Combination therapy for inhibiting sphincter incontinence

Details Combination therapy for inhibiting sphincter incontinence Combination therapy for inhibiting sphincter incontinence

2001-06-29

2002-09-24

Jones, Dwayne C. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06455568

ABSTRACT:

BACKGROUND OF THE INVENTION
Stress incontinence is a problem in which the urethral sphincter is unable to retain urine in the bladder. Such problems may occur as a result from weakened pelvic muscles that support the bladder, or malfunction of the urethral sphincter. Trauma to the urethral area, neurological injury, and some medications may weaken the urethral closure. Male sphincter weakness can occur after prostate surgery. Women may experience similar weakness after pelvic surgery. Women may also experience stress incontinence after multiple pregnancies, pelvic prolapse (protrusion of the bladder or urethra into the vaginal space), cystocele, or rectocele. Additionally, women with low estrogen levels may experience stress incontinence due to decreased vaginal muscle tone. Studies have documented that about 50% of all women have occasional incontinence, and as many as 10% have regular incontinence. In women over 75 years of age, nearly 20% experience incontinence daily. The risk increases with advancing age, obesity, chronic bronchitis, asthma, and childbearing.
Lack of control of the lower esophageal sphincter can lead to stomach acids being refluxed upward into the esophagus, causing heartburn, also known as gastroesophageal reflux disease (GERD), reflux or reflux esophagitis. This condition is often due to failure of the lower esophageal sphincter to close properly. In milder forms, the sufferers experience a burning sensation in the esophagus or heartburn which often leads to pain, lack of sleep, and loss of productivity. Chronic reflux can lead to esophageal ulceration requiring surgery is thought to be possibly contributory to development of esophageal cancer.
Sphincters composed of smooth muscle cells are controlled predominantly by the autonomic nervous system in relation to the conditions in the luminal areas on either side of the sphincter, e.g., food passing through the esophagus triggers the lower esophageal sphincter to relax or open to the stomach, or bladder pressure signals the sphincter opening of the posterior urethra.
Sphincters generally remain closed or contracted in relation to their luminal structures and inhibit flow of materials. Sphincters fail and allow untimely passage of materials for various reasons, including passage obstructions, trauma to the passage, improper nervous system regulation, or loss of muscle tone, often found in aging or with the loss of homeostatic hormone balance.
Estrogen hormone replacement therapy (HRT) has been used for the chronic treatment of urinary incontinence in post-menopausal women. However, poor patient compliance has been noted with HRT because of negative side-effects, such as increased risk of uterine cancer with unopposed estrogen, negative CNS effects when estrogen is combined with progestins, bloating, re-initiation of menses, increased breast cancer risk, etc. Estrogens are also not usually used in men. Therefore, there is a need for better therapies to urinary incontinence in both sexes, especially in the aged.
Fecal incontinence also occurs in the elderly, though with less frequency than urinary incontinence, with post-menopausal women being the most common sufferers. Common management methods include use of absorbent undergarments, frequent changes of clothing, and increased bathing.
WO 99/33454 (Fabiano et al.) teaches a method of treating urinary incontinence using enantiomerically enriched (S)-procyclidine.
WO 97/26876 (Cullinan) teaches methods of increasing sphincter competence using raloxifene or its analogs, having the general structure:
U.S. Pat. No. 5,948,804 (Jeon et al.) teaches the use of substituted indole compounds having the general structure:
in the treatment of urinary incontinence.
EP 0 802 183 A1 and U.S. Pat. No. 5,780,497 describe substituted indole compounds of the formulae below:
as well as their use as estrogenic agents, including the treatment of bone loss, cardiovascular disease, maladies associated with or resulting from the proliferation or abnormal development of endometrial or endometrial-like tissues, and disease states or syndromes associated with estrogen deficiency.
EP 0 802 184 A1, published Oct. 22, 1997, describes comparable uses for substituted indole compounds of the formulae below.
Analogous indole compounds having the general structures:
are described in U.S. Pat. No. 5,880,137 (Miller et al.).
DESCRIPTION OF THE INVENTION
This invention comprises methods of treating, preventing, alleviating or inhibiting sphincter incontinence in a mammal, preferably in a human, the methods comprising administering to a mammal in need thereof one or more estrogens, or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective amount of a compound of the formulae I or II, below:
wherein Z is a moiety selected from the group of:
wherein:
R
1
is selected from H, OH or the C
1
-C
12
esters (straight chain or branched) or C
1
-C
12
(straight chain or branched or cyclic) alkyl ethers thereof, benzyloxy, or halogen; or C
1
-C
4
halogenated ethers including trifluoromethyl ether and trichloromethyl ether;
R
2
, R
3
, R
5
, and R
6
are independently selected from H, OH or the C
1
-C
12
esters (straight chain or branched) or C
1
-C
12
alkyl ethers (straight chain or branched or cyclic) thereof, halogens, or C
1
-C
4
halogenated ethers including trifluoromethyl ether and trichloromethyl ether, cyano, C
1
-C
6
alkyl (straight chain or branched), or trifluoromethyl, with the proviso that, when R
1
is H, R
2
is not OH;
R
4
is selected from H, OH or the C
1
-C
12
esters (straight chain or branched) or C
1
-C
12
alkyl ethers (straight chain or branched or cyclic) thereof, benzyloxy, halogens, or C
1
-C
4
halogenated ethers including trifluoromethyl ether and trichloromethyl ether, cyano, C
1
-C
6
alkyl (straight chain or branched), or trifluoromethyl;
X is selected from H, C
1
-C
6
alkyl, cyano, nitro, trifluoromethyl, halogen;
n is 1, 2 or 3;
Y is selected from:
a) the moiety:
wherein R
7
and R
8
are independently selected from the group of H, C
1
-C
6
alkyl, or phenyl optionally substituted by CN, C
1
-C
6
alkyl (straight chain or branched), C
1
-C
6
alkoxy (straight chain or branched), halogen, —OH, —CF
3
, or —OCF
3
;
b) a five-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C
1
C
4
alkyl)—, —N═, and —S(O)
m
—, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C
1
-C
4
alkyl, trihalomethyl, C
1
-C
4
alkoxy, trihalomethoxy, C
1
-C
4
acyloxy, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulfinyl, C
1
-C
4
alkylsulfonyl, hydroxy (C
1
-C
4
)alkyl, —CO
2
H—, —CN—, —CONHR
1
—, —NH
2
—, C
1
-C
4
alkylamino, di(C
1
-C
4
)alkylamino, —NHSO
2
R
1
—, —NHCOR
1
—, —NO
2
, and phenyl optionally substituted with 1-3 (C
1
-C
4
)alkyl;
c) a six-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C
1
C
4
alkyl)—, —N═, and —S(O)
m
—, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C
1
-C
4
alkyl, trihalomethyl, C
1
-C
4
alkoxy, trihalomethoxy, C
1
-C
4
acyloxy, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulfinyl, C
1
-C
4
alkylsulfonyl, hydroxy (C
1
-C
4
)alkyl, —CO
2
H—, —CN—, —CONHR
1
—, —NH
2
—, C
1
-C
4
alkylamino, di(C
1
-C
4
)alkylamino, —NHSO
2
R
1
—, —NHCOR
1
—, —NO
2
, and phenyl optionally substituted with 1-3 (C
1
-C
4
)alkyl;
d) a seven-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C
1
C
4
alkyl)—, —N═, and —S(O)
m
—, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C
1
-C
4
alkyl, trihalomethyl, C
1
-

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