Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-04-22
2004-06-29
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S401000, C548S355100, C548S349100, C548S311400
Reexamination Certificate
active
06756395
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to imidazolin-2-ylmethyl substituted arylalkylsulfonamide derivatives, compositions comprising the same, methods for use, and methods of preparation thereof.
BACKGROUND OF THE INVENTION
Alpha-1 (&agr;
1
) adrenergic receptors (i.e., (&agr;
1
adrenoceptors) are G-protein coupled transmembrane receptors that mediate various actions of the sympathetic nervous system through the binding of the catecholamines, epinephrine and norepinephrine (NE). Currently, several subtypes of the &agr;
1
adrenergic receptors are known to exist for which the genes have been cloned: &agr;
1A
(previously known as &agr;
1C
), &agr;
1B
and (&agr;
1D
. Recently the existence of a low affinity &agr;
1
adrenoceptor for prazosin named &agr;
1L
, in human prostate has been determined. However, the gene for the &agr;
1L
adrenergic receptor subtype has yet to be cloned. 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. Phannacol
., 249, 307-315 (1993). Pharmacological studies resulting in the subdivision of &agr;
1
adrenergic receptors have let to the suggestion that development of subtype-selective compounds may allow improved treatment with a lower incidence of side effects.
Urinary incontinence is a condition defined as the involuntary loss of urine. Stress urinary incontinence (SUI) occurs when the internal sphincter does not close completely. The primary symptom is minor leakage from activities, such as coughing, sneezing, laughing, running, lifting, or even standing, that apply pressure to a full bladder. Leakage stops when the activity stops. SUI is most common in women between the ages of 25 and 50, and many regularly exercising women have some degree of SUI.
The present methods to treat SUI include physiotherapy and surgery. Treatment with pharmaceuticals is limited to the use of non-selective adrenergic agonists.
Only a limited number of pharmaceutical agents have been employed, with varying success, to treat stress incontinence.
Phenylpropanolamine, pseudoephedrine and midodrine are considered first-line therapy for mild to moderate stress incontinence (Wein, supra; Lundberg (editor),
JAMA
, 1989, 261(18), 2685-2690). These agents are believed to work both by direct activation of &agr;
1
adrenoceptors and indirectly by displacement of endogenous norepinephrine from sympathetic neurons following uptake into the nerve terminal (Andersson and Sjogren,
Progress in Neurobiology
, 1982, 71-89). Activation of &agr;
1
adrenoceptors located on the smooth muscle cells of the proximal urethra and bladder neck (Sourander,
Gerontology
, 1990, 36, 19-26; Wein, supra) evokes contraction and an increase in urethral closure pressure.
The utility of phenylpropanolamine, pseudoephedrine, and midodrine is limited by a lack of selectivity among the &agr;
1
adrenoceptor subtypes and by the indirect action of these agents (i.e., activation of &agr;
1
, &agr;
2
, and &bgr;-adrenoceptors in the central nervous system and periphery). As a result, any desired therapeutic effect of these agents may be accompanied by undesirable side effects, such as an increase in blood pressure. The increase in blood pressure is dose-dependent and therefore limits the ability to achieve therapeutically effective circulating concentrations of these agents (Andersson and Sjogren, supra). Furthermore, in some patients these agents produce insomnia, anxiety and dizziness as a result of their central nervous system stimulant actions (Andersson and Sjogren, supra, Wein, supra).
While some selective &agr;
1A
agonists have recently been disclosed for the treatment of stress incontinence, there continues to be a need for medicaments that are useful for the treatment of incontinence. A compound having the desired &agr;
1A
adrenergic agonist profile is desirable.
SUMMARY OF THE INVENTION
One aspect of the present invention provides a compound of the formula:
a pharmaceutically acceptable salt or a prodrug thereof,
wherein
R
1
is alkyl, —NR
7
R
8
, where each of R
7
and R
8
is independently hydrogen or alkyl;
R
2
is hydrogen or alkyl;
each of R
3
, R
4
, R
5
, and R
6
is independently hydrogen, halide, alkyl, —OR
9
(where R
9
is hydrogen, alkyl, a hydroxy protecting group, or cycloalkylalkyl), —SR
10
(where R
10
is hydrogen or alkyl), or —NR
11
R
12
(where each of R
11
and R
12
is independently hydrogen, alkyl, or a nitrogen protecting group), provided R
3
, R
4
, R
5
, and R
6
are not all simultaneously alkyl); or R
3
and R
4
together with atoms to which they are attached to form heterocyclyl, heteroaryl, or cycloalkyl; and
R
14
is hydrogen, lower alky, or —OR
15
(where R
15
is hydrogen, lower alkyl, or a hydroxy protecting group).
Preferably R
14
is hydrogen, methyl or hydroxy. More preferably R
14
is hydrogen.
In one embodiment of the present invention, R
1
is alkyl. Preferably, R
1
is selected from the group consisting of methyl, ethyl, and isopropyl.
In another embodiment, R
2
is hydrogen.
Yet in another embodiment, each of R
7
and R
8
is independently hydrogen or methyl.
Still in another embodiment, each of R
3
, R
4
, R
5
, and R
6
is independently hydrogen, halide, alkyl, or —OR
10
, where R
10
is hydrogen, alkyl, a hydroxy protecting group, or cycloalkylalkyl; or R
3
and R
4
together with atoms to which they are attached to form heterocyclyl, heteroaryl, or cycloalkyl. Preferably, at least one of R
3
, R
4
, R
5
, and R
6
is alkyl, halide, or —OR
9
, where R
9
is as defined above. More preferably, at least one of R
3
, R
4
, R
5
, and R
6
is bromo, chloro, fluoro, methoxy, ethoxy, methyl, or hydroxy.
In one specific embodiment of the present invention,
(a) R
3
is methoxy, and R
4
, R
5
, and R
6
are hydrogen;
(b) R
3
is methyl, R
6
is methoxy, and R
4
and R
5
are hydrogen;
(c) R
3
is methyl, R
6
is chloro, and R
4
and R
5
are hydrogen;
(d) R
3
is chloro, R
4
is methoxy, and R
5
and R
6
are hydrogen;
(e) R
3
is methyl, R
4
is chloro, and R
5
and R
6
are hydrogen;
(f) R
3
is methyl, R
4
is methoxy, and R
5
and R
6
are hydrogen;
(g) R
4
is chloro, and R
3
, R
5
and R
6
are hydrogen;
(h) R
4
is methoxy, and R
3
, R
5
, and R
6
are hydrogen;
(i) R
3
is methyl, R
6
is bromo, and R
4
and R
5
are hydrogen;
(i) R
3
is bromo, R
4
is methoxy, and R
5
and R
6
are hydrogen;
(k) R
3
is methyl, R
4
is bromo, and R
5
and R
6
are hydrogen; or
(l) R
4
is bromo, and R
3
, R
5
and R
6
are hydrogen.
In another embodiment, R
3
and R
4
together with atoms to which they are attached to form furanyl, dihydrofuranyl, pyrrolyl, or phenyl. Preferably, R
3
and R
4
together with atoms to which they are attached to form furanyl or dihydrofuranyl. Preferred examples include:
Preferably, Compound of Formula I has an IC
50
&agr;
1A/L
receptor agonist activity of about 1 &mgr;M or less.
Another aspect of the present invention provides a method for producing an imidazolin-2-ylmethyl-substituted aromatic compound of the formula:
said method comprising contacting a nitrile compound of the formula:
with ethylene diamine to produce the imidazolin-2-ylmethyl-substituted aromatic compound,
wherein
R
1
is alkyl, —NR
7
R
8
, where each of R
7
and R
8
is independently hydrogen or alkyl;
R
2
is hydrogen or alkyl;
each of R
3
, R
4
, R
5
, and R
6
is independently hydrogen, halide, alkyl, —OR
9
, where R
9
is hydrogen, alkyl, a hydroxy protecting group, or cycloalkylalkyl, —SR
10
, where R
10
is hydrogen or alkyl, or —NR
11
R
12
, where each of R
11
and R
12
is independently hydrogen, alkyl, or a nitrogen protecting group; or R
3
and R
4
together with atoms to which they are attached to form heterocyclyl, heteroaryl, or cycloalkyl; and
R
14
is hydrogen, lower alkyl, or —OR
15
, where R
15
is hydrogen, lower alkyl, or a hydroxy protecting group.
Yet another aspect of the present invention provides a method for producing an imidazolin-2-ylmethyl-substituted aromatic compound of the f
Dillon Michael Patrick
Lin Clara Jeou Jen
O'Yang Counde
Zhang Xiaoming
Hall Robert C.
Roche Palo Alto LLC
Stockton Laura L.
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