HK1069530A - Aryl (or heteroaryl) azolylcarbynol derivatives for the treatment of urinary incontinence - Google Patents

Description

Aryl (or heteroaryl) azolemethanol derivatives for the treatment of urinary incontinence

Technical Field

The invention relates to the use of aryl (or heteroaryl) azolylcarbinol derivatives of general formula (I) and their physiologically acceptable salts as human and/or animal therapeutic agents for the treatment of urinary incontinence.

Background

Urination is the function of the lower urinary tract, which is defined as the discharge of urine through the urinary tract. It is considered normal for adult urination that it is random, continuous, complete, satisfactory, interruptible, spaced apart in time (at socially acceptable intervals), does not cause abdominal stress, is not urgent, and is only occasional during the night.

Urinary incontinence is a urinary disorder, defined as the involuntary discharge of urine, which can be objectively proven. This dysfunction of the bladder is a health problem of increasing social and hygienic importance for the population suffering from it. According to our data, the incidence of urinary incontinence in populations between 15 and 64 years of age is approximately 1.5 to 5% for men and 10 to 30% for women. However, if we select the portion of the non-hospitalized population above 60 years of age, the incidence of this portion is 15% to 35%. On the other hand, the incidence was higher when studying hospitalized patients over 60 years of age. Urinary incontinence affects approximately two million spain.

Urinary incontinence can be considered a symptom, sign or pathological condition. One of the possible classifications for such dysfunction is as follows.

Forced urination or acute incontinence. In this case, involuntary discharge of urine is accompanied by a strong desire to urinate (urgency). This can be classified as either motor urge incontinence or sensitive urge incontinence. Exercise-induced urgency incontinence is associated with detrusor hyperactivity and/or decreased detrusor distension. Hyperactivity is characterized by involuntary contractions of the detrusor muscle during filling, which are spontaneous or stimulated and cannot be completely inhibited by the patient. Overactivity of the detrusor muscle can occur in situations where there is obstruction of voiding urine flow, inflammation and stimulation of the bladder, or its etiology may be unknown (idiopathic).

Too strong reflectionDescribed as a condition which presents uncontrolled detrusor contraction, associated with neurological disorders such as multiple sclerosis or plaque sclerosis, remains after bone marrow traumaSymptoms or Parkinson's disease.

Urinary stress incontinenceAs a result of the urethral insufficiency mechanism, there is involuntary expulsion of urine when the pressure within the bladder exceeds the pressure in the urethra even if the detrusor muscle is not contracted. Involuntary expulsion occurs when certain physical activities are performed, such as jumping, coughing, going downstairs, etc. Another factor may be the structural changes in the urethra caused by postmenopausal hypoestrogenism.

Mixed incontinenceThe term denotes the co-existence of urge incontinence and stress incontinence.

The choice of treatment for urinary incontinence depends on the type of incontinence. In urge incontinence, the first and most effective treatment regimen is drug treatment with a range of hygiene adjustments and patient education, and the second regimen includes other therapies, such as maximal electrical stimulation or surgical treatment. Conservative measures such as pelvic floor exercise and surgical treatment are reserved for stress incontinence as a first option.

Drug treatment of urge incontinence and hyperreflexia is aimed at reducing detrusor activity and increasing bladder capacity. In the case of stress incontinence, treatment is aimed at increasing resistance to urine discharge.

Drugs used to treat urinary incontinence include a variety of therapeutic drugs from different pharmacological groups with different mechanisms of action (Hattori T., Drug treatment of urinary incontinence. drugs of Today 1998, 34 (2): 125-138), although there is a great deal of confusion and their clinical efficacy has not been fully demonstrated.

The first group of drugs has an anticholinergic effect, where propantheline can be considered as a pure anticholinergic. There is also a new drug tolterodine, which has a selective anticholinergic effect but is not selective with respect to the different subtypes of muscarinic receptors, although it appears to be selective in acting around the bladder (detrusor), salivary glands and human gut. An anticholinergic drug, oxybutin, is a drug with a mixed action that is a moderate anticholinergic agent and a potent direct muscle relaxant. Oxybutin is now the drug of choice for this disorder, and although its tolerability is not severe, side effects such as dry mouth, constipation and somnolence are significant, and in some cases may cause patients to abandon treatment.

Several tricyclic antidepressants have beneficial effects in patients with detrusor hyperactivity. The drug micapamine which has been used clinically has been shown to be an effective therapeutic agent for nocturnal enuresis in children and-for example-bladder hyperactivity in the elderly. Since different side effects of this group of drugs have been reported and sometimes strong (e.g. cardiovascular effects), the risk-benefit of this treatment for dysuria has to be studied in certain populations, especially in the elderly.

Some α β -adrenergic antagonists, such as prazosin, terazosin or doxazosin, are able to ameliorate symptoms associated with detrusor dysfunction in patients with detrusor hyperactivity and benign prostatic hyperplasia, although evidence for this effect in hyperactive bladder is currently under discussion and no evidence supports its use in urinary incontinence.

Another group of therapeutic agents corresponds to alpha adrenergic agents, although little information remains available regarding their efficacy. Alpha-adrenergic stimulation is known to relax human bladder in normal conditions. The detrusor muscle, whether under normal conditions or in the case of an unstable bladder, exhibits a similar degree of response to the alpha-agonist, i.e., relaxation. Alpha is alpha₂Adrenergic receptor agonists, such as terbutaline or salbutamol, have been shown to increase bladder capacity. In contrast, this drug has shown efficacy in the treatment of detrusor hypermotility in only a very limited clinical study and a small number of patients.

In our patents EP 289380 and WO99/52525, we have described methanol derivatives of general formula (I) having analgesic activity.

In these compounds of the general formula (I), Ar represents a benzene ring or a thiophene ring with or without a substituent, and R₁Represents a hydrogen atom or C₁To C₄Lower alkyl, R₂Represents dialkylaminoalkyl or azaheterocyclylalkyl, Het represents an azole with or without substituents, and their physiologically acceptable salts.

In our patents WO97/20817, WO 99/02500, WO 99/07684 and WO99/52525, we also describe several methods for preparing enantiomerically pure compounds of the general formula (I).

We have now found that the compounds of formula (I) and their physiologically acceptable salts are particularly useful in the manufacture of medicaments for use in human or veterinary therapeutics to treat or alleviate urinary incontinence.

Detailed description of the invention

The invention relates to the use of aryl (or heteroaryl) azolemethanol derivatives of general formula (I) or one of its physiologically acceptable salts for producing medicaments,

wherein

Ar represents a phenyl group or a thienyl group, unsubstituted or optionally bearing 1, 2 or 3 identical or different substituents, selected from the group consisting of fluorine, chlorine, bromine, methyl, trifluoromethyl and methoxy;

R₁represents a hydrogen atom or C₁To C₄A lower alkyl group;

R₂represents a dialkyl radical (C)₁-C₄) Aminoalkyl radical (C)₂-C₃) Radical or azaheterocyclylalkyl (C)₂-C₃) (ii) a And

het represents an azole, i.e. a five-membered nitrogen-containing aromatic heterocycle which contains one to three nitrogen atoms and is unsubstituted or optionally substituted by 1 or 2 identical or different substituents selected from the group consisting of fluorine, chlorine, bromine and methyl;

the medicament is useful for treating urinary incontinence in mammals, including humans, especially patients presenting with urinary acute or hyperreflexive incontinence.

The term "C₁To C₄Lower alkyl "represents a straight or branched chain group derived from a saturated hydrocarbon of 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

The term "dialkyl (C)₁-C₄) Aminoalkyl radical (C)₂-C₃) Or azaheterocyclylalkyl (C)₂-C₃) "represents an alkyl group and a dialkyl group (C) having two or three carbon atoms therein₁-C₄) Amine or cyclic amine linking groups such as dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, piperidinylethyl, morpholinylpropyl, pyrrolidinylalkyl and the like.

Examples of the compounds included in the present invention include:

(±) -5- { α - [2- (dimethylamine) ethoxy ] benzyl } -1-methyl-1H-pyrazole,

(±) -5- { α - [2- (dimethylamine) ethoxy ] benzyl } -1-methyl-1H-pyrazole citrate,

(+) -5- { alpha- [2- (dimethylamine) ethoxy ] benzyl } -1-methyl-1H-pyrazole,

(-) -5- { alpha- [2- (dimethylamine) ethoxy ] benzyl } -1-methyl-1H-pyrazole,

(+) -5- { alpha- [2- (dimethylamine) ethoxy ] benzyl } -1-methyl-1H-pyrazole citrate,

(-) -5- { alpha- [2- (dimethylamine) ethoxy ] benzyl } -1-methyl-1H-pyrazole citrate,

(±) -5- { α - [2- (dimethylamine) ethoxy ] -2-thienylmethyl } -1-methyl-1H-pyrazole,

(±) -5- { α - [2- (dimethylamine) ethoxy ] -2-thienylmethyl } -1-methyl-1H-pyrazole citrate,

(+) -5- { alpha- [2- (dimethylamine) ethoxy ] -2-thienylmethyl } -1-methyl-1H-pyrazole,

(-) -5- { alpha- [2- (dimethylamine) ethoxy ] -2-thienylmethyl } -1-methyl-1H-pyrazole,

(+) -5- { alpha- [2- (dimethylamine) ethoxy ] -2-thienylmethyl } -1-methyl-1H-pyrazole citrate,

(-) -5- { alpha- [2- (dimethylamine) ethoxy ] -2-thienylmethyl } -1-methyl-1H-pyrazole citrate.

The compounds of formula (I) can be synthesized according to the methods described in patent EP 289380 or WO 99/52525. The invention relates to the use of both pure enantiomers and mixtures of enantiomers. The enantiomers may be prepared by any of the methods described in our patents WO97/20817, WO 99/02500, WO 99/07684 or WO 99/52525.

In the present invention, the activity of the compounds of formula (I) has been demonstrated during overactive bladder and they are therefore useful in the treatment of urinary incontinence caused by hyperreflexia detrusor activity and urgency incontinence.

Some of the properties of (. + -.) -5- { alpha- [2- (dimethylamine) ethoxy ] benzyl } -1-methyl-1H-pyrazole citrate (example 1) of the following formula, which constitute the object of the present invention, are illustrated below:

the following examples of pharmacological tests are provided for illustration only and the present invention is in no way to be construed as being limited to these applications.

The activity of example 1 against cyclophosphamide-induced bladder inflammation in rats has been studied. Cyclophosphamide is an effective treatment for several diseases, including cancer. One possible side effect of this product is acute inflammation of the bladder. Its activity is based on the conversion of active metabolites in the liver.

Treatment with cyclophosphamide can cause several side-effect complications, including cystitis, which is mainly caused by another cyclophosphamide metabolite, namely acrolein.

Cyclophosphamide-induced cystitis is known to be caused by direct contact of acrolein with the epithelium of the urinary tract, although the exact mechanism of this inflammatory response is mostly unknown. One of the manifestations of the inflammatory response is plasma extravasation within the bladder. For this reason, example 1 has been studied for its activity against rat cystitis induced by cyclophosphamide and its effect on the extravasation of plasma proteins in the bladder was determined.

Extravasation of plasma proteins was measured by means of the permeability technique using evans blue (Evan's blue) stain as described by a.saria and j.m.lundberg (j.neurosci. methods 8: 41-49, 1983). First, rats were administered example 1(80mg/kg, ip) or vector. After five minutes, they were given cyclophosphamide (150mg/kg ip). Three and a half hours later, the rats were anesthetized with urethane (1.2gr/kg, ip), cannulated with the jugular vein, and given H with Evans blue dye₂O solution (50mg/2.5ml) at a dose of 50mg/kg, iv. Fifteen minutes after injection of the dye, the rats were bled by cardiac puncture by infusion of 50ml saline solution (0.9%) at 37 ℃. The bladder was then removed, weighed, and the content of evans blue dye was determined spectrophotometrically (620mm) after 24 hours of extraction with a known volume of formamide at 60 ℃. Plasma protein extravasation is expressed as the content of evans blue dye in micrograms per gram of tissue.

The results obtained show that example 1 significantly inhibited the extravasation of plasma proteins by more than 75%. Thus, the protective effect of example 1 in bladder inflammatory conditions was evident, the overall process being similar to cyclophosphamide induced cystitis.

Extravasation of group rat quantitative plasma proteins

μ g Evans blue/g tissue

Control 1025

Cyclophosphamide (150mg/kg, ip) 10437

Cyclophosphamide + example 110125

(150mg/kg +80mg/kg, ip) (inhibition 75.7%)

In view of the good pharmacokinetic properties, the aryl (or heteroaryl) azolylcarbinol derivatives according to the present invention can be satisfactorily used in human and animal therapeutics for the treatment and alleviation of urinary incontinence.

In human therapeutics, the dose of the compounds of the invention administered depends on the severity of the infection being treated. The dosage is usually between 50 and 400 mg/day. The compounds of the invention are administered, for example, in the form of capsules or tablets.

By way of example, specific pharmaceutical dosage forms of the compounds of the invention are illustrated below.

Examples of formulations for injections (im/iv)

(±) -5- { α - [2- (dimethylamine) ethoxy ] benzyl } -1-methyl-1H-50 mg

Pyrazole citrate

0.1N sodium hydroxide c.s.pH 6

C.s.p.1 ml of water for injection

Examples of tablet formulations

(±) -5- { α - [2- (dimethylamine) ethoxy ] benzyl } -1-methyl-400 mg

1H-pyrazole citrate

Croscarmellose sodium (Ac-Di-Sol) 32mg

Colloidal silica (Aerosyl 200) 8mg

Magnesium stearate NF 16mg

Povidone K-3040 mg

Microcrystalline cellulose (Avicel PH-102) 146mg

Lactose monohydrate (Farmatose 200M) 158mg

A total of 800mg

Examples of Per Capsule formulations

(±) -5- { α - [2- (dimethylamine) ethoxy ] benzyl } -1-methyl-200.0 mg

1H-pyrazole citrate

Colloidal silica 0.8mg

Magnesium stearate 2.4mg

Lactose 276.8mg

A total of 480mg

Claims (5)

1. Examples of aryl (or heteroaryl) azolemethanol derivatives of the general formula (I) or one of its physiologically acceptable salts in the preparation of medicaments,

wherein

Ar represents a phenyl group or a thienyl group, unsubstituted or optionally bearing 1, 2 or 3 identical or different substituents, selected from the group consisting of fluorine, chlorine, bromine, methyl, trifluoromethyl and methoxy;

R₁represents a hydrogen atom or C₁To C₄A lower alkyl group;

R₂represents a dialkyl radical (C)₁-C₄) Aminoalkyl radical (C)₂-C₃) Radical or azaheterocyclylalkyl (C)₂-C₃) (ii) a And

het represents a five-membered nitrogen-containing aromatic heterocycle which contains one to three nitrogen atoms and is unsubstituted or optionally substituted by 1 or 2 identical or different substituents selected from the group consisting of fluorine, chlorine, bromine and methyl;

the medicament is useful for treating urinary incontinence in mammals, including humans.

2. Examples of compounds of general formula (I) according to claim 1 in the preparation of medicaments, wherein R₁Selected from the group consisting of a hydrogen atom or methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, for use in the treatment of urinary incontinence in mammals, including humans.

3. Examples of compounds of general formula (I) according to claim 1 in the preparation of medicaments, wherein R₂Selected from the group consisting of dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, piperidinylethyl, morpholinylpropyl and pyrrolidinylethyl, for use in the treatment of urinary incontinence in mammals, including humans.

4. Use of a compound of general formula (I) according to claim 1, selected from:

(±) -5- { α - [2- (dimethylamine) ethoxy ] benzyl } -1-methyl-1H-pyrazole,

(±) -5- { α - [2- (dimethylamine) ethoxy ] benzyl } -1-methyl-1H-pyrazole citrate,

(+) -5- { alpha- [2- (dimethylamine) ethoxy ] benzyl } -1-methyl-1H-pyrazole,

(-) -5- { alpha- [2- (dimethylamine) ethoxy ] benzyl } -1-methyl-1H-pyrazole,

(+) -5- { alpha- [2- (dimethylamine) ethoxy ] benzyl } -1-methyl-1H-pyrazole citrate,

(-) -5- { alpha- [2- (dimethylamine) ethoxy ] benzyl } -1-methyl-1H-pyrazole citrate,

(±) -5- { α - [2- (dimethylamine) ethoxy ] -2-thienylmethyl } -1-methyl-1H-pyrazole,

(±) -5- { α - [2- (dimethylamine) ethoxy ] -2-thienylmethyl } -1-methyl-1H-pyrazole citrate,

(+) -5- { alpha- [2- (dimethylamine) ethoxy ] -2-thienylmethyl } -1-methyl-1H-pyrazole,

(-) -5- { alpha- [2- (dimethylamine) ethoxy ] -2-thienylmethyl } -1-methyl-1H-pyrazole,

(+) -5- { alpha- [2- (dimethylamine) ethoxy ] -2-thienylmethyl } -1-methyl-1H-pyrazole citrate,

(-) -5- { alpha- [2- (dimethylamine) ethoxy ] -2-thienylmethyl } -1-methyl-1H-pyrazole citrate,

the medicament is useful for treating urinary incontinence in mammals, including humans.

5. Pharmaceutical composition for the treatment of urinary incontinence in mammals, including humans, characterised in that it contains at least one compound of general formula (I) according to any of claims 1 to 4 or one of its physiologically acceptable salts and a pharmaceutically acceptable excipient.