MXPA97005820A - The use of (s) -oxibutinin and (s) -desetiloxibutinin in the preparation of compositions for the treatment of urinary incontinence, the compositions obtained and the procedure for preparing desetiloxibitin - Google Patents

Abstract

The use of a therapeutically effective amount of a compound selected from the group consisting of (5) -oxybutynin and (5) -desethyloxybutynin or a pharmaceutically acceptable salt thereof, substantially free of its R-enantiomer, is described in the preparation of compositions for the treatment of urinary incontinence while avoiding the concomitant risk of adverse effects, in a human being in need of such treatment, pharmaceutical compositions in the form of tablets and transdermal delivery devices comprising (5) -oxybutynin or (5) are also described. -decyloxybutynin and an acceptable vehicle, as well as synthesis of desetiloxibutini

Description

THE USE OF (S) -OXIBUTININ AND (Si-DESETILOXIBUTININ IN THE PREPARATION OF COMPOSITIONS PflRfl THE TREATMENT OF URINARY INCONTINENCE, THE COMPOSITIONS OBTAINED AND THE PROCEDURE FOR PREPARING DESETILOXIBUTININA FIELD OF THE INVENTION The invention relates to a method for treating urinary incontinence using optically pure (S) -oxibutinin and (S) -desyryloxybutynin (S-DEO), to pharmaceutical compositions containing optically pure (S) -oxib? Tinin or S-DEO. , and a method for preparing individual enantiomers of DEO.

BACKGROUND OF THE INVENTION Racemic oxybutynin is used therapeutically in the treatment of intestinal hyper-otility and in the treatment of urinary incontinence due to instability of the detrusor muscle. The racist oxybutynin exerts a direct antispasmodic effect on the smooth muscle and inhibits the action of acetylcholine on the smooth muscle. It exhibits only one fifth of the anticholinergic activity of atropine on the detrusor muscle of the rabbit, but four to ten times the antispasmodic activity. It is quite selective for muscarinic receptors in the presence of nicotinic receptors and, as a result, no blocking effects are observed in the neuromuscular skeletal joints or in the autonomic ganglia. Racemic oxybentin relaxes the smooth muscle of the bladder and, in patients with conditions characterized by involuntary contractions of the bladder, skeletal studies have shown that racemic oxybutynin increases the capacity of the gallbladder, decreases the frequency of involuntary contractions of the bladder. detrusor muscle, and delays the initial desire to urinate. Therefore, it is useful in the treatment and prevention of both incontinence and frequent voluntary urination. The efficacy of racemic oxybutynin in the bladder has been attributed to a combination of anti-uecarinic effects, direct spasmolysis, and local anesthetics on the detrusor smooth muscle. Due to the antimuscarinic activity of the racemic drug, xerosis (dry mouth) and mydriasis (dilated pupils), which involve märinaric cholinergic receptors, are very common side effects. In fact, at least one researcher has referred to the "inevitable symptoms of mydriasis, xerostomia, tachycardia, etc." that accompany the administration of racemic oxybutynin CLish and others, fírch. Int. Phar acodyn. 156, 467-488 (1965), 4813. The high incidence of secondary anticholinergic effects (40 to 80%) often results in dose reduction or discontinuation of therapy.

Pharmacological studies of the individual enantiomers have suggested that the enantiomer R is the effective enantiomer. Noronha-Blob and others Í3. Pharmacol. Exp.

Ther. 256, 552-567 (1991) 3 concluded that the cholinergic antagonism of racemic oxybutynin (measured in vitro by its affinity for the subtypes of M, M2 and H3 receptors, and in vivo for diverse physiological responses) can be attributed mainly to the activity of the R enantiomer. For all the answers, they found that the hierarchy order of the racemic oxybutynin potency and its enantiomers is the same, namely, (R) -oxybutynin greater than, or equal to, the racemic oxybutynin, which it was much greater than (S) -oxybutynin, being the SS) -oxibutinin 1 to 2 orders of magnitude less potent than (R) -oxybutynin.

BRIEF DESCRIPTION OF THE INVENTION It has now been unexpectedly found that the substantially optically pure S-enantiomer of oxybutynin and its metabolite of dßsetil, provide superior therapy for the treatment of urinary incontinence. Optically pure (S) -oxibutinin (S-OXY) and (S) ~ desethyloxybutynin (S-DEO) provide this treatment, while substantially reducing the adverse effects that arise primarily from anticholinergic activity and that are associated with the administration of racemic oximutinin. These include, but are not limited by, xerostomia, rnidriasis, somnolence, nausea, constipation, palpitations and tachycardia. The improvement of the secondary cardiovascular effects of racemic oxybutynin, such as tachycardia and palpitations, by administration of (S) -oxybutynin or S-DEO, is of particular therapeutic value. The active compounds of these compositions and methods are optical isomers of oxybutynin and deeethyloxybutynin. The racemic oxybutynin preparation is described in the specification of British Patent 940,540. Chemically, the active compounds are (1) the S-enantiomer of 4- (diethylamino) -2-butynyl a-cyclohexyl-a-hydroxybenzeneacetate, also known as 4- (diethylamino) -2-butynyl phenylcyclohexylglycollate, and referenced hereinafter as oxybutynin; and (2) the S-enantiomer of 4- (ethylamino) -2-butynyl a-cyclohexyl-α-hydroxybenzeneacetate, and referred to below as desethyloxybutynin. The generic name given to the hydrochloride salt of racemic oxybutynin by the USAN Council is oxybutynin chloride; it is sold under the commercial name of Ditropan *. The isomer of oxybutynin having the absolute stereochemistry S (registration number 119618-22-3) is dextrorotate io, and is shown in formula I: The S-enantiomer of the desethyloxybutynin is shown in formula II: II The synthesis of (S) -oxibutinin CKachur and others has been described. 3. Pharmacol. Exp. Ther.247, 867-872 (1988) 3, but the (S) -oxybutynin itself does not currently exist in commerce.

All the clinical results that have been reported have been obtained with the racemic mixture, although the pharmacology of the individual enantiomers has been described in guinea pigs and rats Csee Kachur and others 3. Pharmacol. Exp. Ther. 247, 867-872 (1988) and Noronha-Blob et al. 3. Pharmacol. Exp.

Ther. 256, 562-567 (1991) 3. (S) -Desethyloxybutynin has not been previously described; its synthesis is carried out in accordance with the method described below.

In one aspect, the invention relates to a method for treating urinary incontinence while avoiding the concomitant tendency of adverse effects, which comprises administering to a human in need of such treatment, a therapeutically effective amount of (S) -oxybutynin, ( S) -Desethyloxobutynin or a pharmaceutically acceptable salt of any of them, substantially free of the corresponding R-enantiomer. The phrase "substantially free of its R-enantiomer", as used herein, means that the compositions contain at least 90% by weight of (S) -oxybutynin or (S) -decyloxybutynin and 10% by weight or less of (R) -oxybutynin or (R) -decyloxybutynin. In a more preferred embodiment, the compositions contain at least 99% by weight of the S-enantiomer and 1% or less of the R-enantiomer. The (S) -oxybutynin or the (S) ~ desethyloxybutynin. Substancially optically pure can be administered parenterally, The entity, intravesically, transdermally, orally or by aerosol, orally or transdermally being the preferred routes, at a rate of about 1 RNG to about 100 G per day. In another aspect, the invention relates to a pharmaceutical unit dosage form in the form of a tablet or capsule comprising a therapeutically effective amount of (S) -oxybutynin, (S) -desyryloxybutynin or a pharmaceutically acceptable salt of any of them , substantially free of the corresponding R-steroisomer, and a pharmaceutically acceptable carrier. The tablet or capsule preferably contains from D.5 to 25 rng of (S) -oxybutynin or (S) -decyloxybutynin, and is prepared by conventional methods, well known in the art. The invention also relates to a dosage form in the form of a transdermal device. Transdermal administration is improved by the inclusion of a permeation enhancer in the transdermal delivery device, for example, as described in the PCT application UO 92/20377. In a further aspect, the invention relates to a process for preparing desethyloxybutynin, preferably a single enantiomer of DEO, more preferably S-DEO, comprising the steps of, first, reacting methyl-cyclohexyl-a-hydroxybenzeneacetate with 4- r_N-ethyl- (4-methoxyphenyl) -methylamino3-2-butin-1-ol in the presence of an anhydrous base to produce a-cyclohexyl-a-hydroxybenzeneacetate of 4-CN-ethyl- (4-methoxyphenyl) methylamino3-2- Butynyl; and then secondarily with a carbonylhydrate and methanol to produce 4- (ethylamino) -2-butynyl (desethyloxybutynin) a-cyclohexyl-α-hydroxybenzeacetate. The process may further comprise reacting N-ethyl-4-methoxybenzenemethanamine with 2-propyn-1-ol and formaldehyde or one equivalent of formaldehyde in the presence of a copper (I) salt to produce 4-CN-ethyl- (4) -methoxyphenyl) methylamino-3-butin-1-ol necessary for the first step.

DETAILED DESCRIPTION OF THE INVENTION The S-enantiomers of oxybutynin and DEO can be obtained by resolution of the intermediate mandelic acid followed by esterification. The esterification can be carried out as described by Kachur et al. (Above) for OXY, or by the improved method described in the scheme below for S-DEO.

SCHEME A acetone V I I The graphical representations of the racemic, ambiscalemic and scaemic compounds or of the enantiomerically pure compounds used in the present invention are taken from Maehr, 3. Chem. Ed. 62, 114-120 (1985). Thus, solid and loose portions (such as those shown in formula I) are used to denote the absolute configuration of a chiral element; sketches of dotted or interrupted portions and lines (such as are shown in formula III) denote enantiomerically pure compounds of determined absolute configuration. The general procedure for DEO encompasses: (a) reacting N-ethyl-4-rnetoxybenzenemetanarnine with 2-propionyl and pair forrn ldehi or in an inert solvent in the presence of cuprous chloride to produce 4-CN-ethyl- ( 4-ethoxyphenyl) methylamino32-butin-1-ol (V); (b) reacting a single enantiomer of methyl α-cyclohexyl-α-hydroxybenzeneacetate (IV) with 4-CN-ethyl- (4-rnetoxy phenyl) rnetilarnino3-2-butynol (V) in the presence of a catalytic amount of sodium rateoxide in toluene to produce a single enantiomer of a-cyclohexyl-α-hydroxybenzenacetaate of 4-CN-ethyl- (4-methoxyphenyl) methylamino-3-butynyl (VI); and (c) reacting 4-tN-ethyl- (4-methoxyphenyl) methylamino-3-butynyl (VI) -cyclohexyl-a-hydroxybenzeneacetate sequentially with a-chloroethylcarbonate hydrochloride in dichloroethane, followed by methanol to produce an individual enantiomer of DEO (VII). The process obviously applies to also produce racemic DEO from racemic methyl oc-cyclohexyl-α-hydroxybenzeneacetate. Paraformaldehyde is used as a convenient source of formaldehyde, but can be substituted by any formaldehyde source, as is well known in the art. Also, a-chloroethyl carblochloride is used for dealkylation, but other carbon-chlorohydrates (e.g. vinyl) may be used. Alternatively, the S-enantiomers of OXY and DEO can be obtained by resolution of racemic oxybutynin or DEO using conventional means such as fractional crystallization of diastereomeric salts with chiral acids. Other standard resolution methods known to those skilled in the art including, but not limited to, simple crystallization and chromatography on a chiral substrate can also be used. The magnitude of a prophylactic or therapeutic dose of (S) -oxybutynin or S-DEO in the acute or chronic management of the disease will vary with the severity and nature of the condition to be treated and the route of administration. The dose and perhaps the dose frequency will also vary according to the age, body weight and response of the individual patient. In general, the total daily dose scale for (S) -oxybutynin or S-DEO for the conditions described in the present invention is from about 1 mg to about 100 mg in single or divided doses, preferably in divided doses. In the management of the patient, therapy should be started at a lower dose, perhaps around 0.25 mg to about 25 mg, and increased to approximately 100 mg, depending on the overall response of the patient. It is also recommended that patients over 65 years of age and those with impaired renal or hepatic function, receive initially low doses and be titrated based on the individual response (s) and the (s) level (s) of blood. In some cases, it may be necessary to use doses outside these scales, as will be apparent to those skilled in the art. In addition, it is observed that the clinician or treating physician will know how and when to interrupt, adjust or terminate the therapy in conjunction with the patient's individual response. The phrases "a therapeutically effective amount" and "an amount sufficient to treat incontinence but insufficient to cause adverse effects" are encompassed by the dose amounts described above and by the dose frequency schedule. Any suitable route of administration can be used to provide the patient with an effective dose of (S) -oxybutynin or S-DEO. For example, oral, rectal, parenteral (subcutaneous, intramuscular, intravenous), transdermal, aerosol and similar administration forms can be used. Additionally, the drug can be administered directly into the bladder through the urethra, as described for racemic oxybutynin by Masead and others. 3- Urol, 148, 595-597 (1992) 3. Dosage forms include tablets, troches, dispersions, suspensions, solutions, caps, transdermal delivery systems, and the like. The pharmaceutical compositions of the present invention comprise (S) -oxybutynin or S-DEO as the active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and, optionally, other therapeutic ingredients. The phrases "pharmaceutically acceptable salts" or "a pharmaceutically acceptable salt thereof" refers to salts prepared from pharmaceutically acceptable non-toxic acids. Suitable pharmaceutically acceptable acid addition salts for the compound of the present invention include acetic acid, benzenesulonic acid (besylate), benzoic acid, phonic camphor, citric, ethansulonic, phylic, gluconic, glutamic, brornhydric, hydrochloric, isethionic, lactic, maleic, malic, andlic, phonic, rnicucic, nitric, pamoic, pantothenic, phosphoric, euccinic, sulfuric, tartaric, p-toluenosul phonic and the like. The hydrochloride has particular utility and was, in fact, the salt used in the studies described below. The compositions of the present invention include suspensions, solutions, elixirs or solid dosage forms. In the case of solid oral preparations (such as powders, capsules and tablets), carriers such as starches, sugars and microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like are suitable, solid oral preparations are preferred over liquid oral preparations Due to their ease of administration, tablets and capsules represent one of the most advantageous oral dosage forms, in which case solid pharmaceutical carriers are used.If desired, the tablets can be coated by normal aqueous techniques or non-aqueous In addition to the common dosage forms indicated above, the compounds of the present invention may also be administered by controlled release means and delivery devices such as those described in US Patent Nos. 3,845,770; 3,916,899 3,536,809; 3,598,123; and 4,008,719, and the application d e PCT UO 92/20377, the descriptions of which are incorporated in this co reference. The pharmaceutical compositions of the present invention suitable for oral administration can be presented as discrete unit dose forms such as capsules, wafers or tablets, each containing a predetermined amount of the active ingredient, co or a powder or granules, or as a solution or as a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Said compositions can be prepared by any of the pharmacy methods, but all methods include the step of bringing into association the active ingredient with the vehicle constituting one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary, shaping the product into the desired presentation, as is known for the racemic mixture. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a freely flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or dispersing agent. The molded tablets can be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. All the above techniques are well known to those skilled in the pharmaceutical art. Each tablet can contain from about 0.5 g to about 25 mg of the active ingredient.

EXAMPLES EXAMPLE 1 FORMULATION OF ORAL UNIT DOSE TABLETS Ingredients Per tablet Per batch of 10,000 tablets (S) -Oxybutynin or 5mg 50g (S) -Desethyl ibutinine Microcrystalline cellulose 30mg 300g Lactose 70mg 700g Calcium Stearate 2mg 20g Blue Lacquer # 1 of FDRC 0.03rng 300rng The (S) -oxybutynin or desethyloxybutynin is mixed with the lactose and the cellulose until a uniform mixture is formed. The lacquer is added and then mixed. Finally, the calcium stearate is mixed with them, and the resulting mixture is compressed into tablets using a shallow 7mm concave punch. Tablets of other potencies can be prepared by altering the ratio of active ingredient to excipients or the final weight of the tablet. The surprising utility of the S-enantiomer, both OXY and DEO, has been established by means of the following studies.

OXYBUTININ ENANTIOMERS Union of (R) ~ and (5) -Oxybutynin to Receptor Subtypes Muscarinic Human MI, M2, M3 and I14 MATERIALS AND METHODS The experiments were carried out on membranes prepared from SF9 cells infected with baculovirus to express the subtypes of human rechargeable muscarinic receptor Mi, M2, M3 and M • Binding tests TABLE 1 After incubation, the tests were quickly filtered under vacuum through GF / B glass fiber filters (Uhatman) and washed with an ice-cooled pH regulator using a Brandel Cell Harvester. The bound radioactivity was determined with a liquid scintillation counter (LS 6,000, Beckman), using a liquid scintillation mixture (Formula 99, DuPont NEN).

Experimental Protocol The compounds were tested on each receptor at 10 concentrations in duplicate to obtain competition curves. In each experiment, the reference compound for the receptor under investigation was tested simultaneously * - at 8 concentrations in duplicate to obtain a proficiency curve to validate this experiment.

Analysis and expression of the results The specific radioligand binding of each receptor was defined as the difference between the total binding and the non-specific binding determined in the presence of an excess of unlabeled ligand. CIso values (concentrations required to inhibit 50% of the specific binding) were determined by non-linear regression analysis of the competition curves. These parameters were obtained by adjusting the curve using Sig aplotTM software. The CIso for R- and S-OXY is given in Table 2.

TABLE 2 Binding of R-oxybutynin and S-oxybutynin to human muscarinic subtypes M1-M4 These results indicate that S-OXY has less affinity for muscarinic receptor subtypes than R-OXY.

Union of (R) - and (S) -Oxybutynin to Calcium Channels MATERIALS AND METHODS Binding tests Binding tests were performed using the following methods: TABLE 3 The conditions of the experiment were: TABLE 4 After incubation, the tests were quickly filtered under vacuum through glass fiber filters GF / B or GF / C (Uhatman) and washed with pH regulator cooled with ice using a Brandel Cell Harvester. The bound radioactivity was determined with a liquid scintillation counter (LS6000, Beckman) using a liquid scintillation mixture (Formula 989, DuPont NEN).

Experimental Protocols The compounds were tested in duplicate on each receptor at a concentration of 10_5M. In each experiment, the reference compound for the receptor under investigation was tested simultaneously at 8 concentrations in duplicate to obtain a competence curve to validate this experiment.

Analysis and expression of results The specific radioligand binding of each receptor was defined as the difference between the total binding and the non-specific binding determined in the presence of an excess of unlabeled ligand. The mean values, expressed as a percentage of inhibition of specific binding, are presented in Table 5. CIso values (concentration required to inhibit 50% of specific binding) were determined by means of non-linear regression analysis of their competence curves. . These parameters were obtained by adjusting the curve using SigrnaplotTM software.

TABLE 5 Binding of R-oxybutynin and S-oxybutynin to calcium channels [Inhibition (in%) of diltiazem and verapamil binding to calcium channel receptors.3 These results indicate that S-OXY has calcium entry blocking activity similar to that of R-OXY. 00 DESETILOXIBUTININ ENANTIOMERS The main metabolite of racemic oxybutynin is RS-desethyloxybutynin (DEO). The R and y enantiomers of DEO have not been described, and the antispasmodic and blocking activities of the calcium entry of the individual enantiomers, R- and S-DEO, were unknown until before these studies. The present authors have synthesized these enantiomers and studied their antimuscarinic, spasmolytic and blocking effects of calcium entry in receptor binding and bladder functioning models. They have found that in each enantiomer of the metabolite retains the relative pharmacological profile of its "prototype" oxybutynin enantiomer.

Junction in Subtypes of Muscarinic Receptor The percentage of inhibition of radioligand specific binding, induced by three concentrations of each compound (R-, S-, and RS-DEO) was tested in subtypes of cloned human muscarinic receptor (M1-M4), as described above for the oxybutynin enantiomers. The following tables (tables 6 and 7) give the percentage of inhibition in each subtype. In addition, the CIso values for the human receptor subtypes Mi and 2 were determined and presented in table 6.

TABLE 6 TABLE 7 These results indicate that S-DEO has less affinity for muscarinic receptor subtypes than either R- or racemic DEO.

Union in the Calcium Channels The percentage of inhibition of specific radioligand binding induced by each compound (R-, S-, and RS-DEO) was tested in the diltiazem and verapamil sites of the L-type calcium channel. they are shown in table 8.

TABLE 8 These results indicate that S-DEO has calcium entry blocking activity similar to that of racemic R- and DEO.

Functional Characterization of Antimuscarinic / Antispasmodic Activity The effects of R-, S-, and RS-oxybutynin (OXY) and R-, S-, and RS-DEO were studied in an in vitro model of bladder function. As described below, isolated strips of guinea pig bladder smooth muscle were mounted in a tissue bath and contracted with either the carbachol uscarinic agonist or increasing external potassium concentrations.

MATERIALS AND METHODS Bladder Strips. Experiments were performed using methods similar to those described by Kachur et al, 1988 and Noronha-Blob and Kachur, 1991. Strips of tissue (approximately 10 mm long and 1.5 mm wide) were removed from the body of the urinary bladder of guinea pigs. from India Hartley males weighing 400-600 g. (The Hill Breeding Laboratories, Chelmsford, Massachusetts). The tissues were suspended in an oxygenated pH regulator of the following composition, in M: NaCl, 133; KCl, 4.7; CaCl2, 2.5; MgSO *, 0.6; NaH2 P0 <; , 1.3; NaHCO3, 16.3; and glucose, 7.7. They were maintained at 37.5 ° C. Contractions were recorded with iso-etric transducers (Model FT-10) and an ink-printing polygraph (Model 7) (Astro-Med, Inc., Grass Instru ent. Div., Uest Uarwick, Rhode Island). A resting tension of 0.5 grams was maintained in all tissues at all times. In each experiment, up to 7 strips were removed from a single bladder, suspended in individual tissue chambers and left to equilibrate with the bath solution for 1 hour before proceeding with the experiment. Contractions induced with carbacol. A series of experiments focused on the anticholinergic actions of oxib? Tinin. In these experiments, to determine the viability of each tissue and to serve as a frame of reference, contractions of each tissue strip were initially recorded in response to exposure to tissue medium in which NaCl was replaced with KCl to give a concentration of 137.7 M KCl in the medium. This was followed by return to the normal medium, and then by exposures to progressively increasing concentrations of carbachol, with separate exposures at each concentration only until the peak response was recorded. Then, leaving an untreated strip and / or a strip exposed to 17 M ethanol to serve as control tissue, each of the remaining strips was exposed for 1 hour to a concentration of an antagonist. The ethanol controls were used when, due to low solubility, solutions for the supply of test substances in ethanol had to be prepared, as a result of which the fabric baths experienced an effective concentration of 17 mM ethanol. Finally, the responses to increasing concentrations of carbachol followed by exposure to KCl 137.7 were recorded for the second time. Potassium-induced contractions. A second series of experiments focused on the spasmolytic action of the substances under study. Contractions were recorded in response to the sequential increase in potassium concentration in the medium. Data analysis. To determine if antagonists decreased the peak response to agonists, the peak attention developed by each strip during the second group of determinations was expressed as a percentage of the peak voltage developed during the first concentration-effect determination. Then, the resulting data for each antagonist were analyzed for the differences related to the treatment by means of analysis of a sense of variance (ANOVA). Since only one antagonist concentration was studied in each bladder strip, the procedures of Arunlakshana and Schild (1959) were used in modified form to estimate pA2 and the slope of the Schild regression. First, the agonist concentrations that produce a mean maximum response (the EC50) for each strip of the second group of concentration-effect data were estimated. The EC50 was obtained from the adjustment of the linear regression lines to the logarithm of the drug concentration and the responses, which groups the maximum average level of response. For each drug-treated strip, a "concentration ratio" (RC) was calculated as the ratio of the EC50 of the treated tissue divided by the EC50 of the tissue without treatment. For each experiment where two or more strips were exposed to the same chemical agent but at different concentrations, the logarithm of this ratio minus one Testo is., Log (RC-D3 plotted against the logarithm of the concentration of the antagonist to which exposed the strip to produce "Schild graphs." A regression analysis was used that relates to log (CR-1) with the logarithm of the antagonist concentration to estimate the pA2 and the slope of the regression line. Experiments were grouped by chemical agent and the mean + _ EE of pA2 were calculated, and the slope.95% confidence limits (LC) were estimated for the slope from their EE using normal methods. only one strip was exposed to a given chemical agent, a pKD co or (antagonist concentration) / (CR-1) was calculated and the negative logarithm of the KD was then pooled with the pA2 values to give an expanded group of goes lords of pA2.

RESULTS Table 8 below summarizes the effects of racemic oxybutynin and DEO and their respective enantiomers on the contraction induced by carbachol. The given values are the summary of Schild's analyzes that give values of pA2 [mean + _ EE3 and slope [mean + _ EE3.

TABLE 9 These results indicate that both S-OXY and S-DEO are less potent antagonists of the bladder uscarinic receptors than are R-OXY and racemic OXY and R-DEO and racemic DEO.

The effects of racemic oxybutynin and its enantiomers on potassium-induced contraction are summarized in Table 10 below. (The given values are the amount of contraction induced by K + 137.7 rnM after 60 minutes of exposure to the compound, divided by the amount of contraction induced before exposure to the drug).

TABLE 10 10 fifteen twenty ? * Significantly different from the corresponding value for untreated tissues (p < 0.01). These results indicate that oxybutynin and its enantiomers and desethyloxybutynin and its enantiomers are equipotentials as spasmolytic smooth muscle of the bladder.

CONCLUSIONS Although it is well known that normal emptying of the bladder is measured by cholinergic mechanisms, the instability of the bladder seen in patients suffering from incontinence seems to be related to non-cholinergic contractions of the bladder. Andersson et al. [Neurourol Urodyn 5, 579-586 (1986) 3 have shown in animals that the atropi.no resistant muscle destroyer is highly sensitive to calcium antagonists. The study of the receptor binding affinities of (R) - and ()) - oxybutynin to the receptor sites for diltiazem and veraparnil calcium channel blockers described above allows us to conclude that S-oxybutynin and (S) -desyryloxybutynin have therapeutic effects on involuntary micturition, whereas (unlike the R-isomers and racematoe, it has very little effect on the normal mechanism of gap formation.) Both also show significantly reduced anticholinergic side effects compared to the R-isomer and race The avoidance of cardiovascular side effects arising from the anticholinergic action of racemic oxybutynin is of particular importance.We conclude that S-oxybutynin and S-desethyloxybutynin are effective drugs for the treatment of urinary incontinence in humans with side effects in greatly reduced on racemates or R-enantiomers pure (R) -acylohexyl-? -hydroxybenzeneacetate methyl (IV) To a mixture of (R) -a-cyclohexyl-α-hydroxybenzenacetic acid (III) (12.2 g, 52.1 mmol) and K2CO3 (10.8 g, 78.2 mmol) in lOOrnl of acetone was added methyl iodide (Mel) (13.0 ml). , 208 mmol) dropwise at 0 ° C (ice bath). After the addition (ca.lh) of Mel, the reaction mixture was stirred at room temperature overnight. The mixture was filtered through a pad of celite and rinsed with acetone 2 times. The filtrate was concentrated to give a white suspension which was diluted with water and extracted with heptane. The combined extracts were washed with water, brine, dried and concentrated to give the product (R) -IV (11.9 g, 92% yield) as a white solid.

(S) -th-cyclohexyl-oc-hydroxymethylene methyl acetate (IV) Following the same procedure above, we obtained (S) -IV (11.2 g, 100% yield) as a white solid from (S) -III (10.6 g, 45.3 rnoles). 1? (R) -c-cyclohexyl- "-hydroxybenzeneacetate of 4-CN-ethyl- (4-methoxy-enyl) methylamino-3-butynyl (VI) To a solution of (R) -IV (11.9 g, 47.7 mmol) and 4- [N-ethyl- (4-rnetoxy phenyl) methylamino] -2-butin-1-ol (V) (9.30 g, 39. 9 mmol) in 120 ml of toluene was added NaOMe (0.222 g, 4. 11 rnmoles). The reaction mixture was stirred at reflux for hours and a total of 6 ml of the solvent was removed by means of a Dean-Stark apparatus. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, brine, dried and concentrated. The residue was chromatographed on silica gel (elution with 1% MeOH, 2.5% and then 5% in CH 2 Cl 2) to give the product (R) -VI (14.1 g, 79% yield) as an oil.

(S) -ot-cyclohecyl-c (4-CN-ethyl- (4-oxethoxyphenyl) methylamino-3-butynyl-hydroxybenzene acetate (VI) Following the same procedure as above, (S) ~ VI (4.24 g, 58% yield) was obtained as an oil from (S) -IV (4.07 g, 16.4 mmoles) and V (4.24 g, 18.2 mmoles).

(S) - «- cyclohexyl-tt-hydroxybenzeneacetate of racemic 4-CN-ethyl- (4-methoxyphenyl) methylamino-3-butynyl Following the same procedure as before, the racemic precursor for DEO (2.05 g, 43% yield) was obtained as an oil from racemic IV (2.98 g, 12.0 mol) and V (2.48 g, 10.6 mmol).

Hydrochloride salt of (R) -ot-cyclohexyl-α-hydroxybenzene acetate of 4- (ethylamino) -2-Putinyl (VII) -HCl A solution of (R) -VI (14.0 g, 31.2 mmol) and a-chloroethyl carblochloride (4.0 ral, 37.4 mmol) in 1,2-dichloroethane was stirred under reflux for 1 hour. After cooling, the reaction mixture was concentrated and 200 ml of MeOH was added to the residue. The reaction mixture was stirred at reflux for 20 minutes and cooled to room temperature. The mixture was concentrated and the residue was chromatographed on silica gel (elution with 1% MeOH and then 50% in CH 2 Cl 2) and then triturated with ether to give the product (R) -VII-HCl (8.93 g, 87% of yield) as a tan solid. Then this tan solid was purified by recrystallization from EtOH / Et2? and by sequential treatment with 10% aqueous K2CO3 and EtOAC, activated carbon and a solution of 1N HCl in ether to give (R) -DEO-HCl (6.44 g) as an off-white solid.

Salt of (S) -a-cyclohexyl-a-4- (ethylamino) -2-butynyl hydroxybenzene hydrochloride (VII) -HCl Following the same procedure as before, (S) -DEO-HCl (5.27 g, 57% yield) was obtained as an off-white solid from (S) -VI (11.4 g, 25.4 mmol).

Hydroxybenzene acetate hydrochloride salt of racemic α-cyclohexyl-a-4- (ethylamino) -2-butynyl Following the same procedure as before, (+) ~ DEO-HC1 (0.63 g) was obtained as an off-white solid from the precursor (±) (2.28 g, 5.08 mmol). S-oxybutynin can be prepared by the same route, replacing the intermediary V prot € > by 4- (diethylamino) -2-butin-l-ol. • 4- [N-Ethyl- (4-rethoxyphenyl) methylamino3-2-butin-l-ol (V) used as an intermediate is synthesized as follows: N-Ethyl-4-methoxybenzene ethanamine To a mixture of anisaldehyde (15.6 g, 115 mmol) and ethylamine (2.0 M in THF, 87 mL, 174 mmol) in 1,2-dichloroethane (450 mL) was added glacial acetic acid (10.0 mL, 174 mmol) under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 30 minutes and then cooled to 0 ° C with an ice bath. NaBH (0Ac) 3 (36.9 g, 174 mmol) was added portionwise and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was diluted with a basic solution (10 g of NaOH in 100 ml of water) to make the solution slightly basic. This aqueous layer was extracted with ether. The combined extracts were washed with water, brine, dried and concentrated. The residue was chromatographed on silica gel (elution with 5% MeOH in C 2 Cl 2 and then 50% MeOH in CH 2 Cl 2 containing 4% Et 3) to give the product (11.2 g, 59% yield) as an oil. 4-CN-ethyl- (4-methoxyphenyl) ethylaminol-2-butin-1-ol (V) A mixture of N-ethyl-4-methoxybenzenemetanarnine (13.3 g, 80.6 mol), paraformaldehyde (3.63 g), propargyl alcohol (6.33 g, 113 mmol) and CuCl (0.311 g) in 350 rnl of 1,4-dioxane was stirred reflux for 30 minutes. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with 200 ml of 50% NH 4 OH and extracted with EtOAc. The combined extracts were washed with water, brine, dried and concentrated. The residue was chromatographed on silica gel (elution with MeOH in CH 2 Cl 2 and then 5% MeOH in CH 2 Cl 2) to give product V (15.1 g, 81% yield) as an oil.

Claims (14)

NOVELTY OF THE INVENTION CLAIMS

1. The use of a therapeutically effective amount of a compound selected from the group consisting of (S) -oxybutynin and (S) -decyloxybutynin or a pharmaceutically acceptable salt thereof, substantially free of its R-enantiomer, in the preparation of compositions for the treatment of urinary incontinence while avoiding the concomitant risk of adverse effects, in a human being who needs such treatment.

2. The use according to claim 1, further characterized in that the compound contains at least 90% by weight of (S) -oxybutynin or (S) -decyloxybutynin and 10% by weight of (R) -oxybutynin or ( R) -Desethyloxybutynin, for the manufacture of a medicament for the treatment of urinary incontinence.

3. The use according to any of claims 1 and 2, further characterized in that the composition obtained is in a form suitable to be administered by inhalation or by parenteral, transdermal, rectal administration? oral.

4. The use according to any of claims 1-3, further characterized in that the compound contains at least 99% by weight of (S) -oxybutynin or (S) -decyloxybutynin and 1% by weight of (R) -oxybutynin or (R) -decyloxybutynin, for the manufacture of a medicament for the treatment of urinary incontinence.

5. A dosage unit dosage form in the form of a tablet or capsule comprising a therapeutically effective amount of a compound selected from the group consisting of (S) -oxybutynin and (S) -desyryloxybutynin or a pharmaceutically acceptable salt thereof , wherein the compound contains at least 90% by weight of (S) -oxybutynin or (S) -desyryloxybutynin and 10% by weight of (R) -oxybutynin or (R) -decyloxybutynin, and a pharmaceutically acceptable carrier of the same.

6. A dosage unit dosage form according to claim 5, further characterized in that the compound contains at least 99% by weight of (S) ~ oxybutynin or (S) -desyryloxybutynin and 1% by weight of (R) -oxibutinin or (R) -decyloxybutynin, and a pharmaceutically acceptable carrier thereof.

7. A dosage unit dosage form according to claims 4 or 5, comprising 0.5 to 100 mg of (S) -oxybutynin or (S) -decyloxybutynin.

8. The unit dosage dosage form, according to claims 5 or 6, further characterized in that the dosage form is in line with a transdermal assortment diepoeitive.

9. A pharmaceutical dosage form in accordance with claim 8, further characterized in that the pharmaceutically acceptable carrier comprises a penetration enhancer.

10. A process for preparing desethyloxybutynin comprising the steps of: (a) reacting methyl-cyclohexyl-α-hydroxybenzeneacetate with 4- [N-ethyl- (4-methoxy phenyl) methylamino-3-buty- l-ol in presence < an anhydrous base to produce 4- [N-ethy] - (4 ~? -nuclexyphenyl) ethylamino] -2-b-tinyl o-cyclohexyl-e ~ hydroxybenzene acetate; and (b) reacting said 4- [N-ethyl- (4-ethoxyphenyl) methylamino-2-butynyl α-cyclohexy-1-or-hydroxybenzeneacetate sequentially with 4- (ethylamino) -cyclohexyl-α-hydroxybenzene acetate) -2-butynyl.

11. A process according to claim 10, comprising the additional step of reacting N-e + il-4-methoxybenzenemethamine with 2-propyn-l-ol and formaldehyde or formaldehyde equivalent in the presence of a copper salt (I) to produce 4- [N-ethyl-4-methoxyphenyl) methylamino-3-butin-1-ol.

12. A process according to claim 10, further characterized in that the reaction of N-ethyl-4-methoxybenzeneamine with 2-propin-1-ol is carried out with ormaldehyde in an inert solvent in the presence of cuprous chloride to produce said 4-CN-eti l- (4-methoxy phenyl) methylamino-3-butin-1-ol; the reaction of methyl. cyclohexyl-α-hydroxybenzeneacetate with said 4- [N-ethyl- (4-methoxyphenyl) methylamino-3-butin-1-ol is carried out in the presence of sodium methoxide to produce said 4- [N-ethyl- (4-ethoxy phenyl) -nethenylamino-3-butynyl -cyclohexyl-a-hydroxybenzeneacetate; and the reaction of said 4-CN-ethyl- (4-methoxyphenyl) methylamino-3-butynyl a-cyclohexyl-a-hydroxybenzeneacetate is carried out sequentially with a-chloroethylcarbonate hydrochloride in dichloroethane, followed by methanol to produce the 4- (Ethylamino) -2-butynyl (desethyloxy-butynyne) -cyclohexyl-α-hydroxybenzeneacetate.

13. A process according to claim 10, further characterized in that said desethyloxybutynin is enriched in a single enantiomer.

14. A process according to claim 13, further characterized in that said desethyloxybutynin is S-desethyloxybutynin.