KR19990082056A - How to increase sphincter response - Google Patents

Abstract

A method of increasing sphincter responsiveness, comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof to a person in need thereof.

<Formula I>

Where

R ¹ and R ³ are independently hydrogen, —CH ₃ , (a) Or (b) Wherein Ar is optionally substituted phenyl;

R ² is selected from the group consisting of pyrrolidino, hexamethyleneimino or piperidino.

Description

How to increase sphincter response

Background of the Invention

FIELD OF THE INVENTION The present invention relates to the field of medical treatment characterized by a lack of or reduced sphincter control of the gastrointestinal tract and urethra, in particular the lack of control present in hormone-deficient or unstable patients such as postmenopausal women.

The sphincter is a structure within the body that controls the flow of matter between the interior and exterior of the body or between various structures within the body. They act in the same way as gates or valves in pipes. The sphincter consists of loops or flaps of syntactic or smooth muscle cells between different coronary structures: for example, between the lower esophagus and the upper part of the stomach or between the bladder and the hip urethra, while the lower colon and the external (Anal sphincter). The sphincter, such as the external urethral sphincter or the upper esophageal sphincter, which is composed of syntactic muscles and controlled by the sympathetic nervous system, can be controlled to some degree by conscious action. The sphincter consisting of smooth muscle cells is mainly controlled by the parasympathetic nervous system and not consciously controlled. Smooth muscle sphincter is controlled by internal signals associated with conditions in both coronary areas of the sphincter (eg, irritating the lower esophageal sphincter where food moving along the esophagus relaxes or opens the stomach, or pressure in the bladder Signals the sphincter opening to the urethra to open). Opening of the sphincter is achieved by relaxing the muscle tension. In general, most sphincters remain closed or contracted with respect to the tubular structure to which they are attached to block the flow of material. Failure of the sphincter to function properly can result in loss of muscle tension due to obstructions in the passage, mechanical breakage by trauma or surgery, incorrect control by nervous system signals, or muscle degeneration often observed in elderly or patients who have lost homeostatic balance of hormones. It can come from many different reasons. (For further explanation, see "Harrison's Princinples of Internal Medicine", 9th edition, Isselbacher et al., McGraw-Hill Book Co., NYC, Chap. 44, p. 22-3 and Chap. 239, p. See 1365-7)

Most closely related to the present invention is loss of hormonal balance and dysfunction of the sphincter following its frailty. In particular, the sphincter dysfunction closely related to the present invention and the symptoms thereof are related to the function of the lower esophageal sphincter causing the dysfunction of the hip urethral sphincter causing urinary incontinence, the dysfunction of the anal sphincter causing stool incontinence, and gastroesophageal reflux disease. Dysfunction.

Urinary incontinence is a common social problem that affects more than 15% of the elderly population. The incidence increases by 60% in patients living in group care facilities. Although symptoms are not life threatening, they not only embarrass the patient, but also have inherent problems in maintaining adequate hygiene protection for this population. Economically, urinary incontinence means a substantial expense for a facility that protects older people. There are mainly two types of urinary incontinence common to older people. The first type is stress incontinence that prevents urination when physical stress, such as laughter, coughing or stressful physical activity, is applied to the inner abdominal region. The second type is pressurized incontinence, in which the patient cannot delay urination if he is aware that the bladder is full. Both types are common in postmenopausal women, especially women who have had pelvic muscles and connections weakened or damaged due to childbirth. Treatment of this condition can be alleviated by using absorbent undergarments or, in severe cases, alpha adrenergic blockers such as clonidine. However, drugs such as clonidine show substantial cardiovascular side effects, which may not be useful for prolonged administration as the sole measure of incontinence. Long-term treatment of urinary incontinence in postmenopausal women is to use estrogen hormone replacement therapy (HRT).

HRT is not usually identified as an exception for the treatment of urinary incontinence: this is a beneficial effect. However, HRT is poorly compatible with patients due to side effects such as, for example, increased risk of uterine cancer due to non-resistance estrogen, CNS effects when estrogen is combined with progestin, swelling, resumption of menstruation, and increased threat of breast cancer. It is a disadvantage. Of course, estrogen is not commonly used in men. Therefore, there is a need for better treatments, particularly for urinary incontinence in the elderly.

Fecal incontinence occurs in older people in a similar fashion to that found in urinary incontinence, but at a much lower rate. The situation of patients suffering from this condition is much worse in hygiene, and is much worse than those suffering from incontinence. More attention and economic expense should be used to avoid problems such as infectious diseases in these patients. The cause of fecal incontinence appears to be similar to that of causing urinary incontinence, and therefore the patient population suffering from the disease is similar. In other words, most menopausal women with labor experience suffer the most. Treatment of this symptom is limited to relieving measures such as absorbent undergarments, frequent changing of underwear and frequent washing. There are many reasons that are thought to have potential beneficial effects, but the use of HRT in postmenopausal women is uncertain as an effective treatment. Perhaps this lack of certainty is due to the small number of female patients who can withstand the specific nature of the symptoms or the negative side effects of HRT, especially the postmenopausal elderly (70+) women most susceptible to the disease. It is due to the fact that there is no. It is clear that better treatment in this area would be helpful (for additional details see the literature "Hormones and Aging", editorial Timiras et al., CRC Press, Boca Raton Fl, Chap. 8, p. 141-142 and See references herein.

GERD is a condition in which the contents of the stomach overflow into the esophagus. This symptom is often due to the inability to close the lower esophageal sphincter. As a result of this reflux, the patient may be offended and become serious. In moderate form, the patient complains of burning or chest pain in the esophagus, which often results in pain, lack of sleep and loss of motivation. In more severe cases, chronic reflux can be thought to lead to ulceration of the esophagus requiring surgical intervention or to contribute to the development of esophageal cancer.

Populations of all ages, regardless of gender, can suffer from the disease, but are more prevalent in older people. Although women report changes (increase or decrease in symptoms) during the menstrual cycle, during pregnancy, and during menopause, the validation of the relationship between hormone levels and GERD is uncertain. It is well known that hormones such as estrogen affect other sphincter muscles of similar physiological function, and it is also known that estrogen affects other upper GI functions such as gastric motility and emptying of the stomach. However, other factors leading to dysfunction of the esophageal sphincter, such as gastric hernia, hyperesophageal hypersensitivity and excessive gastric acid, can interfere with a clear understanding of the role of the hormone in this condition.

Treatment of GERD consists of mechanical and pharmacological interventions. Mechanical interventions can be made in several ways: patients with GERD can be placed in an upright upper body at night to prevent the stomach contents from entering the esophagus by gravity, causing them to fall asleep and losing excessively fat patients. Can be exercised, exercise can increase the tension of the support muscles, or surgical intervention can be used to correct damaged tissue. Pharmacological interventions lower the acidity of the stomach with antacids or anticholinergic agents such as betanechol, but long-term use is problematic due to side effects. New reagents will be added on their own or to known effective agents to improve current GERD treatment regimens.

The present invention relates to the discovery that the compounds of the present invention increase sphincter response as described below.

Summary of the Invention

The present invention provides a method of increasing sphincter response, comprising administering an effective amount of a compound of Formula (I), and a pharmaceutically acceptable salt and solvate thereof, to a person in need thereof.

(Wherein

R ¹ and R ³ are independently hydrogen, -CH ₃ , or Wherein Ar is optionally substituted phenyl;

R ² is selected from the group consisting of pyrrolidino, hexamethyleneimino and piperidino)

The invention also includes methods of inhibiting urine and fecal incontinence and gastroesophageal reflux disease.

Detailed description of the invention

The present invention relates to the discovery that a selected group of 2-phenyl-3-aroylbenzothiophene (benzothiophene), a compound of Formula I, is useful for increasing sphincter reactivity. The method of use provided by the present invention is carried out by administering to a person or mammal in need thereof a dose of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof effective to increase sphincter response. This method includes both medical and / or prophylactic treatment.

The term “inhibit” includes its generally understood meaning including limiting, preventing, inhibiting, delaying, stopping or reversing progression, severity or outcome symptoms or effects.

The term "effective amount" refers to the amount of compound necessary to inhibit stool or urinary incontinence or gastroesophageal reflux disease or, in some cases, increase the sphincter response.

One of the compounds of the present invention, raloxyphene, is a hydrochloride of the compound of formula (I) wherein R ¹ and R ³ are hydrogen and R ² is 1-piperidinyl.

Generally, the compounds are formulated with conventional excipients, diluents or carriers, compressed into tablets, formulated with elixirs or solutions for convenient oral administration, or administered by the intramuscular or intravenous route. The compound may be administered transdermally, and may be formulated in a sustained release dosage form and the like.

The compounds used in the methods of the invention can all be prepared according to established methods as detailed in US Pat. Nos. 4,133,814, 4,418,068 and 4,380,635, which are incorporated herein by reference. In general, the process uses benzo [b] thiophene having 6-hydroxyl groups and 2- (4-hydroxyphenyl) groups as starting materials. The starting compounds are protected, alkylated or acylated and deprotected to form compounds of formula (I). Examples of preparation of such compounds are shown in the above-mentioned US patents. Optionally substituted phenyl replaces phenyl and phenyl substituted once or twice with C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, hydroxy, nitro, chloro, fluoro or tri (chloro or fluoro) methyl. Include.

The compounds used in the methods of the present invention form pharmaceutically acceptable acid addition salts and base addition salts with a wide variety of organic and inorganic acids and bases, and include physiologically acceptable salts often used in pharmaceutical chemistry. These salts also form part of the present invention. Typical inorganic acids used to form these salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and hypophosphorous acid and the like. Salts derived from organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids and hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids can also be used. Accordingly, these pharmaceutically acceptable salts include acetates, phenylacetates, trifluoroacetates, acrylates, ascorbates, benzoates, chlorobenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates , Methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, β-hydroxybutyrate, butyne-1,4-dirate, hexin-1, 4-Dirate, Caprynate, Caprylate, Chloride, Cinnamic Acid, Citrate, Formate, Fumarate, Glycolate, Heptanate, Hypurate, Lactate, Malate, Maleate, Hydroxy Maleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terraphthalate, phosphate, monohydrogen phosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate , Propionate, phenylprop Sulphate, salicylate, sebacinate, succinate, suverate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzene-sulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate , Ethane sulfonate, 2-hydroxyethane sulfonate, methane sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluene sulfonate, xylene sulfonate, tartarate and the like. Preferred salts are hydrochlorides.

Pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of Formula I with an equimolar or excess acid. The reactants are usually mixed in a cosolvent such as diethyl ether or benzene. Salts generally precipitate out of solution in about 1 hour to 10 days and can be isolated by filtration or the solvent can be stripped by conventional methods.

Bases commonly used to form salts include ammonium hydroxide, and alkali and alkaline earth metal hydroxides, carbonates, as well as aliphatic and primary, secondary and tertiary amines, aliphatic diamines. Particularly useful bases for the preparation of addition salts include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, ethylene diamine and cyclohexylamine.

Pharmaceutically acceptable salts generally have increased solubility compared to the parent compound from which they are derived and are therefore often easier to formulate in liquid or emulsion.

Pharmaceutical formulations may be prepared by methods known in the art. For example, the compounds may be formulated with common excipients, diluents or carriers to form tablets, capsules, suspensions, powders, and the like. Examples of excipients, diluents and carriers suitable for such formulations include fillers and extenders such as starch, sugars, mannitol and silicic acid derivatives; Binders such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin and polyvinyl pyrrolidone; Humectants, such as glycerol; Disintegrants such as calcium carbonate and sodium bicarbonate; Dissolution retardants such as paraffin; Resorption accelerators such as quaternary ammonium compounds; Surfactants such as cetyl alcohol and glycerol monostearate; Adsorptive carriers such as kaolin and bentonite; And lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols.

The compounds may also be formulated as elixirs or solutions for convenient oral administration or as solutions suitable for parenteral administration, for example by the intramuscular, subcutaneous or intravenous route. In addition, the compounds of the present invention are very suitable for formulating into sustained release dosage forms and the like. The formulations may be formulated to release only the active ingredient or, preferably, at a specific site of the intestine, possibly over a period of time. For example, coatings, envelopes and protective matrices can be made with polymeric materials or waxes.

The specific dosage of the compound of formula (I) necessary to increase sphincter responsiveness or to suppress urine or stool incontinence or gastroesophageal reflux disease in accordance with the present invention will depend on the severity and nature of the symptoms, the route of administration and related factors, It will be decided by your doctor. Generally, an acceptable and effective daily dose will be about 0.1 to about 1000 mg / day, and more typically about 50 to about 200 mg / day. These dosages will be administered to patients in need of such treatment once to about three times daily, or more frequently as needed, to effectively increase sphincter response or to suppress urine or fecal incontinence or gastroesophageal reflux disease. .

As is typical for the administration of a medicament comprising a basic group such as a piperidino ring, it is generally preferred to administer the compound of formula (I) in the form of an acid addition salt. It is also advantageous to administer such compounds by oral route. The following oral dosage forms are available for this purpose.

Formulation example

In the following formulations, "active ingredient" means a compound of formula (I).

Formulation Example 1: Gelatin Capsule

Hard gelatin capsules were prepared using the following ingredients:

ingredient Amount (mg / capsules) Active ingredient 0.1-1000 Starch, NF 0-650 Fluid starch powder 0-650 Silicone Latex (Viscosity 350 Centistokes) 0-15

The ingredients are combined and No. 45 mesh U.S. After passing through a sieve, the hard gelatin capsules were filled.

Specific examples of the capsule formulation of raloxyphene prepared include those shown below.

Formulation Example 2: Raloxyphene Capsule

ingredient Amount (mg / capsules) Raloxyfen One Starch, NF 112 Fluid starch powder 225.3 Silicone Latex (Viscosity 350 Centistokes) 1.7

Formulation Example 3: Raloxyphene Capsule

ingredient Amount (mg / capsules) Raloxyfen 5 Starch, NF 108 Fluid starch powder 225.3 Silicone Latex (Viscosity 350 Centistokes) 1.7

Formulation Example 4: Raloxyphene Capsule

ingredient Amount (mg / capsules) Raloxyfen 10 Starch, NF 103 Fluid starch powder 225.3 Silicone Latex (Viscosity 350 Centistokes) 1.7

Formulation Example 5: Raloxyphene Capsule

ingredient Amount (mg / capsules) Raloxyfen 50 Starch, NF 150 Fluid starch powder 397 Silicone Latex (Viscosity 350 Centistokes) 3.0

The specific formulations may vary depending upon the reasonable parameters provided.

Tablet formulations were prepared using the following ingredients:

Formulation Example 6: Tablet

ingredient Amount (mg / tablet) Active ingredient 0.1-1000 Cellulose (microcrystalline) 0-650 Silicon Dioxide (Smoke) 0-650 Stearic acid 0-15

The components were combined and compressed to form tablets.

Alternatively, tablets containing 0.1 to 1000 mg of active ingredient each were prepared as follows:

Formulation Example 7: Tablet

ingredient Amount (mg / tablet) Active ingredient 0.1-1000 Starch 45 Cellulose (microcrystalline) 35 Polyvinylpyrrolidone (10% solution in water) 4 Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc One

The active ingredient, starch and cellulose are no. 45 mesh U.S. Pass through the sieve and mix well. A solution of polyvinylpyrrolidone was mixed with the resulting powder and then No. 14 mesh U.S. Passed through a sieve. The granules thus produced are dried at 50 to 60 ° C. and No. 18 mesh U.S. Passed through a sieve. No. in advance 60 mesh U.S. Sodium carboxymethyl cellulose, magnesium stearate and talc passed through a sieve were added to the granules, mixed and compressed on a tableting machine to give tablets.

Suspensions containing 0.1 to 1000 mg of active ingredient per 5 ml dose each were prepared as follows.

Formulation Example 8: Suspension

ingredient Volume (mg / 5 ml) Active ingredient 0.1-1000 mg Sodium carboxymethyl cellulose 50 mg syrup 1.25 mg Benzoic acid solution 0.10 ml Spice Enough coloring agent Enough Purified water The total amount of 5 ml

Active ingredient No. 45 mesh U.S. Passed through a sieve and mixed with sodium carboxymethyl cellulose and syrup to form a soft paste. The benzoic acid solution, flavor and colorant were diluted with a portion of water and added with stirring. Subsequently, a sufficient amount of water was added to fill the required volume.

As mentioned above, the compounds of formula (I) may be used as single agents or in combination with other known effective agents. Combination therapy may be in a single or separate form as exemplified above, so that the attending physician may determine a wide range of protocols. If a single dose formulation is chosen it may include, but is not limited to, the following other beneficial compounds: clonidine 0.2 to 2 mg for urinary incontinence, antacids 10-50 milliliter equivalents for GERD (Goodman and Gilman, See "The Pharmacologic Basis of Therapeutics", 6th Ed., Macmillan Publishing Co., NYC, 1980, Chap. 42) or betaneol 25 mg for GERD. In addition, the combination (as a single dose or in separate form) may be administered at specific time intervals, for example after meals or before bedtime, as directed by the attending garment.

The following examples demonstrate the utility of the present invention. These examples are illustrative only and are not intended to limit the use of the invention in any way.

Running 1

50 women were selected to participate in the survey. The criteria for screening are women aged 50 to 70 years, menopause more than one year, good mental and physical health, and suffering from stress and / or stress incontinence for a period of time (at least once a week). . Each patient was randomly assigned to a patient receiving the compound of formula (I) (treatment) and to a placebo receiving (control). Prior to entering the investigation, each patient was asked for the incidence of urinary incontinence for a six week period. The parameters recorded are the number of occurrences, the time of occurrence, and the degree of incontinence, for example, whether only the underwear was soiled, how many times, whether the incontinence had to change clothes, the bedding was soiled, was it possible to stop urination, embarrassment or anxiety I felt like.

Twenty-five women received the corresponding placebo. The remaining 25 were given a dosage form, for example, once daily, containing a 60 mg raloxyphene compound. The investigation was conducted for three months. During the investigation, patients recorded the same data on the number and extent of urinary incontinence. After the investigation, the patients' records were analyzed. Because of the specific nature of the disease, data were analyzed using appropriate multivariate analysis.

Running 2

This example was identical to run 1 except that the control group received a compound containing formula I and an estrogen once daily.

Running 3

This investigation was identical to run 1 except that the treatment group received an additional 0.2 mg of clonidine orally before bedtime.

Running 4

This survey was identical to run 1 except that the treatment period was extended to one year.

Run 5

One hundred postmenopausal women (women who were menopause at least one year before the start of the study) were selected. The criteria for admission for these patients were as follows; GERD occurs more than once a week, or occurs more than four times a month and other general health conditions are good. The diagnosis that these women are suffering from GERD, not other diseases, must be determined by the attending physician. Such diagnosis can be made by methods known in the medical arts (see Harrison's Principles of Internal Medicine, ibid., Chap. 289, p. 1366-7). In each patient, the number of occurrences of GERD and its severity, for example, when GERD occurred, where was the pain (chest) area, what the patient was doing (bending, sitting, lying down) and inhaling the substance It was recorded whether or not it was done.

Fifty patients (control) received oral corresponding placebo once daily. The remaining 50 patients (treatment group) were given a formulation containing a compound of formula (I), for example a formulation tablet containing 60 mg of raloxyphene, to be taken once daily. During the investigation period, patients recorded the occurrence of GERD and the surrounding conditions in which this GERD occurred using the same parameters as used during the pre-investigation period. The investigation lasted six months. The records of each patient were analyzed and the appropriate statistical analysis was used to compare the frequency and extent of GERD incidence between preliminary and actual studies.

Running 6

This investigation was essentially the same as run 5 except that the control group received an additional 25 mg of betanechool orally at bedtime. The control group also received the corresponding placebo orally at bedtime.

Running 7

This investigation was essentially the same as run 5 except that the treatment group received an additional 20 ml of an antacid such as Maalox® after each meal and before bedtime.

The utility of the compounds of the invention is demonstrated to have a positive effect in any of the above assays.

Claims (7)

A method of increasing sphincter response, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof to a person in need thereof. <Formula I> Where R ¹ and R ³ are independently hydrogen, -CH ₃ , or Wherein Ar is optionally substituted phenyl; R ² is selected from the group consisting of pyrrolidino, hexamethyleneimino or piperidino. The method of claim 1 wherein the human is a female. The method of claim 1, wherein the compound is a compound of the formula: A method of inhibiting urine or bowel incontinence comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof to a person in need thereof. <Formula I> Where R ¹ and R ³ are independently hydrogen, -CH ₃ , or Wherein Ar is optionally substituted phenyl; R ² is selected from the group consisting of pyrrolidino, hexamethyleneimino or piperidino. The method of claim 4, wherein the compound is a compound of formula A method of inhibiting gastroesophageal disease, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to a person in need thereof. <Formula I> Where R ¹ and R ³ are independently hydrogen, -CH ₃ , or Wherein Ar is optionally substituted phenyl; R ² is selected from the group consisting of pyrrolidino, hexamethyleneimino or piperidino. 7. The method of claim 6, wherein said compound is a compound of formula: