Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-29
2003-01-07
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S397000, C514S400000, C548S204000, C548S336500, C548S342100
Reexamination Certificate
active
06503935
ABSTRACT:
TECHNICAL FIELD
This invention relates to compounds which are &agr;
1A
agonists, pharmaceutical compositions containing these compounds, and methods of treatment using these compounds.
BACKGROUND OF THE INVENTION
The &agr;
1
adrenoceptor plays a part in the sympathetic maintenance of smooth muscle tone and &agr;
1
-adrenergic agonists are known to increase muscle tone in the lower urinary tract (Testa, R. Eur. J. Pharmacol. (1993) 249, 307-315). Phenylpropanolamine (Cummings, J. M. Drugs of Today (1996) 32, 609-614) and midodrine are &agr;
1
agonists which have been used for the treatment of urinary incontinence. These agents act by stimulating the &agr;
1
receptors present in the urethra and bladder neck (trigone) leading to an increase in intraurethral pressure. However, these agents suffer from cardiovascular related side effects (Taniguchi, N. Eur. J. Pharmacol. (1996) 318, 117-122). Thus an agent that is effective in the treatment of urinary incontinence without cardiovascular side effects is needed.
At least 3 subtypes of the &agr;
1
adrenoceptor (&agr;
1A
, &agr;
1B
, and &agr;
1D
) have been identified via pharmacological techniques. The corresponding molecular clones (&agr;
1a
, &agr;
1b
, &agr;
1d
) have been identified (Hancock, A. H. Drug Development Research (1996) 39, 54-107). Studies have shown that the &agr;
1A
receptor is present in the lower urinary tract (Testa, R. Eur. J. Pharmacol. (1993) 249, 307-315). The &agr;
1A
subtype has been shown to be the predominant subtype in the urethra (Takahashi, H. Neurourol. Urodyn. (1996), 15, 342-343).
Urinary stress incontinence is the involuntary loss of urine due to a stress such as coughing, sneezing, bending or lifting heavy objects. This condition may occur due to a weakening in the ability of the urethra to constrict. Selective stimulation of the &agr;
1A
receptor can result in the contraction of the bladder neck (trigone) and urethra leading to an increase in urethral pressure with reduced blood pressure effects. The compounds of the present invention are selective &agr;
1A
agonists which may preferentially increase intraurethral pressure relative to nonselective &agr;
1
agonists such as midodrine and phenylpropanolamine. Therefore, these agents may be useful for the treatment of urinary incontinence.
FR 2768054-A1 and FR 2768055-A1 disclose a series of sulfonamides and sulfonanilides as agents which constrict trigonal smooth muscle and are claimed to be useful for the treatment of ejaculation disorders, especially retrograde ejaculation or aspermia. The compounds of the present invention may be also usefull for the treatment of ejaculatory disorders.
The compounds of the present invention may be useful for the treatment of nasal decongestion (Proctor Pharmac. Ther. B. (1976) 2, 493-509) and septic shock (Cole, L. Blood Purif (1997) 15, 309-318).
EP 0717037 A1 discloses a group of 4-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazoles that are claimed as &agr;
2
agonists and &agr;
1
antagonists for the treatment of ischemia and hypertension. Imidazole compounds that are &agr;
2
-adrenergic ligands are disclosed in (Zhang, et. al. J. Med. Chem (1997) 40, 3014-4024). The compounds of the present invention are structurally and pharmacologically distinct from EP 0717037 A1 and Zhang, et. Al.
WO 99/05115 discloses a group of substituted imidazole derivatives that are claimed as H
3
(histamine-3) receptor ligands potentially useful as sedatives, as sleep regulators, as anticonvulsants, as regulators of hypothalamo-hypophyseal secretion, as antidepressants, as modulators of cerebral circulation, in the treatment of asthma, in the treatment of irritable bowel syndrome and as tools in the study of the role of histamine.
EP 0887346 A2 discloses a group of 4-imidazole derivatives of phenyl-alkylsulfonamides as &agr;
1A/1L
adrenoceptor agonists for the treatment of urinary incontinence and nasal decongestion.
SUMMARY OF THE INVENTION
In its principle embodiment, the present invention discloses compounds having formula I:
or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, wherein
R
1
is selected from the group consisting of —S(O)
2
R
9
and —C(O)R
10
;
R
9
is selected from the group consisting of alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, and —NZ
1
Z
2
wherein Z
1
and Z
2
are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl;
R
10
is selected from the group consisting of alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, and —NZ
1
Z
2
;
R
2
is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, halo, haloalkyl, and hydroxy;
R
3
is selected from the group consisting of hydrogen, alkenyloxy, alkyl, alkoxy, alkoxyalkyl, alkynyloxy, arylalkyl, cycloalkylalkyl, haloalkyl, and hydroxy;
R
4
is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, and hydroxy; or
R
3
and R
4
together with the carbon atoms to which they are attached form a 5-, 6-, or 7-membered carbocyclic ring; or
R
3
and R
4
together with the carbon atoms to which they are attached form a 5- or 6-membered ring containing 1 heteroatom selected from the group consisting of O, NR
11
, and S(O)
n
;
R
11
is selected from the group consisting of hydrogen, alkenyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, arylalkyl, formyl, —C(O)NZ
1
Z
2
, and —SO
2
NZ
1
Z
2
;
n is 0-2;
R
5
is selected from the group consisting of imidazol-4-yl, imidazol-5-yl, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, triazole, thiadiazole, pyridine, pyrimidine, pyrazine, and pyridazine optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkynyl, arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, hydroxy, lower alkoxy, lower alkyl, —NZ
1
Z
2
, (NZ
1
Z
2
)alkyl, —C(O)NZ
1
Z
2
, and —SO
2
NZ
1
Z
2
;
R
6
is selected from the group consisting of hydrogen, alkoxy, alkyl, halo, haloalkyl, and hydroxy;
R
7
is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, and haloalkyl; and
R
8
is selected from the group consisting of hydrogen and alkyl; or
R
3
and R
8
together with the carbon atom to which they are attached form a 3-, 4-, 5-, or 6-membered carbocyclic ring; or
R
3
and R
8
together form
R
12
and R
15
are independently selected from the group consisting of hydrogen, alkoxy, alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl; or
R
12
and R
15
together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic ring; or
R
12
and R
4
together with the carbon atoms to which they are attached form a 5-, 6-, or 7-membered carbocyclic ring;
provided that when R
12
and R
4
together with the carbon atoms to which they are attached form a 5-, 6-, or 7-membered carbocyclic ring then R
15
is hydrogen; or
R
12
and R
4
together with the carbon atoms to which they are attached form a 5- or 6-membered ring containing 1 heteroatom selected from the group consisting of O, NR
11
, and S(O)
n
;
provided that when R
12
and R
4
together with the carbon atoms to which they are attached form a 5- or 6-membered ring containing 1 heteroatom selected from the group consisting of O, NR
11
, and S(O)
n
, then R
15
is hydrogen.
Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I-X or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
Another embodiment of the invention relates to a method of treating ejaculatory dysfunction including, but not limited, to retrograde ejaculation comprising administering a therapeutically effective amount of a compound of formula I-X or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof
Y
Altenbach Robert J.
Carroll William A.
Holladay Mark W.
Kerwin, Jr. James F.
Khilevich Albert
Abbott Laboratories
Lambkin Deborah C.
Ward Michael J.
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