Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-19
2001-08-14
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S250000, C544S251000, C544S252000
Reexamination Certificate
active
06274587
ABSTRACT:
TECHNICAL FIELD
Novel tricyclic dihydropyrimidine compounds and their derivatives can open potassium channels and are useful for treating a variety of medical conditions.
BACKGROUND OF INVENTION
Potassium channels play an important role in regulating cell membrane excitability. When the potassium channels open, changes in the electrical potential across the cell membrane occur and result in a more polarized state. A number of diseases or conditions may be treated with therapeutic agents that open potassium channels; see (K. Lawson, Pharmacol. Ther., v. 70, pp. 39-63 (1996)); (D. R. Gehlert et al., Prog. Neuro-Psychopharmacol & Biol. Psychiat., v. 18, pp. 1093-1102 (1994)); (M. Gopalakrishnan et al., Drug Development Research, v. 28, pp. 95-127 (1993)); (J. E. Freedman et al., The Neuroscientist, v. 2, pp. 145-152 (1996)); (D. E. Nurse et al., Br. J. Urol., v. 68 pp. 27-31 (1991)); (B. B. Howe et al., J. Pharmacol. Exp. Ther., v. 274 pp. 884-890 (1995)); and (D. Spanswick et al., Nature, v. 390 pp. 521-25 (Dec. 4, 1997)). Such diseases or conditions include asthma, epilepsy, hypertension, male sexual dysfimction, female sexual dysfunction, migraine, pain, urinary incontinence, stroke, Raynaud's Syndrome, eating disorders, finctional bowel disorders, and neurodegeneration.
Potassium channel openers also act as smooth muscle relaxants. Because urinary incontinence can result from the spontaneous, uncontrolled contractions of the smooth muscle of the bladder, the ability of potassium channel openers to hyperpolarize bladder cells and relax bladder smooth muscle provides a method to ameliorate or prevent urinary incontinence.
U.S. Pat. No. 4,918,074, EP 183848 B1, EP 217142, EP 328700, JP 63060985, JP 63243029, JP 61227584, and Atwal, K.S., Bioorg. Med. Chem. Lett (1991) 1, 291-294 disclose bicyclic 4,7-dihydropyrazolo[1,5-a]pyrimidines.
The compounds of the present invention are novel, hyperpolarize cell membranes, open potassium channels, relax smooth muscle cells, inhibit bladder contractions, and are useful for treating diseases that can be ameliorated by opening potassium channels.
SUMMARY OF THE INVENTION
In its principle embodiment, the present invention discloses compounds of formula I:
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein,
n is an integer 0-1;
m is an integer 1-2;
provided that when m is 2, n is 0;
R
1
is selected from aryl and heterocycle;
Q is selected from C(O), S(O), and S(O)
2
;
V is selected from C(R
6
)(R
7
), O, S, and NR
2
, wherein R
2
is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, —NR
4
R
5
, and (NR
4
R
5
)alkyl wherein R
4
and R
5
are independently selected from hydrogen and lower alkyl;
R
6
and R
7
are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, —NR
4
R
5
, and (NR
4
R
5
)alkyl wherein R
4
and R
5
are as defined above;
X is selected from N and CR
3
wherein R
3
is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, —NR
4
R
5
, and (NR
4
R
5
)alkyl wherein R
4
and R
5
are as defined above;
A and B are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, —NR
4
R
5
, and (NR
4
R
5
)alkyl wherein R
4
and R
5
are as defined above; and
D and E are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, —NR
4
R
5
, and (NR
4
R
5
)alkyl wherein R
4
and R
5
are as defined above.
DETAILED DESCRIPTION OF THE INVENTION
All patents, patent applications, and literature references cited in the specification are herein incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.
In its principle embodiment, the present invention discloses compounds of formula I:
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein,
n is an integer 0-1;
m is an integer 1-2;
provided that when m is 2, n is 0;
R
1
is selected from aryl and heterocycle;
Q is selected from C(O), S(O), and S(O)
2
;
V is selected from C(R
6
)(R
7
), O, S, and NR
2
, wherein R
2
is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, —NR
4
R
5
, and (NR
4
R
5
)alkyl wherein R
4
and R
5
are independently selected from hydrogen and lower alkyl;
R
6
and R
7
are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, —NR
4
R
5
, and (NR
4
R
5
)alkyl wherein R
4
and R
5
are as defined above;
X is selected from N and CR
3
wherein R
3
is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, —NR
4
R
5
, and (NR
4
R
5
)alkyl wherein R
4
and R
5
are as defined above;
A and B are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, —NR
4
R
5
, and (NR
4
R
5
)alkyl wherein R
4
and R
5
are as defined above; and
D and E are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, —NR
4
R
5
, and (NR
4
R
5
)alkyl wherein R
4
and R
5
are as defined above.
In another embodiment of the present invention, compounds have formula I wherein, R
1
is aryl; X is CR
3
; R
3
is hydrogen; and A, B, D, E, Q, V, m, and n are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein, R
1
is heterocycle; X is CR
3
; R
3
is hydrogen; and A, B, D, E, Q, V, m, and n are as defined in formula I.
In a preferred embodiment, compounds of the present invention have formula II:
or a pharmaceutically acceptable salt, ester, amide,
Carroll William A.
Drizin Irene
Holladay Mark W.
Yi Lin
Zhang Henry Q.
Abbott Laboratories
Liu Hong
Shah Mukund J.
Ward Michael J.
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