198]
3-(1,1-Dimethyl-2-phenyl-ethylamino)-4-(3-bromo-4,5-dimethoxy-pheny-
l)-cyclobut-3-ene-1,2-dione.
EXAMPLE 17
[0199]
3-(1,1-Dimethyl-propylamino)-4-(3-bromo-4,6-dimethoxy-phenyl)-cyclo-
but-3-ene-1,2-dione.
EXAMPLE 18
[0200]
3-(1,1-Dimethyl-2-phenyl-ethylamino)-4-(3-bromo-4,6-dimethoxy-pheny-
l)-cyclobut-3-ene-1,2-dione.
EXAMPLE 19
[0201]
3-(1,1-Dimethyl-propylamino)-4-(2-bromo-4,6-dimethoxy-phenyl)-cyclo-
but-3-ene-1,2-dione.
EXAMPLE 20
[0202]
3-(1,1-Dimethyl-2-phenyl-ethylamino)-4-(2-bromo-4,6-dimethoxy-pheny-
l)-cyclobut-3-ene-1,2-dione.
EXAMPLE 21
3-[2-Oxo-1-(4-trifluoromethyl-phenyl)-propyl]-4-(1,2,2-trimethyl-propylami-
no)-cyclobut-3-ene-1,2-dione
[0203] Step 1
[0204] Preparation of
3-[2-Oxo-1-(4-trifluoromethyl-phenyl)-propyl]-4-etho-
xy-cyclobut-3-ene-1,2-dione.
[0205] 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.degree. C.) solution of potassium
bis(trimethyl-silyl)emide (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.degree. C. for 15 min. and was then stirred at room
temperature for 2.5 hours. The enolate solution was cooled to
-78.degree. C. and added by cannula to a cooled (-78.degree. 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.degree. 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 HCl and ethyl
acetate. The organic phase was washed with brine, dried
(MgSO.sub.4) 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: .sup.1H NMR
(DMSO-d.sub.6).delta.11.51(s,1H), 7.60(ABq,2H), 7.24(ABq,2H),
4.59(q,2H), 1.89(s,3H), 1.19(t,3H).
[0206] Step 2
[0207] Preparation of
3-[Oxo-1-(4-trifluoromethyl-phenyl)-propyl]-4-(1,1,1-
-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione.
[0208]
3-[2-Oxo-1-(4-trifluoromethyl-phenyl)-propyl]-4-ethoxy-cyclobut-3-e-
ne-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 (.sup.1H NMR in
CDCl.sub.3 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.degree. C.; .sup.1H NMR (CDCl.sub.3)
.delta.11.74(s,1H), 7.73(ABq,2H), 7.39(ABq,2H), 3.92(m,1H),
1.86(s,3H), 0.93(d,3H), 0.69(s,9H); IR (KBr) 3310, 2970, 2600,
1775, 1710, 1560, 1395, 1260, 1160, 1125, 850 cm.sup.-1; MS (m/z)
381 [M.sup.+].
[0209] Elemental analysis for C.sub.20H.sub.22NO.sub.2F.sub.3:
13 Calc'd: C, 62.98; H, 5.81; N, 3.67. Found: C, 62.67; H, 5.72; N,
3.56.
EXAMPLE 22
3-(4-Bromo-phenyl)-4-(1,2,2-trimethyl-propylamino-cyclobut-3-ene-1,2-dione
[0210] To a heterogeneous mixture of
3-(4-bromo-phenyl)-4-isopropoxycyclob- ut-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 .mu.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.degree. C., affording a light yellow
solid (225 mg, 68%): m.p. 210.6-211.3.degree. C.; .sup.1H NMR
(DMSO-d.sub.6).delta.8.81(d,1H), 8.00((ABq,2H), 7.75(ABq,2H),
4.29(dq,.sub.1H), 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 cm.sup.-1; MS (m/z) 335/337 [M.sup.+].
[0211] Elemental analysis for C.sub.16H.sub.18BrNO.sub.2:
14 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-Methoxy-benzyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-di-
one one-quarter hydrate
[0212] Step 1) Preparation of 3-(4-Methoxy-benzyl)-4-
isopropoxycyclobut-3-ene-1,2-dione
[0213] 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-dio- ne
(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.times.100 mL), 10% potassium fluoride (3.times.100 mL)
and brine (100 mL). The organic phase was dried over
Na.sub.2SO.sub.4/activated carbon and submitted to flash
chromatography (elution with 40% ether-petroleum ether), affording
a golden brown oil (1.04 g, 43%): .sup.1H NMR (CDCl.sub.3)
.delta.7.20(ABq,2H), 6,85(ABq,2H), 5.38(hept,1H), 3.83(s,2H),
3.79(s,3H), 1.43(d,6H).
[0214] Step 2
[0215] Preparation of
3-(4-Methoxy-benzyl)-4-(1,2,2-trimethyl-propylamino)-
-cyclobut-3-ene-1,2-dione one-quarter hydrate
[0216] 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, affording 124 mg (31%) of the
title compound (.sup.1H NMR in DMSO-d.sub.6 suggested the presence
of amide rotamers in a ratio of approximately 3:1): m.p.
131.4-138.1.degree. C.; .sup.1H NMR (DMSO-d.sub.6)
.delta.8.63(d,1H), 7.16(ABq,2H),6.87(ABq,2H), 3.90(m,1H),
3.70(s,2H), 1.15(d,3H), 0.84(s,9H); IR (Ksr) 3460, 3160, 2980,
2930, 1780, 1730, 1610, 1560, 1510, 1495, 1445, 1430, 1420, 1245,
1190, 1150, 1080, 1030, 775 cm.sup.-1; MS (m/z) 301 [M.sup.+].
[0217] Elemental analysis for C.sub.18H.sub.23NO.sub.3.0.25
H.sub.2O:
15 Calc'd: C, 70.68; H, 7.74; N, 4.58. Found: C, 70.43; H, 7.77; N,
4.55.
EXAMPLE 24
{2-[1-(4-Methoxy-phenyl)-2-oxo-propyl]-3,4-dioxo-cyclobut-1-enyl}-(1,2,2-t-
rimethyl-propyl)-carbamic acid tert-butyl ester
[0218] Step 1
[0219] Preparation of
1-ethoxy-2-(1,2,2-trimethyl-propylamino)-cyclobut-3--
ene-1,2-dione
[0220] 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 (96%) of an off-white
solid which was used without further purification.
[0221] Step 2
[0222] Preparation of
1-ethoxy-3,4-dioxo-cyclobut-1-enyl-(1,2,2-trimethyl--
propyl)-carbamic acid tert-butyl ester
[0223] 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-tert-butyl
dicarbonate (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 evaporation 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.
[0224] Step 3
[0225] Preparation of
{2-[1-(4-Methoxy-phenyl)-2-oxo-propyl)]-3,4-dioxo-cy-
clobut-1-enyl}-(1,2,2-trimethyl-propyl)-carbamic acid tert-butyl
ester
[0226] 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.degree. 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.degree. 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.degree.
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.times.100 mL) and brine (100 mL). The
combined organic phases were dried over Mg.sub.2SO.sub.4/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 (.sup.1H NMR in DMSO-d.sub.6 suggested the presence
of keto-enol tautomers in a ratio of approximately 4:1): m.p.
137.4-138.1.degree. C.; .sup.1H NMR
(DMSO-d.sub.6).delta.11.03(s,1H), 7.07(ABq,2H), 6.88(ABq,2H),
4.65(m,1H), 3.74(s,3H), 2.03(s,3H), 1.40(br s,12H), 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 cm.sup.-1;
MS (m/z) 444 [(M+H).sup.+]/466 [(M+Na).sup.+].
[0227] Elemental analysis for C.sub.25H.sub.33NO.sub.6:
16 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-phenyl-ethylamino)-4-(3-methoxy-phenyl)-cyclobut-3-ene-1-
,2-dione
[0228] Step 1
[0229] Preparation of
3-isopropoxy-4-(3-methoxy-phenyl)-cyclobut-3-ene-1,2- -dione
[0230] The title intermediate was prepared using
3-isopropoxy-4-(tri-n-but- ylstannyl)-3-cyclobut-3-ene-1,2-dione
and 3-iodoanisole in a manner similar to the cited literature
method [J. Org. Chem. 1990, 55, 5359-5364], providing 1.336 g (26%)
of a tan solid.
[0231] Step 2
[0232] Preparation of
3-(1,1-Dimethyl-2-phenyl-ethylamino)-4-(3-methoxy-ph-
enyl)-cyclobut-3-ene-1,2-dione
[0233] 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 .mu.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 drying in vacuo afforded 171 mg (42%) of
a white solid: m.p. 115.8-116.3.degree. C.; .sup.1H NMR
(DMSO-d.sub.6).delta.8.47(s,1H), 7.51(m,3H), 7.08(ddd,1H),
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 cm.sup.-1; MS (m/z) 273 [M.sup.+].
[0234] Elemental analysis for C.sub.16H.sub.19NO.sub.3:
17 Calc'd: C, 70.31; H, 7.01; N, 5.13. Found: C, 70.09; H, 7.05; N,
5.08.
EXAMPLE 26
3-[(E)-2-(4-Bromo-phenyl)-vinyl]-4-(1,2,2-trimethyl-propylamino)-cyclobut--
3-ene-1,2-dione
[0235] Step 1
[0236] 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.degree. 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, 10.8
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.
[0237] Step 2
[0238] Preparation of
4-isopropoxy-3-[(E)-2-(4-bromophenyl)-vinyl]-cyclobu-
t-3-ene-1,2-dione
[0239] In a manner similar to Step 1 of Example 1 was prepared 298
mg (17%) of the title intermediate.
[0240] Step 3
[0241] Preparation of
3-[(E)-2-(4-bromophenyl)-vinyl]-4-(1,2,2-trimethyl-p-
ropylamino)-cyclobut-3-ene-1,2-dione
[0242] 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-dimethylbutan- e (241 .mu.L, 1.80 mmol) in anhydrous
ethyl alcohol (3.50 mL), affording the title compound (127 mg, 39%)
as a hygroscopic yellow solid (.sup.1H NMR
(DMSO-d.sub.6).delta.8.87(d,1H), 7.71(m,5H), 7.46(d,1H),
4.02(dq,.sub.1H), 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 cm.sup.-1; MS (m/z) 361/363 [M.sup.+].
[0243] Elemental analysis for C.sub.18H.sub.20BrNO.sub.2:
18 Calc'd: C, 59.68; H, 5.56; N, 3.87. Found: C, 59.55; H, 5.38; N,
3.72.
EXAMPLE 27
4-{(E)-2-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-vinyl-
}-benzonitrile
[0244] 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-bromophenyl-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, 0.662 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.degree. C., stirred 18 hours, then worked up by dilution with
toluene (150 mL), followed by consecutive extraction with ammonium
hydroxide (3.times.50 mL) and brine (50 mL). The organic phase was
further diluted with ethyl acetate (300 mL), dried over MgSO.sub.4,
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.degree. C. yielded the title compound (248 mg,
73%) as a hydroscopic yellow solid (.sup.1H NMR in DMSO-d.sub.6
suggested the presence of amide rotamers in a ratio of
approximately 4:1): m.p. 240.2-241..degree. C.; .sup.1H NMR
(DMSO-d.sub.6).delta.8.96(d,1H), 7.83(m,4H), 7.64(d,1H),
7.48(d,1H), 4.03(dq,1H), 1.20(d,3H), 0.90(s,9H); IR (KBr) 3450,
3250, 3290, 2960, 1770, 1725, 1620, 1600, 1500, 1480, 14490, 1405,
1170, 1140, 1080, 980, 825, 755; MS (m/z) 309 [(M+H).sup.+], 331
[(M+Na).sup.+].
[0245] Elemental analysis for C.sub.19H.sub.20N.sub.2O.sub.2:
19 Calc'd: C, 74.00; H, 6.54; N, 9.08. Found: C, 73.59; H, 6.51; N,
8.83.
[0246] 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:
[0247] Sprague-Dawley rats (150-200 g) are rendered unconscious by
CO.sub.2 asphyxiation and then euthanized by cervical dislocation.
The bladder is removed into warm (37.degree. C.) physiological salt
solution (PSS) of the following composition (mM): NaCl, 118.4; KCl,
4.7; CaCl.sub.2, 2.5; MgSO.sub.4, 4.7; H.sub.2O, 1.2; NaHCO.sub.3,
24.9; KH.sub.2PO.sub.4, 1.2; glucose, 11.1; EDTA, 0.023; gassed
with 95% O.sub.2; 2/5% CO.sub.2; 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 .mu.M 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 KCl are
introduced into the tissue bath. This increase in KCl concentration
results in a large increase in the amplitude of spontaneous
contractions (and initiation of contractions in previously
quiescent strips) superimposed upon a small increase in basal tone.
Following stabilization of this enhanced level of contractile
activity, incremental increases in the concentration of test
compound or vehicle are introduced into the tissue bath.
Contractile activity is measured for each compound or vehicle
concentration during the last minute of a 30 minute challenge.
[0248] The isometric force developed by the bladder strips is
measured using a concentration required to elicit 50% inhibition of
pre-drug contractile activity (IC.sub.50 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 .mu.M.
[0249] 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:
[0250] Male Sprague-Dawley rats (150-200 g) are rendered
unconscious by CO.sub.2 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; KCl, 4.7; CaCl.sub.2, 2.5;
MgSO.sub.4.7H.sub.2O, 1.2; NaHCO.sub.3, 24.9; KH.sub.2PO.sub.4,
1.2; glucose, 11.1; EDTA, 0.023; gassed with 95% O.sub.2/5%
CO.sub.2; 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 KCl 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 KCl 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 KCl
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.
[0251] 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
(IC.sub.50 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
IC.sub.50 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 80% region of the curve]. The
maximum percentage inhibition of contractile force evoked by a test
compound is also recorded for concentrations of test compound <
or = to 30 .mu.M. Data collected from 2 animals are averaged for
primary screens.
[0252] The results of these studies are shown in Table I.
20TABLE I Ratio Aorta Ex. Bladder Tissue Aorta Tissue IC.sub.50 No.
n IC.sub.50 (.mu.M) n IC.sub.50 (.mu.M) Bladder IC.sub.50 1 2 1.2
.+-. 0.26 2 3.25 .+-. 0.35 2.71 2 4 2.5 .+-. 0.49 2 37.65 .+-. 6.05
15.1 3 4 11.99 .+-. 2.4 3 46.2 .+-. 7.8 3.85 4 4 9.51 .+-. 1.8 5
24.2 .+-. 6.3 2.56 5 4 1 = 9.75 .+-. 4.4%* -- -- 6 2 26.9 .+-. 0.3
-- -- 7 2 1 = 7.4 .+-. 5.7% -- -- 8 1 11.2 -- -- 9 3 1 = 27.2 .+-.
8.6% -- -- 10 2 15.6 .+-. 3.7 -- -- 11 2 1 = 34.2 .+-. 6.0% -- --
12 2 1 = 26.0 .+-. 2.2% -- -- 21 3 16.2 .+-. 6.82 -- -- 22 3 25.7
.+-. 1.1 -- -- 23 2 1 = 10.2 .+-. 5.6% -- -- 24 1 15.9 -- -- 25 2 1
= 30.35 .+-. 0.52%* -- -- 26 3 15.6 .+-. 8%* -- -- 27 5 2.94 .+-.
0.62 -- -- *Percent inhibition at 30 .mu.M
[0253] 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, parenterally, or by aspiration to a
patient in need thereof.
* * * * *