CN1213303A - Method of increasing sphincter competence - Google Patents

Method of increasing sphincter competence Download PDF

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Publication number
CN1213303A
CN1213303A CN97191918A CN97191918A CN1213303A CN 1213303 A CN1213303 A CN 1213303A CN 97191918 A CN97191918 A CN 97191918A CN 97191918 A CN97191918 A CN 97191918A CN 1213303 A CN1213303 A CN 1213303A
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Prior art keywords
compound
chemical compound
sphincter
acid
following formula
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CN97191918A
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Chinese (zh)
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G·J·库利南
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Eli Lilly and Co
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Eli Lilly and Co
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Priority claimed from GBGB9603147.1A external-priority patent/GB9603147D0/en
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of CN1213303A publication Critical patent/CN1213303A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Abstract

A method of increasing sphincter competence comprising administering to a human in need of treatment an effective amount of a compound having formula (I), wherein R<1> and R<3> are independently hydrogen, -CH3, (a) or (b), wherein Ar is optionally substituted phenyl; R<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 (I).

Description

Strengthen the method for sphincter competence
Background of invention
The present invention relates to gastrointestinal tract and sphincter of urethra control forfeiture and be reduced to the medical treatment field of feature, especially common because the treatment of patient's sphincter (for example postmenopausal women) out of control due to hormonoprivia or the imbalance.
Sphincter be regulate in the health inside and outside between flow of matter, or the body inner structure of flow of matter between each structure in the health.Their function is very similar to the joint door or the valve of pipeline.Sphincter is made up of the ring or the lobe of stricture of vagina shape flesh between the different cavity body structure or smooth muscle cell; Inner for example descends between esophagus and the epigastric, or between bladder and the back urethra; Outside, for example colon bottom and appearance (anal sphincter).If sphincter is made up of stricture of vagina shape flesh, can under instructing, the consciousness behavior control to a certain degree for example urethra appearance sphincter or upward esophageal sphincter by sympathetic nervous system.And if sphincter is made up of smooth muscle cell,, be unconscious control then mainly by parasympathetic nervous system control.The smooth muscle sphincter is by the internal signal control relevant with the intracavity situation of a certain side of sphincter, for example be delivered into the food of esophagus downwards, can start lower esophageal sphincter and loosen, or stomach is opened wide, perhaps intravesical pressure sends signal makes sphincter open wide the back urethra.Sphincteral opening wide realized by the tonicity slacken of muscle.That is to say most of sphincter with respect to its continuous cavity body structure, keep closing or contraction state, therefore flowing material is closed.Sphincter can not may cause owing to a variety of causes by proper handling, passage obstacle for example, the passage mechanical disruption that causes by wound or operation, the unsuitable Signal Regulation of nervous system, or because the muscular tone disappearance that muscle deterioration causes, as the frequent visible situation of old people, perhaps because hormone in vivo imbalance causes etc. (sees for details: " the gloomy principle of Harry of innerlich anwenden thing " book, i.e. " 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.)
With theme of the present invention the properest be because the out of control and sequela of sphincter that hormonal imbalance causes.Specifically, the out of control and symptom that cause of the sphincter relevant with the present invention is; The back sphincter of urethra urinary incontinence that causes out of control, anal sphincter is out of control to cause the feces incontinence, and lower esophageal sphincter is out of control to be directed at gastroesophageal reflux disease.
Urinary incontinence is the very general problem of old group, and sickness rate at least 15% then accounts for 60% for the patient who lives in the public medical mechanism (nursing home).Though this disease is threat to life safety not, it is to make the embarrassment of patient's situation and make the root that keeps the suitable hygienic state of this colony to become problem.From economically, urinary incontinence is represented as the main cost that the old people provides the mechanism of treatment.For the old man, there is the urinary incontinence of two kinds of main types jointly.First type is the tonicity incontinence, when physics tension force places the abdomen inner region, for example laughs at, coughs or nervous physical exertion etc., can not stop and urinate.Second type is urge incontinence, too impatient to wait will the discharge when perceiveing bladder and be full of.This two type all is common in the postmenopausal women, especially owing to bearing child pelvic muscles is died down or impaired and multiparity women ligation.Use process such as absorbing material underwear that this disease is covered up, severe cases can be scolded agent with the alpha-1 adrenergic resistance, for example treatment such as Minoxidil.But these medicaments mainly can cause cardiovascular side effects, can not be the patient of unique indication in urinary incontinence with its chronic administration therefore.More successfully the method for the treatment of urinary incontinence for the postmenopausal women is to use controversies in hormone replacement in the elderly (HRT).
HRT does not think to treat the specially good effect method of urinary incontinence usually, but it is very effective really.But because the side effect followed, HRT also makes the patient perplex, and for example because the estrogen that does not offset has increased the danger of suffering from uterus carcinoma, produces the CNS effect of bearing, edema, psychosis and recur, increase breast carcinoma danger etc. again when estrogen and progestogen share.And estrogen can not be used for the male certainly.Therefore need the therapy of better healing urinary incontinence.Especially to the old people.
Fecal incontinence situation for old group is similar to the finding urinary incontinence.But this example is much lower.But, suffer from the problem that this sick patient brings compared with urine incontinence and want much serious from sanitary condition.Be the problem that this colony is avoided infection and so on, need pay more treatment and economic spending.The cause of disease of fecal incontinence be it seems similar to urinary incontinence, patient colony that therefore should disease also similarly, promptly the multiparity postmenopausal women is modal victim.The processing of this disease is only limited to the method for appeasing, and for example absorbing material underwear, duty are changed one's clothes and had a bath etc. by, duty.HRT is used for the postmenopausal women as effectively treatment and unclear, although curative effect that various reasons believe that its tool is possible and useful effect are arranged.Perhaps, unclear is because the idiosyncrasy of this disease is perhaps quite few because of the women that can stand the HRT side reaction, and does not have enough data to prove, especially advanced age, (more than 70 years old) postmenopausal women least may stand.Clearly, this field preferably therapy will be people look forward to (see for details: " hormone and aging " Ed.Timiras et al., CRCPress, Boca Raton FL, Chap.8, p.141-142, herein as a reference.)。
GERD is that gastric content overflows the disease that (anti-stream) enters esophagus.This disease is usually because due to lower esophageal sphincter can not suitably close.The consequence of anti-stream makes the patient be difficult to be subjected to, and may be in state of necessity.Under the slight situation, patient main suit's esophagus has burning sensation, or heartburn, and causes pain usually, has a sleepless night, loses the labour force.Can cause esophageal ulcer than the long-term anti-stream of severe disease example, need make surgical operation, perhaps think to bring out the inducement of esophageal carcinoma.
Any age and sex can suffer from this disease per capita, but then more general to aging population.What is interesting is, menstrual phase, the variation that period of pregnancy and menopause, the women was showed (sx or alleviate) makes this evidence of being related between hormonal readiness and the GERD keep some illusions.Other has the sphincter of similar physiologic function the hormonal effects of known estrogen and so on, and known estrogen influences GI function on gastric motility and other, for example gastric emptying etc.But cause the other factors that esophageal sphincter is out of control, for example stomach hernia, esophagus hypersensitivity stomach function regulating peracidity etc. also make people to know and understand hormone role in this disease.
The treatment of GERD is got involved by machinery and pharmacology to be formed.The machinery intervention can be raised health, be utilized gravity to avoid gastric content to enter esophagus like this by the patient that several modes realized, suffered from GERD evening in bed, the adiposis patient fat-reducing, exercise can improve the tension force of supporting muscle, or with the surgical repair affected tissue.The pharmacology gets involved and to comprise with antacid or anticholinergic, and for example bethanechol reduces gastric acid, these medicines use separately or two kind one reinstate and have effect, but because the adverse side effect life-time service has problem.New medicament own, or add in the known drug, the curative effect of present GERD should be able to be improved as effective agent.
The present invention is directed to the discovery of The compounds of this invention, this chemical compound such as following defined, it can strengthen sphincteral function.
The invention outline
The invention provides the method that strengthens sphincter competence, this method comprises that the people to the disposal of this kind of needs uses the formula I chemical compound of effective dose, and officinal salt and solvate,
Figure A9719191800071
R wherein 1And R 3Each naturally hydrogen,
Figure A9719191800081
Or
Figure A9719191800082
Wherein Ar is the phenyl that replaces arbitrarily;
R 2Be selected from pyrrolidino, hexamethylene imine and piperidino.
The present invention also comprises inhibition urinary incontinence and fecal incontinence, and the method for gastroesophageal reflux disease.Invention is introduced in detail
The discovery of a class 2-phenyl that the present invention relates to select-3-aroyl benzothiophene (benzothiophene kind) chemical compound, promptly the formula I chemical compound is used it for the enhancing sphincter competence.By using method provided by the invention, by giving people or the mammal need this kind treatment, use the formula I chemical compound that can effectively strengthen sphincter competence dosage, or its pharmaceutically useful salt and being achieved.The present invention includes medical treatment and/or prevention disposal.
So-called " inhibition " comprises the notion of generally being accepted, and comprises prevention, avoids, retrains and slow down, and stops, or reverses its development, reverses its seriousness or reverse symptom or the influence that occurs.
So-called " effective dose " refers to suppress the amount of the required chemical compound of stool or urinary incontinence or gastroesophageal reflux disease, maybe can strengthen the compound amount of sphincter competence when the patient's condition occurring.
Raloxifene is a The compounds of this invention, is the hydrochlorate of formula I chemical compound, wherein R 1And R 3Be hydrogen, and R 2It is piperidino.
In general, this chemical compound is prepared with ordinary excipients, diluent or carrier, and compacting in flakes, or is made into the elixir or the solution of suitable for oral administration, or is made into the preparation of using through intramuscular or intravenous.But this chemical compound is transdermal administration also, and is made into slow releasing preparation form etc.
The chemical compound that is used for the inventive method can make according to fixed method, for example sees USP4 for details, and 133,814,4,418,068 and 4,380,635, these patents are listed this paper in as a reference.Generally speaking, this method is protected precursor compound from benzo (b) thiophene of 6-hydroxyl and 2-(4-hydroxyphenyl) is arranged, and carries out alkylation, or acyl groupization, sloughs protecting group then and forms the formula I chemical compound.The preparation example of this compounds is provided by above-mentioned United States Patent (USP).The phenyl of described any replacement comprises phenyl and with C 1-C 6Alkyl, C 1-C 4Alkoxyl, hydroxyl, nitro, chlorine, fluorine or three (chlorine or fluorine) methyl substituted once, or the phenyl of secondary.
Used this chemical compound of the inventive method can form pharmaceutically acceptable acid addition salts and base addition salts with various organic and inorganic bronsted lowry acids and bases bronsted lowries very widely, and comprise that being generally used for pharmaceutical chemical physiology goes up acceptable salt, and these salt also are the present invention's parts.The mineral acid that is used to form this kind salt comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid, hypophosphoric acid etc.From the organic acid salt derivative, alkanoic acid, hydroxyl alkane acid and hydroxyl chain docosandioic acid, aromatic acid, aliphatic series and aromatic sulfonic acid that for example available aliphatic list or dicarboxylic acids, phenyl replace.Therefore, such officinal salt comprises acetate, phenylacetic acid salt, trifluoroacetate, acrylates, Ascorbate, benzoate, chloro-benzoate, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt ar-Toluic acid salt, acetoxybenzoic acid salt, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyric acid salt, beta-hydroxy-butanoic acid salt, butine-1, the 4-diacid salt, hexin-1, the 4-diacid salt, caprate, caprylate, chloride, cinnamate, citrate, formates, fumarate, glycollate, enanthate, hippurate, lactate, malate, maleate, hydroxymaleic acid salt, malonate, mandelate, mesylate, nicotinate, .gamma.-pyridinecarboxylic acid salt, nitrate, oxalates, phthalate, terephthalate, phosphate, one hydrogen orthophosphate, dihydrogen orthophosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionic acid salt, Salicylate, the certain herbaceous plants with big flowers diacid salt, succinate, suberate, sulfate, disulfate, pyrosulfate, sulphite, bisulfites, sulfonate, benzene sulfonate, to bromophenyl sulfonate, closilate, esilate, the 2-isethionate, mesylate, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, tosilate, xylenesulfonate, Tartaric acid salt etc.Preferred salt is hydrochlorate.
Generally be with formula I chemical compound and equimolar amounts, or the acid reaction of excess quantity, make described pharmaceutically acceptable acid addition salts.Described reactant for example combines in ether or the benzene generally at its cosolvent.Usually within 1 hour to 10 days, described salt is precipitated out from solution.By filtration it is isolated, or available conventional process go out the solvent stripping.
Be generally used for the salifiable alkali of shape and comprise ammonium hydroxide and alkalies and alkaline earth hydroxide (or its carbonate), and aliphatic series primary, secondary, tertiary amine, aliphatic diamine.The alkali that is used in particular for preparing addition salts comprises ammonium hydroxide, potassium carbonate, methylamine, diethylamine, ethylenediamine and cyclohexylamine.
Compare with their parent compound, the general dissolubility of officinal salt has improved, and therefore is more suitable for usually with its obtaining liq or emulsion.
Tablet, capsule, suspending agent, powder etc. are prepared and be shaped to available means known in the art compounding pharmaceutical for example with chemical compound with usual excipients, diluent or carrier.The excipient, diluent and the carrier that are suitable for these preparations for example comprise filler and extenders such as starch, sugar, mannitol and silica derivative, carboxymethyl cellulose and other cellulose derivative, binding agents such as alginate, gelatin and polyvinylpyrrolidone; Wetting agent such as glycerol; Disintegrating agent such as calcium carbonate and sodium bicarbonate; Alkanes etc. postpone lytic agent; Surfactants such as absorption enhancers such as quaternary ammonium compound, Cetyl Alcohol, glyceryl monostearate; Absorption carrier such as Kaolin and bentonite; And Pulvis Talci, calcium stearate and lubricants such as magnesium stearate, solid polyethylene glycol.
This chemical compound also can be made into to be convenient to oral elixir or solvent or to be suitable for parenteral use, for example the solution of intramuscular, subcutaneous or intravenously administrable.In addition, this chemical compound also is well suited for being mixed with slow release formulation or the like.
Also can make whole during only at the preparation of the specific part release of active agent of (or preferably existing) intestinal.Can make coating, strip of paper used for sealing and protection matrix form are for example made by high polymer or paraffin wax.
For strengthening sphincter competence.Suppress gatism, or suppress the required concrete dosage of formula I chemical compound of the present invention of gastroesophageal reflux disease, depend on the order of severity and the character of disease, the correlative factor of route of administration and doctor in charge's decision.In general.Receptible effective daily dose is about 0.1 to 1000mg/ day.More commonly used is 50 to 200mg/ days.When needs effectively strengthen sphincter competence, or when suppressing gatism or suppressing gastroesophageal reflux disease, this dosage divides about 1-3 time or more times number to use to the patient that need treat every day.
Usually when using the medicine that has basic group, for example piperidino ring, preferably this formula I chemical compound is used with the form of acid-addition salts.Such chemical compound for this reason, can utilize following peroral dosage form by Orally administered favourable.
Preparation
" active component " refers to the formula I chemical compound in the following preparation.Preparation 1: gelatine capsule
By this hard gelatin capsule of preparation shown in following:
Composition Content (mg/ capsule)
Active component starch, NF starch flowable powder silicone fluid 350 centistokes ????0.1-1000 ????0-650 ????0-650 ????0-15
Mentioned component is mixed, cross 45 mesh sieves (U.S. sieve), and insert in the gelatine capsule.
The example of the concrete capsule preparations of Raloxifene is made by following compositions: preparation 2:Raloxifene capsule
Composition Content (mg/ capsule)
Raloxifene starch, NF starch flowable powder silicone fluid 350 centistokes ????1 ????112 ????225.3 ????1.7
Preparation 3:Raloxifene capsule
Composition Content (mg/ capsule)
Raloxifene starch, NF starch flowable powder silicone fluid 350 centistokes ????5 ????108 ????225.3 ????1.7
Preparation 4:Raloxifene capsule
Composition Content (mg/ capsule)
Raloxifene starch, NF starch flowable powder silicone fluid 350 centistokes ????10 ????103 ????225.3 ????1.7
Preparation 5:Raloxifene capsule
Composition Content (mg/ capsule)
Raloxifene starch, NF starch flowable powder silicone fluid 350 centistokes ????50 ????150 ????397 ????3.0
Top preparation can change the needs that provide various rational different preparations to satisfy.
Tablet uses following compositions to make: preparation 6: tablet
Composition Content (mg/ sheet)
Active component cellulose crystallite fumed silica stearic acid ????0.1-1000 ????0-650 ????0-650 ????0-15
Mentioned component is mixed, also suppresses in flakes.
In addition, every preparation tablets that contains the 0.1-1000mg active component is as follows: preparation 7: tablet
Composition Content (mg/ sheet)
Active component farinose crystallite polyvinylpyrrolidone (10% aqueous solution) sodium carboxymethylcellulose magnesium stearate talc ????0.1-1000 ????45 ????35 ????4 ????4.5 ????0.5 ????1
Active component, starch and cellulose are all crossed 45 order U.S. sieve, are also fully mixed.The gained powder is mixed with polyvinylpyrrolidonesolution solution, cross 14 order U.S. sieve then.Made particulate matter in 50 ° of-60 ° of dryings, and is crossed 18 order U.S. sieve.After carboxymethyl starch sodium, magnesium stearate and the Talcum of crossing 60 order U.S. sieve in advance added in the particulate matter, mix, compacting in flakes on tablet machine.
The suspension preparation that every 5ml preparation contains the 0.1-1000mg medicine is as follows: preparation 8: suspension
Composition Content (mg/5ml)
Active component sodium carboxymethyl cellulose syrup benzoic acid solution spice pigment pure water adds to ????0.1-1000mg ????50mg ????1.25mg ????0.10ml ????q.v. ????q.v. ????5ml
This active matter is crossed 45 order U.S. sieve, mix, form homogenate with sodium carboxymethyl cellulose and syrup.Benzoic acid solution, spice and pigment with some water dilutions, are stirred adding down wherein then.Supply water at last again to reach volume required.
As mentioned above, the formula I chemical compound can use separately, and can be used in combination with known effective agent.Combined therapy can be made into the entity of single dosage form as mentioned above, or separate formulation separately, therefore gives the very big leeway of selecting of the doctor in charge.If select single coalition for use, then also can comprise following beneficial compound (but being not limited to these): 0.2-2mg Minoxidil (controlling urinary incontinence), 10-50 milliequivalent antacid (controlling GERD) (is seen: " Drug therapy basis " book, promptly " Goodman and Gilman ' s, The Pharmacologic Basis of Therapeutics, 6th Ed.; Macmillan Publishing Co.; NYC, 1980, Chap.42) or 25mg bethanechol (controlling GERD).These conjugates (single entity, or separate formulation) separately are in the certain time interval administration, for example after meal or before sleeping, accuse it by the doctor in charge.
The following examples illustrate application of the present invention, and these embodiment are the purpose for illustrating only, and do not mean that by any way application of the present invention is limited.Urinary incontinence test 1
Select 50 women to enter this research.Criteria for selection: 50-70 year, at least one year of menopause has good psychology and physical condition, but suffers from periodically (weekly at least once) catatonic type and/or urgent type urinary incontinence.Each patient specifies at random and accepts formula I chemical compound (treatment group), or placebo (matched group), before the test, inquires about each patient and notes interior urinary incontinence situation of 6 week.Are the data that write down the time of incontinence number of times, appearance, certain appraisal of its order of severity, for example only are that underwear is made dirty? how many times? need change one's clothes after your incontinence? make dirty the bed? can you control and urinate? do you feel embarrassed or uneasy? or the like.
25 women give and corresponding placebo, give and the formula I chemical compound for other 25, for example obey the capsule preparations that contains 60mg Raloxifene once a day.This test was carried out three months.Duration of test, the same data of relevant urinary incontinence occurrence number of record patient and degree.Off-test, analysis patient's record.Because this sick idiosyncrasy character, it is more suitable to use the multivariate analysis method to analyze these data.Test 2
1 identical with test, have only matched group to give and contain formula I chemical compound and estrogenic preparation, once a day.Test 3
This test is identical with test 1 substantially, also oral 0.2mg dosage Minoxidil before just the treatment group is gone to bed.Fecal incontinence test 4
This test has only the treatment phase to extend to 1 year as same design as described in testing 1.GERD test 5
Select 100 postmenopausal women (before the test menopause 1 year) at least.These patients select by following standard and enter research: GERD falls ill once or every month four times or more at least weekly, and other general health in order.Diagnose these women to suffer from GERD and do not have other disease and want doctor in charge decision.The available medical field known technology of this kind diagnosis is made, and sees: Harrison ' s Principles of Internal Medicine ", ibid.Chap.289 is p.1366-7.Inquire about each patient and note its GERD morbidity number of times, and degree, for example when fall ill? do you where ache (heartburn)? during morbidity what if? (stoop body, sit down, lie down)? what is sucking-off? Deng.
50 patients (matched group) every day oral once corresponding placebo.All the other 50 (treatment group) gives and the preparation that contains the formula I chemical compound, for example contains the tablet of 60mg Raloxifene.Oral 1 time of every day.Duration of test is used and is tested preceding identical reference record GERD morbidity number of times, follows situation during morbidity.Test was carried out 6 months.Analyze each patient's record, adopt suitable statistical analysis method, GERD morbidity number of times and degree before testing and in the test are compared.Test 6
This test is identical with test 5 basically, and just h.d. is returned the oral 25mg bethanechol of matched group.The also oral corresponding placebo of this matched group h.d..Test 7
This test is identical with test 5 basically, and just the treatment group is also taken Maatox at every meal in addition after meal He before going to bed And so on antacid 20ml.
Find out by above-mentioned arbitrary test, use The compounds of this invention to show the positivity effect.

Claims (7)

1. strengthen the method for sphincter competence, this method comprises that the people to this disposal of needs uses the effective dose following formula: compound, and officinal salt or solvate.
Figure A9719191800021
R wherein 1And R 5Each naturally hydrogen ,-CH 3,
Figure A9719191800022
Or
Figure A9719191800023
Wherein Ar is the phenyl that replaces arbitrarily;
R 2Be selected from pyrrolidino, hexamethylene imine and piperidino.
2. the process of claim 1 wherein that described people is the women.
3. the process of claim 1 wherein that described chemical compound is following formula: compound or its hydrochlorate.
Figure A9719191800024
4. suppress the method for urinary incontinence or fecal incontinence, this method comprises that the people to this treatment of needs uses effective dose following formula: compound or its officinal salt or its solvate,
Figure A9719191800031
R wherein 1And R 3Each naturally hydrogen,
Figure A9719191800032
Or Wherein Ar is the phenyl that replaces arbitrarily;
R 2Be selected from pyrrolidino, hexamethylene imine and piperidino.
5. the method for claim 4, wherein said chemical compound is following formula: compound or its hydrochlorate.
Figure A9719191800034
6. suppress the method for stomach esophageal disease, comprise that the people to the treatment of this kind of need uses the following formula: compound of effective dose, or its officinal salt, or its solvate, R wherein 1And R 3Each naturally hydrogen,
Figure A9719191800042
Or
Figure A9719191800043
Wherein Ar is the phenyl that replaces arbitrarily;
R 2Be selected from pyrrolidino, hexamethylene imine and piperidino.
7. the method for claim 6, wherein said chemical compound is a following formula: compound, or its hydrochlorate.
Figure A9719191800044
CN97191918A 1996-01-29 1997-01-27 Method of increasing sphincter competence Pending CN1213303A (en)

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US1077196P 1996-01-29 1996-01-29
US60/010,771 1996-01-29
GB9603147.1 1996-02-15
GBGB9603147.1A GB9603147D0 (en) 1996-02-15 1996-02-15 Methods of increasing sphincter competence

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