Methods of increasing sphincter competence

A method of increasing sphincter competence comprising administering to a human in need of treatment an effective amount of a compound having the formula ##STR1## wherein R.sup.1 and R.sup.3 are independently hydrogen, ##STR2## wherein Ar is optionally substituted phenyl; R.sup.2 is selected from the group consisting of pyrrolidino, hexamethyleneimino, and piperidino; or a pharmaceutically acceptable salt of solvate thereof. Also encompassed by the invention is a method of inhibiting urinary or fecal incontinence, or gastroesophageal disease or its symptoms, which includes administering to a human in need thereof an effective amount of a compound of formula 1.

BACKGROUND OF THE INVENTION 
The current invention relates to the field of medical treatment which is 
characterized by the absence or diminution of control of sphincters of the 
gastrointestinal and urinary tracts, especially, that lack of control as 
seen in patients with hormonal deprivation or imbalance, e.g., 
post-menopausal women. 
Sphincters are structures in the body which regulate the flow of materials 
between the interior and exterior of the body or between various 
structures within the body. They function in much the same manner as a 
gate or valve in a pipe. Sphincters are composed of rings or flaps of 
either striated or smooth muscle cells between different luminal 
structures: interior, e.g., between the lower esophagus and upper part of 
the stomach or between the bladder and the posterior urethra; exterior, 
e.g., the lower colon and the exterior (the anal sphincter). Sphincters 
composed of striated muscle and controlled by the sympathetic nervous 
system can, to some extent, be directed by conscious action, e.g., the 
external urethral sphincter or the upper esophageal sphincter. Sphincters 
composed of smooth muscle cells are mainly controlled by the 
parasympathetic nervous system and are not consciously controlled. Smooth 
muscle sphincters are controlled by internal signals relating to the 
conditions in the luminal areas on either side of the sphincter, e.g., 
food traveling down the esophagus triggers the lower esophageal sphincter 
to relax or open to the stomach, or pressure in the bladder signals the 
sphincter to the posterior urethra to open. Opening of a sphincter is 
accomplished by the relaxation of the muscle's tone. Normally, most 
sphincters maintain remain closed or contracted in relation to their 
attached luminal structures, thus shutting off the flow of materials. 
Failure of sphincters to operate properly may be due to a variety of 
causes such as an obstruction in the passage, mechanical disruption of the 
passage by trauma or surgery, improper regulation by signals of the 
nervous system, or loss of muscle tone due to deterioration of the muscle, 
often seen in aging or with the loss of homeostatic balance of hormones. 
(For further details see: "Harrison's Principles of Internal Medicine", 
9th Ed., Isselbacher, et al., McGraw-Hill Book Co., NYC, Chap.44, p. 22-3 
and Chap. 239, p. 1365-7.) 
It is the failure of sphincters due to the loss of hormonal balance and 
their sequelae which are most germane to the current invention. In 
particular, the sphincter failure and resulting conditions germane to this 
invention would be: failure of the posterior urethral sphincter leading to 
urinary incontinence, failure of the anal sphincter leading to fecal 
incontinence, and failure of the lower esophageal sphincter leading to 
gastroesophageal reflux disease. 
Urinary incontinence is a common problem with the elderly population with 
at least 15% incidence. The incidence increases to 60% in patients living 
in community care facilities (nursing homes). Although the condition is 
not life-threatening, it is a source of both embarrassment to the patient 
and a potential problem for the maintenance of proper hygienic care for 
this population. In economic terms, urinary incontinence represents a 
substantial cost for the institution providing care for the aged. There 
are two major types of urinary incontinence which are common to the aged. 
The first type is stress incontinence which the is inability to hold back 
micturition when a physical stress is placed in the intraabdominal area, 
e.g., laughing, coughing, or stressful physical activity. The second type 
is urge incontinence where the patient can not delay voiding when the 
bladder is perceived to be full. Both of these types are common in 
post-menopausal women, especially parous women with weaken or damaged 
pelvic muscles and ligatures due to child birth. Treatment of this 
condition may be palliative such as using absorbent undergarments or in 
severe cases the use of alpha adrenergic blockers such as clonidine. 
However, agents such as clonidine have substantial cardiovascular 
side-effects which can make them not useful for chronic administration for 
urinary incontinence as a sole indication. Much more successful for the 
chronic treatment urinary incontinence in post-menopausal women is the use 
of estrogen hormone replacement therapy (HRT). 
HRT is not usually indicated for the singular use for treatment of urinary 
incontinence; however, this is a beneficial effect. However, HRT is 
plagued with poor patient compliance due to the negative side-effects, 
e.g., increased risk of uterine cancer with un-opposed estrogen, negative 
CNS effects when estrogen is combined with progestins, bloating, 
re-initiation of menses, increased breast cancer risk, etc. Certainly, 
estrogens are not usually used in males. Therefore, there is a need for 
better therapies to urinary incontinence, especially in the elderly. 
Fecal incontinence occurs in the elderly population in a pattern similar to 
that seen with urinary incontinence; however, at a much reduced rate. The 
consequence of patients suffering from this condition can be much worse 
than those suffering from urinary incontinence in that hygiene becomes a 
much more serious problem. More care and economic outlay must be used to 
avoid such problems as infection with this population. Causes for fecal 
incontinence appear to be similar to those which cause urinary 
incontinence and therefore, the patient population suffering from this 
malady is similar, i.e., parous post-menopausal women are the most common 
suffers. Treatment for this condition is confined to palliative measures, 
such as absorbent undergarments, frequent changes of garments, and 
frequent bathing. The use of HRT in post-menopausal women as an effective 
treatment is not clear, although there is every reason to believe that it 
has the potential for beneficial effects. Perhaps, the lack of clarity is 
due to the idiosyncratic nature of this condition or the fact that 
insufficient data exists because of the relatively few women who will 
tolerate the negative side-effects of HRT, especially older(70+) 
post-menopausal women who are the most likely to suffer. It is clear that 
better therapy in this area would be of benefit. (Further details see; 
"Hormones and Aging", Ed. Timiras et al., CRC Press, Boca Raton Fla., 
Chap. 8, p.141-142 and references therein.) 
GERD is a condition where the contents of the stomach are spilled up 
(refluxed) into the esophagus. This condition is often due to a failure of 
the lower esophageal sphincter to close properly. The consequences of this 
reflux are annoying to the patient and potentially serious. In milder 
forms, the patient complains of a burning sensation in the esophagus or 
heartburn and this often leads to pain, lack of sleep, and loss of 
productivity. In more serious cases, chronic reflux can lead to ulceration 
of the esophagus leading to surgical intervention or it is thought to be 
contributory to the development of esophageal cancer. 
People of all ages and sexes can suffer from this malady; However, it is 
more prevalent in the older population. Anecdotally, women report changes 
(increase or decrease in symptoms) during menstrual cycles, during 
pregnancy, and during menopause, yet verification of a linkage between 
hormonal levels and GERD remains illusive. It is well known that hormones 
such as estrogen effect other sphincters of similar physiology and it is 
known that estrogens effect stomach motility and other upper GI functions 
such as gastric emptying. However, other factors causing failure of the 
esophageal sphincter, such as herniation of the stomach, hypersensitivity 
of the esophagus and hyperacidity of the stomach, may cloud a clear 
understanding of the role of hormones in this condition. 
Treatment for GERD consists of mechanical and pharmacologic intervention. 
Mechanical intervention can be achieved by in several ways, patients who 
suffer GERD at night can sleep in a more elevated position, thus allowing 
gravity to keep the stomachs contents from entering the esophagus, obese 
patients can lose weight, exercise can increase the tone of the supporting 
muscles, or surgical intervention can be used to repair the effected 
tissues. Pharmacological intervention consists of lowering the stomachs 
acidity with antacids or with anticholinergic drugs, such as bethanechol, 
each or both of these may be effective, but are problematic for long term 
use due to negative side-effects. New agents by themselves or in addition 
to known, effective agents would improve current therapies for the 
treatment of GERD. 
The present invention is directed to the discovery that the compounds of 
the present invention, as defined below, increase sphincter competence. 
SUMMARY OF THE INVENTION 
This invention provides methods of increasing sphincter competence 
comprising administering to a human in need thereof an effective amount of 
a compound of formula I 
##STR3## 
wherein R.sup.1 and R.sup.3 are independently hydrogen, 
##STR4## 
or wherein Ar is optionally substituted phenyl; 
R.sup.2 is selected from the group consisting of pyrrolidino, 
hexamethyleneimino, and piperidino; and pharmaceutically acceptable salts 
and solvates thereof. 
Also encompassed by the invention are methods for inhibiting urinary and 
fecal incontinence, and gastroesophageal reflux disease. 
DETAILED DESCRIPTION OF THE INVENTION 
The current invention concerns the discovery that a select group of 
2-phenyl-3-aroylbenzothiophenes (benzothiophenes), those of formula I, are 
useful for increasing sphincter competence. The methods of use provided by 
this invention are practiced by administering to a human or mammal in need 
thereof a dose of a compound of formula I or a pharmaceutically acceptable 
salt or solvate thereof, that is effective to increase sphincter 
competence. The present method includes both medical therapeutic and/or 
prophylactic treatment, as appropriate. 
The term "inhibit" includes its generally accepted meaning which includes 
prohibiting, preventing restraining, and slowing, stopping, or reversing 
progression, severity, or a resultant symptom or effect. 
The term "effective amount" means the amount of compound necessary to 
inhibit fecal or urinary incontinence, or gastroesophageal reflux disease, 
or increase sphincter competence, as the case may be. 
Raloxifene, a compound of this invention is the hydrochloride salt of a 
compound of formula 1, wherein R.sup.1 and R.sup.3 are hydrogen and 
R.sup.2 is 1-piperidinyl. 
Generally, the compound is formulated with common excipients, diluents or 
carriers, and compressed into tablets, or formulated as elixirs or 
solutions for convenient oral administration, or administered by the 
intramuscular or intravenous routes. The compounds can be administered 
transdermally, and may be formulated as sustained release dosage forms and 
the like. 
The compounds used in the methods of the current invention can be made 
according to established procedures, such as those detailed in U.S. Pat. 
Nos. 4,133,814, 4,418,068, and 4,380,635 all of which are incorporated by 
reference herein. In general, the process starts with a benzo[b]thiophene 
having a 6-hydroxyl group and a 2-(4-hydroxyphenyl) group. The starting 
compound is protected, alkylated or acylated, and deprotected to form the 
formula I compounds. Examples of the preparation of such compounds are 
provided in the U.S. patents discussed above. Optionally substituted 
phenyl includes phenyl and phenyl substituted once or twice with C.sub.1 
-C.sub.6 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, nitro, chloro, fluoro, 
or tri(chloro or fluoro) methyl. 
The compounds used in the methods of this invention form pharmaceutically 
acceptable acid and base addition salts with a wide variety of organic and 
inorganic acids and bases and include the physiologically acceptable salts 
which are often used in pharmaceutical chemistry. Such salts are also part 
of this invention. Typical inorganic acids used to form such salts include 
hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, 
hypophosphoric and the like. Salts derived from organic acids, such as 
aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, 
hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and 
aromatic sulfonic acids, may also be used. Such pharmaceutically 
acceptable salts thus include acetate, phenylacetate, trifluoroacetate, 
acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, 
hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, 
naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, 
.beta.-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate, 
caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, 
heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, 
mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, 
phthalate, teraphthalate, phosphate, monohydrogenphosphate, 
dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, 
phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, 
bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzene-sulfonate, 
p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 
2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, 
naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, 
and the like. A preferred salt is the hydrochloride salt. 
The pharmaceutically acceptable acid addition salts are typically formed by 
reacting a compound of formula I with an equimolar or excess amount of 
acid. The reactants are generally combined in a mutual solvent such as 
diethyl ether or benzene. The salt normally precipitates out of solution 
within about one hour to 10 days and can be isolated by filtration or the 
solvent can be stripped off by conventional means. 
Bases commonly used for formation of salts include ammonium hydroxide and 
alkali and alkaline earth metal hydroxides, carbonates, as well as 
aliphatic and primary, secondary and tertiary amines, aliphatic diamines. 
Bases especially useful in the preparation of addition salts include 
ammonium hydroxide, potassium carbonate, methylamine, diethylamine, 
ethylene diamine and cyclohexylamine. 
The pharmaceutically acceptable salts generally have enhanced solubility 
characteristics compared to the compound from which they are derived, and 
thus are often more amenable to formulation as liquids or emulsions. 
Pharmaceutical formulations can be prepared by procedures known in the art. 
For example, the compounds can be formulated with common excipients, 
diluents, or carriers, and formed into tablets, capsules, suspensions, 
powders, and the like. Examples of excipients, diluents, and carriers that 
are suitable for such formulations include the following: fillers and 
extenders such as starch, sugars, mannitol, and silicic derivatives; 
binding agents such as carboxymethyl cellulose and other cellulose 
derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing 
agents such as glycerol; disintegrating agents such as calcium carbonate 
and sodium bicarbonate; agents for retarding dissolution such as paraffin; 
resorption accelerators such as quaternary ammonium compounds; surface 
active agents such as cetyl alcohol, glycerol monostearate; adsorptive 
carriers such as kaolin and bentonite; and lubricants such as talc, 
calcium and magnesium stearate, and solid polyethyl glycols. 
The compounds can also be formulated as elixirs or solutions for convenient 
oral administration or as solutions appropriate for parenteral 
administration, for instance by intramuscular, subcutaneous or intravenous 
routes. Additionally, the compounds are well suited to formulation as 
sustained release dosage forms and the like. The formulations can be so 
constituted that they release the active ingredient only or preferably in 
a particular part of the intestinal tract, possibly over a period of time. 
The coatings, envelopes, and protective matrices may be made, for example, 
from polymeric substances or waxes. 
The particular dosage of a compound of formula I required to increase 
sphincter competence, inhibit urinary or fecal incontinence, or 
gastroesophageal reflux disease, according to this invention, will depend 
upon the severity and nature of the condition, the route of 
administration, and related factors that will be decided by the attending 
physician. Generally, accepted and effective daily doses will be from 
about 0.1 to about 1000 mg/day, and more typically from about 50 to about 
200 mg/day. Such dosages will be administered to a subject in need of 
treatment from once to about three times each day, or more often as needed 
to effectively increase sphincter competence, or inhibit urinary or fecal 
incontinence, or gastroesophageal reflux disease. 
It is usually preferred to administer a compound of formula I in the form 
of an acid addition salt, as is customary in the administration of 
pharmaceuticals bearing a basic group, such as the piperidino ring. It is 
also advantageous to administer such a compound by the oral route. For 
such purposes the following oral dosage forms are available. 
FORMULATIONS 
In the formulations which follow, "active ingredient" means a compound of 
formula I. 
Formulation 1: Gelatin Capsules 
Hard gelatin capsules are prepared using the following: 
______________________________________ 
Ingredient Quantity (mg/capsule) 
______________________________________ 
Active ingredient 0.1-1000 
Starch, NF 0-650 
Starch flowable powder 
0-650 
Silicone fluid 350 centistokes 
0-15 
______________________________________ 
The ingredients are blended, passed through a No. 45 mesh U.S. sieve, and 
filled into hard gelatin capsules. 
Examples of specific capsule formulations of raloxifene that have been made 
include those shown below: 
Formulation 2: Raloxifene Capsule 
______________________________________ 
Ingredient Quantity (mg/capsule) 
______________________________________ 
Raloxifene 1 
Starch, NF 112 
Starch flowable powder 
225.3 
Silicone fluid 350 centistokes 
1.7 
______________________________________ 
Formulation 3: Raloxifene Capsule 
______________________________________ 
Ingredient Quantity (mg/capsule) 
______________________________________ 
Raloxifene 5 
Starch, NF 108 
Starch flowable powder 
225.3 
Silicone fluid 350 centistokes 
1.7 
______________________________________ 
Formulation 4: Raloxifene Capsule 
______________________________________ 
Ingredient Quantity (mg/capsule) 
______________________________________ 
Raloxifene 10 
Starch, NF 103 
Starch flowable powder 
225.3 
Silicone fluid 350 centistokes 
1.7 
______________________________________ 
Formulation 5: Raloxifene Capsule 
______________________________________ 
Ingredient Quantity (mg/capsule) 
______________________________________ 
Raloxifene 50 
Starch, NF 150 
Starch flowable powder 
397 
Silicone fluid 350 centistokes 
3.0 
______________________________________ 
The specific formulations above may be changed in compliance with the 
reasonable variations provided. 
A tablet formulation is prepared using the ingredients below: 
Formulation 6: Tablets 
______________________________________ 
Ingredient Quantity (mg/tablet) 
______________________________________ 
Active ingredient 
0.1-1000 
Cellulose, microcrystalline 
0-650 
Silicon dioxide, fumed 
0-650 
Stearate acid 0-15 
______________________________________ 
The components are blended and compressed to form tablets. 
Alternatively, tablets each containing 0.1-1000 mg of active ingredient are 
made up as follows: 
Formulation 7: Tablets 
______________________________________ 
Ingredient Quantity (mg/tablet) 
______________________________________ 
Active ingredient 0.1-1000 
Starch 45 
Cellulose, microcrystalline 
35 
Polyvinylpyrrolidone 
4 
(as 10% solution in water) 
Sodium carboxymethyl cellulose 
4.5 
Magnesium stearate 0.5 
Talc 1 
______________________________________ 
The active ingredient, starch, and cellulose are passed through a No. 45 
mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone 
is mixed with the resultant powders which are then passed through a No. 14 
mesh U.S. sieve. The granules so produced are dried at 
50.degree.-60.degree. C. and passed through a No. 18 mesh U.S. sieve. The 
sodium carboxymethyl starch, magnesium stearate, and talc, previously 
passed through a No. 60 U.S. sieve, are then added to the granules which, 
after mixing, are compressed on a tablet machine to yield tablets. 
Suspensions each containing 0.1-1000 mg of medicament per 5 mL dose are 
made as follows: 
Formulation 8: Suspensions 
______________________________________ 
Ingredient Quantity (mg/5 ml) 
______________________________________ 
Active ingredient 0.1-1000 mg 
Sodium carboxymethyl cellulose 
50 mg 
Syrup 1.25 mg 
Benzoic acid solution 
0.10 mL 
Flavor q.v. 
Color q.v. 
Purified water to 5 mL 
______________________________________ 
The medicament is passed through a No. 45 mesh U.S. sieve and mixed with 
the sodium carboxymethyl cellulose and syrup to form a smooth paste. The 
benzoic acid solution, flavor, and color are diluted with some of the 
water and added, with stirring. Sufficient water is then added to produce 
the required volume. 
As mentioned previously, compounds of formula I can be used as single 
agents or in combination with known, effective agents. Combination therapy 
may be in the form a single dosage entity as illustrated above or as 
separate entities, thus giving the attending physician the greatest 
latitude of protocols. If a single entity combination is chosen, other 
beneficial compounds might include, but not be limited to: 0.2 to 2 mg of 
clonidine for urinary incontinence, 10-50 milliequivalents of antacid for 
GERD (see: "Goodman and Gilman's, The Pharmacologic Basis of Therapeutics, 
6th Ed., Macmillan Publishing Co., NYC, 1980, Chap.42), or 25 mg of 
bethanecol for GERD. Additionally, these combinations (either as a single 
entity or as separate entities) may be given at specific time intervals, 
e.g., after meals or before sleep, as directed by the attending physician.

The following examples would demonstrate the utility of the current 
invention. These examples are for purposes of illustration and are not 
meant to limit the use of this invention in any way. 
Urinary Incontinence 
Trial 1 
Fifty women are selected for entrance to the study. Selection criteria is: 
50 to 70 years of age, at least one year post-menopausal, in good mental 
and physical health, and suffering from periods (at least once per week) 
of stress and/or urge urinary incontinence. Each patient is randomly 
assigned to either receiving a compound of formula I (treatment group) or 
placebo (control group). Prior to entry into the study, each patient is 
asked to record incidences of urinary incontinence for a period of six 
weeks. The parameters recorded are the number of incidents, time of their 
occurrence, and some measure of their extent, e.g., were only the 
undergarments soiled?, how many times, did your incontinence require a 
change of clothing?, did the bedding get soiled?, could you control the 
micturation? Did you feel embarrassment or anxiety?, etc. 
Twenty-five of the women are given a matched placebo. The other twenty-five 
are given a compound of formula I, e.g., a formulated capsule containing 
60 mg of Raloxifene to be taken once a day. The study continues for three 
months. During the study, the patients record the same data regarding the 
number and extent of incidents of urinary incontinence. At the end of the 
study, the patient's records are analyzed. Due to the idiosyncratic nature 
of this malady, appropriate, multi-variant analysis would used to analyze 
the data. 
Trial 2 
This example is same as Trial 1, with the exception that the control group 
is given a formulation containing a compound of formula I and an estrogen, 
once a day. 
Trial 3 
This study is essentially the same as that in Trial 1, with the exception 
that the treatment group receives in addition a 0.2mg dose of clonidine 
taken orally prior to bed time. 
Fecal Incontinence 
Trial 4 
This study is of the same design as that described in Trial 1 with the 
exception that the treatment period is extended to one year. 
GERD 
Trial 5 
One hundred post-menopausal women (at least one year menopausal prior to 
the study initiation) are selected. These patients have the following 
entrance criterion: suffer from at least one incident of GERD per week or 
four or more incidents per month and be in otherwise good, general health. 
The diagnosis that these women are suffering from GERD and not some other 
malady must be determined by the attending physician. Such diagnosis can 
be made by techniques known in the medical art, e.g., see: "Harrison's 
Principles of Internal Medicine", ibid., Chap. 289, p.1366-7. Each patient 
is asked to record the number of incidents of GERD and their extent, e.g., 
When did the incidents occur?, Where was the pain (heartburn)?, What was 
the patient doing (bending, sitting, lying down)?, Was any material 
aspirated?, etc. 
Fifty patients (control group) are given a matched placebo to be taken 
orally once a day. The other fifty patients (treatment group) is given a 
formulation containing a compound of formula I, e.g., a formulated tablet 
containing 60 mg of Raloxifene, to be taken orally once a day. During the 
study period, the patients record incidents of GERD and circumstances 
surrounding these incidents using the same parameters as used in the 
pre-study period. The study continues for six months. Each patient records 
are analyzed and compared as to the number and extent of GERD incidents, 
pre-study versus on-study, using appropriate statistical analysis. 
Trial 6 
This study would be essentially the same as Trial 5 with the exception that 
the control group receives in addition 25 mg of bethanecol to be taken 
orally at bed time. The control group in addition receives a matched 
placebo to be taken orally bed time. 
Trial 7 
This study is be essentially the same as that of Trial 5 with the exception 
that the treatment group would, in addition, receive 20 mL of an antacid 
such as Maalox.RTM. to be taken after each meal and before bed time. 
Utility of the compounds of the invention is illustrated by the positive 
impact displayed by any of the above assays.