A method of treating urinary incontinence using (s)-oxybutynin and (s)-desethyloxybutynin

 

(57) Abstract:

The invention relates to medicine, in particular to urology, and for the treatment of urinary incontinence. For this purpose it is proposed to use the introduction of a therapeutically effective amount of (S)-oxybutynin, (S)-desethyloxybutynin or its pharmaceutically acceptable salt is essentially free of the corresponding R enantiomer. Also disclosed pharmaceutical compositions in the form of tablets and percutaneous means, including (S)-oxybutynin or (S)-desethyloxybutynin and an acceptable carrier, as well as the synthesis desethyloxybutynin. The method prevents the negative effects associated with the introduction of racemic oxybutynin. 8 C. and 23 C.p. f-crystals, 11 tab., 1 Il.

The technical field to which the invention relates

The invention relates to a method of treating urinary incontinence using optically pure (S)-oxybutynin and (S)-desethyloxybutynin (S-DEO), to pharmaceutical compositions comprising optically pure (S)-oxybutynin or S-DEO and to the process of obtaining a single enantiomer DEO.

Background of the invention

Racemic, oxybutynin used therapeutically in the treatment of hypermotility ulcers and indicates a direct antispasmodic effect on smooth muscle and inhibits the action of acetylcholine on smooth muscle. He has only one-fifth of the anticholinergic activity of atropine on the muscle, eject urine in rabbits, but antispasmodic activity exceeds the last four to ten times. He is extremely selective in relation to muscarinic receptors in the presence of cholinomimetic receptors and, consequently, does not have a blocking effect on skeletal neuromuscular synapses or autonomic ganglia.

Racemic, oxybutynin relaxes smooth muscle of the bladder and in patients who are in a condition characterized by involuntary contractions of the bladder. Sistematicheskie studies have shown that racemic, oxybutynin increases the capacity of the bladder, reduces the frequency of involuntary contractions of the muscles, eject urine, and delays the initial desire to emptying of the bladder. Therefore, it is suitable for the treatment and prevention as urinary incontinence, arbitrary and frequent urination. The effectiveness of racemic oxybutynin against the bladder is attributed to the combination of antimuskarinovoe act occurs, direct spasmodic and local anesthetic effects on smooth muscle, eject urine. Due to the fast xerostomia (dry mouth) and mydriasis (dilated pupils) with the involvement of muscarinic cholinergic receptors. At least one scholar has pointed to the "inevitable symptoms of mydriasis, xerostomia, tachycardia, etc. that accompany the introduction of racemic oxybutynin (Leash, etc., Lish (Arch. Int. Pharmacodyn. 156, 467-488 (1965), 481). A frequent consequence of the high frequencies of anticholinergic adverse effects (from 40 to 80%) is the reduction in the dose or interrupt treatment.

The results of pharmacological studies of individual enantiomers suggests that effective enantiomer is the R enantiomer. Norona BLOB (Noronha-Blob) and others (J. Pharmacol. Exp. Ther. 256, 562-567 (1991)) have concluded that cholinergic antagonism of racemic oxybutynin (measured in vitro by its affinity for the receptor subtypes M1, M2and M3and in vivo in various physiological reactions) can be attributed mainly to the activity of the R enantiomer. They found that in all reactions orderly activity of racemic oxybutynin and its enantiomers is the same, namely, the activity of (R)-oxibutinina exceeds or equals the activity of racemic oxybutynin, which is far superior to the activity of (S)-oxybutynin, and the activity of (S)-oxybutynin lower activity of (R)-oxibutinina 1-2 order.

Optically pure (S)-oxybutynin (S-OXY) - and (S)-desethyloxybutynin (S-DEO) provides such treatment with a simultaneous significant reduction of the negative effects that arise mainly due to the anticholinergic activity and are associated with the introduction of racemic oxybutynin. These include, but are not limited to, xerostomia, mydriasis, drowsiness, nausea, constipation, palpitations and tachycardia. Special therapeutic value has reduced side effects, provided the racemic oxibutinina in relation to the cardiovascular system, in particular palpitations and tachycardia due to the introduction of (S)-oxybutynin or (S-DEO).

The active components of these compositions and methods are optical isomers of oxibutinina and desethyloxybutynin. Receipt of racemic oxybutynin disclosed in the description of the patent in the UK 940540. Chemically, the active compounds are: (1) S enantiomer 4-(diethylamino)-2-butynyl-cyclohexyl-hydroxyindolacetic, also known as 4-(diethylamino)-2-butylperoxycyclohexyl, referred to in subsequent oxibutinina and (2) S enantiomer 4-(ethylamino)-2-butynyl-ticketsale assigned hydrochloric salt of racemic oxybutynin generic name of oxybutynin chloride; it is sold under the trade name Diropan. Isomer of oxibutinina having the S absolute stereochemical details (Registration number 119618-22-3) is Pervouralsk and represented by formula I:

< / BR>
S enantiomer desethyloxybutynin represented by Formula II:

< / BR>
Synthesizing (S)-oxybutynin described (Kachur (Kachur) et al , J. Pharmacol. Exp. Ther. , 247, 867-872 (1988)), however, the (S)-oxybutynin currently not commercially available. All clinical results reported were obtained with the racemic mixture despite the fact that the pharmacology of the individual enantiomers has been described in Guinea pigs and rats (see Kachur, etc., J. Pharmacol. Exp. Ther., 247, 867-872 (1988) and Noronha BLOB and others ,), J. Pharmacol. Exp. Ther., 256, 562-567 (1991)). (S)-desethyloxybutynin were not previously documented; the synthesis of this compound is carried out in accordance with the method described below.

One of its aspects the invention relates to a method of treating urinary incontinence prevention related probability of occurrence of negative effects, which includes the introduction of a person in need of such treatment, a therapeutically effective amount of (S)-oxybutynin, (S)-desethyloxybutynin or the pharmaceutically priemnik from the corresponding R enantiomer", used in this description, means that the compositions contain at least 90 wt.% (S)-oxybutynin or (S)-desethyloxybutynin and 10 wt.% or less (R)-oxybutynin or (R)-desethyloxybutynin.

In a more preferred embodiment, the compositions contain at least 99 wt.% S enantiomer and 1% or less of the R enantiomer. Essentially optically pure (S)-oxybutynin or (S)-desethyloxybutynin can be entered parenterale, rectal, intravesical, transdermal, oral or aerosol method, and preference is given to oral and percutaneous routes of administration, at a dose of from about 1 to 100 mg per day.

In another aspect the invention relates to standard pharmaceutical dosage form as tablets or capsules, comprising a therapeutically effective amount of (S)-oxybutynin, (S)-desethyloxybutynin or pharmaceutically acceptable salt of any of them, essentially free of the corresponding R stereoisomer, and a pharmaceutically acceptable carrier. The tablet or capsule in the preferred embodiment contains from 0.5 to 25 mg (S)-oxybutynin or (S)-desethyloxybutynin and prepared by conventional methods well-known in the industry. The invention otnoschenia in percutaneous delivery system amplifier penetration, for example, as described in PCT application WO 92/20377.

The subsequent aspect of the invention relates to the process of obtaining desethyloxybutynin, in the preferred embodiment, a single enantiomer DEO, in the preferred embodiment, S-DEO, which includes the steps of, first, the reaction of methyl-cyclohexyl--hydroxyindolacetic 4-[N-ethyl-(4-methoxyphenyl)methylamino] -2-buten-1-I in the presence of an anhydrous base to obtain 4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-butenyl-cyclohexyl-hydroxyindolacetic; then with carbochlorination and methanol to obtain 4-(ethylamino)-2-butynyl-cyclohexyl-hydroxyindolacetic (desethyloxybutynin). The process may optionally include the step of reacting 4-ethyl-4-methoxybenzylideneamino 2-propyne-1-I and formaldehyde or equivalent of formaldehyde in the presence of a salt of copper (I) to obtain 4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-buten-1-ol, required for the first stage.

Detailed description of the invention

S enantiomers of oxybutynin and DEO can be obtained by re-dissolving the intermediate product Mandelieu acid followed by esterification. The etherification can be carried out as described Kachur (upominac the IU And S-DEO.

Graphic racemic, ambisyllabicity and selamicesme or enantiomerically pure compounds used in this description, borrowed from the Measure (Maehr) J. Chem. Ed., 62, 114-120 (1985). Thus, the solid and broken wedges are used (such as that shown in the formula (I), are used to denote the absolute configuration of a chiral element; the outline of the wedge and dash-dotted or broken line (such as that shown in the formula (III) represent enantiomerically pure compounds of indeterminate absolute configuration.

The General process for obtaining DEO includes:

(a) reacting N-ethyl-4-methoxybenzylideneamino 2-propyne-1-I and paraformaldehyde in an inert solvent in the presence of copper chloride to obtain 4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-buten-1-ol (V);

(b) response of a single enantiomer of methyl-cyclohexyl--hydroxyphenylacetate (IV) with 4-[N-ethyl-(4-methoxyphenyl)methylamino] -2-buten-1-I (V) in the presence of catalytic amounts of sodium methoxide in toluene to obtain a single enantiomer 4-[N-ethyl-(4-methoxyphenyl)methylamino] -2-butenyl-cyclohexyl-hydroxyindolacetic (VI);

(c) reacting 4-[N-ethyl-(4-methoxyphenyl)methylamino] -2-butenyl-cyclohexyl-Gruzovaya single enantiomer DEO (VII).

The process, obviously, suitable for receiving racemic DEO of racemic methyl-cyclohexyl--hydroxyindolacetic. Paraformaldehyde is used as a convenient source of formaldehyde, but it can be replaced by any source of formaldehyde, which is well known in the art. Similarly-chloroethylnitrosourea used for dealkylation, however, can be used and other carbonochloridic (e.g., vinyl).

Alternatively, S enantiomers OXY and DEO can be obtained by re-dissolving the racemic of oxibutinina or DEO by conventional techniques, for example, fractional crystallization of the diastereomeric salts of chiral acids. You can also use other standard ways of re-dissolution, well-known experts in this field, including, but not limited to, simple crystallization, chromatography was carried out on a chiral substrate.

The magnitude of prophylactic or therapeutic dose of (S)-oxybutynin or S-DEO in acute or chronic disease will vary depending on the severity and nature of the condition to be treated, and the route of administration. Dose and possibly the frequency of introduction is BSA daily dose (S) of oxibutinina or S-DEO for these States ranged from approximately 1 to 100 mg as a single dose or a small dose, repeat at certain intervals of time, with preference being given a small dose, repeated at intervals of time. In the patient's treatment course starts with a lower dose, perhaps, from about 0.25 to 25 mg increasing to approximately 100 mg depending on the overall response of the patient. It is also recommended that patients older than 65 years and patients with impaired liver or kidney initially received a lower dose, which should be chosen based on individual response (s) and level (s) in the blood. In some cases it may be necessary to use dosages outside these ranges, which is understandable for specialists in this field. Further, it should be noted that practitioner or physician knows how and when to terminate, change or terminate a course of treatment depending on the individual reactions of the patient. The terms "therapeutically effective amount" and "amount sufficient for the treatment of incontinence, but insufficient to cause adverse effects" are included in the scope of the above-described dosage amounts and patterns of use of drugs.

To ensure what I am. For example, can be used orally, rectally, parentalia (subcutaneous, intramuscular, intravenous), transdermal, aerosol, etc., form the introduction. In addition, the drug may be injected directly into the bladder through the urethra, as described for racemic of oxibutinina the Massada (Massad) and others (J. Urol. 148, 595-597 (1992)). Among the dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, transdermal delivery systems, etc.

The pharmaceutical compositions of the present invention include (S)-oxybutynin or S-DEO as the active ingredient or its pharmaceutically acceptable salt and, in addition, may also include pharmaceutically acceptable carrier or, optionally, other therapeutic ingredients.

The terms "pharmaceutically acceptable salts or its pharmaceutically acceptable salt" refers to salts derived from pharmaceutically acceptable non-toxic acids. Among the pharmaceutically acceptable acid salts of the compounds of the present invention include acetic, benzolsulfonat (basilinna), benzoic, camphorsulfonic, lemon, econsultancy, fumaric, gluconic, CH is methansulfonate, mucus, nitrogen, Panova, Pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluensulfonate, etc., Especially suitable was hydrochloric salt, which was used in the following studies.

Among the compounds of the present invention include suspensions, solutions, elixirs or solid dosage forms. In the case of oral solid dosage forms such as powders, capsules and tablets) suitable devices such as starches, sugars, and microcrystalline cellulose, diluents, granulating tools, lubricants, binding agents, substances that contribute to the decay, etc. Solid oral preparations are preferred compared to liquid oral preparations.

Due to the simplicity of the introduction of tablets and capsules represent one of the more preferred oral dosage forms, and in this case you use solid pharmaceutical carriers. If necessary, the tablets can be coated using standard aqueous or nonaqueous techniques.

In addition to the above-mentioned conventional dosage forms of the compounds of the present invention may that the tah USA 3845770, 3916899, 3536800, 3598123 and 4008719, as well as in PCT application WO 92/20377, the description of which is included in the present description as a reference.

The pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete standard dosage forms, for example capsules, starch wafers or tablets, each of which includes a preferred amount of the active ingredient in the form of powder or granules or as a solution or suspension in an aqueous liquid, non-aqueous liquids, emulsions of the type oil-in-water or a liquid emulsion of the type water-in-oil". Such compositions can be prepared by any of pharmacological methods, but all methods include the step of connection of the active ingredient with the carrier which constitutes one or more necessary ingredients. In General, the formulations are prepared uniform and thorough mixing of the ingredient with liquid carriers, or finely powdered solid carriers or both and then, if necessary, by giving the product the necessary forms in accordance with what is known for the racemic mixture.

For example, a tablet may be made optional PR is otovitsa by compressing in a suitable machine the active ingredient in free-flowing form, such as powder or granules, optionally mixed with a binder agent, a lubricating agent, an inert diluent, surface active substance or a substance that promotes decay. Molded tablets may be made by molding, in a suitable machine a mixture of the powdered compound moistened inert liquid diluent. All the above mentioned methods well known to experts in the field of pharmacology. The composition of each tablet may include from about 0.5 to 25 mg of active ingredient.

Examples

Example 1. Oral standard dosage form (see tab. 1A).

(S)-oxybutynin or desethyloxybutynin mixed with lactose or cellulose prior to the formation of a homogeneous mixture. Add colorful lacquer and continue mixing. Add calcium stearate, and the resulting mixture is pressed into tablets using a hollow concave punch 9/32 inch (7 mm). Tablets with different content of active substance can be prepared by altering the ratio of active ingredient and excipients or final weight of the tablets.

When conducting the following studies was established causes surprisingly sentence is and subtypes of muscarinic receptors man M1, M2, M3and M4< / BR>
Materials and methods

The experiments were performed on membranes prepared from SF9 cells infected with baculoviruses for ekspressirovali recombinant subtypes of muscarinic receptors man M1, M2, M3and M4.

Samples on binding are given in table. 1.

After incubation the samples were subjected to rapid filtration under vacuum through glass fiber filters GF/B (Whatman) and washed with ice-cold buffer using pandilovski harvester cells. Bound radioactivity was determined by liquid scintillation counter (LS 6000, Beckman) using a liquid scintillation mixture (formula 99, DuPont NEN).

The scheme of experiments

Compounds were tested at each receptor 10 concentrations repeat for competitive curves. In each experiment, the reference compound for the studied receptor simultaneously tested at 8 concentrations repeat for competitive curve for the evaluation of this experiment.

Analysis and expression of results

Specific binding of radioligand at each receptor was determined as the difference regimechange ligand. The values of the IC50(concentration required to inhibit 50% of specific binding) were determined by nonlinear regression analysis of the competition curves. These parameters were obtained by matching the empirical curve using SigmaplotTM. IC50for R - and S-OXY shown in table. 2.

These results indicate that S-OXY has a lower affinity for subtypes of muscarinic receptors in comparison with R-OXY.

The binding of (R)-oxybutynin and (S)-oxibutinina with calcium channels

Materials and methods

Samples on linking set using methods that are listed in the table. 3.

Conditions of the experiments are given in table. 4.

After incubation the samples were subjected to rapid filtration under vacuum through glass fiber filters GF/B (Whatman) and washed with ice-cold buffer using pandilovski harvester cells. Bound radioactivity was determined by liquid scintillation counter (LS 6000, Beckman) using a liquid scintillation mixture (formula 99, DuPont NEN).

The scheme of experiments

Compounds were tested at each receptor at concentrations of 10-5M repeat. In every experience the m to obtain competitive curve for the evaluation of this experiment.

Analysis and expression of results

Specific binding of radioligand at each receptor was determined as the difference between total binding and nonspecific binding determined in the presence of excess unlabeled ligand. Average values, expressed as percent inhibition of specific binding, are presented in table. 5. IC50(concentration required to inhibit 50% of specific binding) were determined by nonlinear regression analysis of the relevant competitive curves. These parameters were obtained by matching the empirical curve using SigmaplotTM.

These results indicate that S-OXY has an activity of blocking the penetration of calcium, similar to the R-OXY.

Enantiomers desethyloxybutynin

The main metabolite of racemic oxybutynin is RS desethyloxybutynin (DEO). R and S enantiomers DEO not documented and antispasmodic activity and the activity of blocking the penetration of calcium individual enantiomers, R - and S - DEO was to conduct our research unknown. We synthesized these enantiomers and studied their antimuskarinovoe act occurs, antispasmodic, aktivnosti, each enantiomer metabolite retains the relative pharmacological profile "parent" oxibutinina enantiomer.

Binding on subtypes of muscarinic receptor

Inhibition (%) of specific binding of radio-due to three concentrations of each compound (R-, S - and RS-DEO) was tested on cloned subtypes of muscarinic receptors person (M1-M4), as described previously for the enantiomers of oxybutynin. In table. 6 and 7 shows the inhibition (%) at each subtype. In addition, determine the values of the IC50for receptor subtypes man Ml and M2; they are presented in table 6.

These results indicate that S-DEO has less affinity for subtypes of muscarinic receptors than R - or racemic DEO.

Binding to calcium channels

Inhibition (%) of specific binding of radio-caused by each compound (R-, S - and RS-DEO), experienced in areas of diltiazem and verapamil calcium channel type L. the Results are presented in table. 8.

The results indicate that S-DEO has an activity of blocking the penetration of calcium, such activity R - and racemic DE/BR> The influence of R-, S - and RS-oxybutynin (OXY), and R-, S - and RS-DEO studied on the model of functioning of the urinary bladder in vitro. As described further isolated strips of smooth muscles of the urinary bladder of the Guinea pigs were placed in a tissue bath and cause them to reduce or through muscarinic agonist carbachol, or by high concentrations of exogenous potassium.

Materials and methods

Strips of the bladder. The experiments were conducted using methods similar to those described Kachur and others 1988, and Noronha-BLOB and Kachur, 1991. Strips of fabric (length of approximately 10 mm and a width of 1.5 mm) was removed from the body of the bladder of the Guinea pigs (males) (line Hartley, weighing 400-600 g) (Elm Hill Breeding Laboratories, Chelmsford, MA). Tissue suspended in oxygeneration buffer of the following composition, mm: NaCl, 133; KS1 4,7; CaCl22,5; MgS40,6; NaH2PO41,3; NaHCO316.3 and glucose 7,7, at a temperature of 37.5oC. Reduction was recorded using isometric transducers (Model FT-10) and ink polygraph (Model 7) (Astro-Med, Inc., Grass Instrument Div. , West Warwick, RI). For all tissues to maintain the residual voltage of 0.5 g

In each experiment one of the bladder was cut to seven stripes. They who before continuing the experiment.

Carbachol-induced contraction. In one series of experiments focuses on the anticholinergic action of oxibutinina. In these experiments to assess the viability of each tissue and for use as a reference framework for the reduction of each strip of fabric first register in response to exposure of the tissue environment in which NaC1 was replaced with KCl to obtain the concentration of KCl in the medium level 137,7 mm. After that went back to a standard environment, then the impact of gradually increasing concentrations of carbachol separate effects of each concentration only after the registration of the maximum response. Then, leaving one strip of raw and/or one strip exposed to 17 mm ethanol as control tissue (s), all other strips were subjected for one hour to effect a single concentration of antagonist. Ethanol controls used in the case when due to poor solubility, it was necessary to prepare the uterine solutions experimental substances in ethanol, resulting in tissue baths were influenced by the effective concentration of 17 mm ethanol. In the end, was re-made for the data reduction. Attention in the second series of experiments focused on the spasmolytic action of the investigated substances. Reductions were recorded in response to successively increasing the concentration of potassium in the environment.

Analysis of the data. To determine reduced if the antagonists of the maximum response to the action of agonists, the maximum voltage developed by each strip during the second series of definitions, expressed in percentage of the maximum stress developed during the first determination of exposure concentrations. After that, the obtained data for each antagonist were analyzed for differences associated with the treatment, by means of variance analysis. Since each strip of the bladder underwent only one concentration, to assess RA2 and slope of the regression line of Silica used a modified version of the methodology Arunachala and Schild (1959). First, for each strip on the basis of the second data set in ascending concentrations were determined concentration of agonist causing premaxillary reaction (EC50). The EU was determined by fitting the curves of the linear regression to the logarithm of the concentration of drugs and reactions that groups Ecient concentration" (CR) as the ratio of EU processed fabric to the EU raw fabric. For each experiment, in which two or more strips were exposed to the same chemical, but in different concentrations, were drawn graph of the relationship between the logarithm of this ratio minus one (i.e., log(CR-l)) and the logarithm of the concentration of antagonist, the impact of which was subjected to strip, to obtain the "graphs shilda". To determine RA2 and slope of the regression curve used regression analysis, relating log(CR-l) with the logarithm of the concentration of antagonist. Finally, experiments were grouped according to chemical substances and calculated the average mean-square error RA2 and tilt. Using standard methods for slope was determined by the 95% confidence level (CL) on the basis of its mean square error. For experiments in which the effects of the chemical were subjected to only one strip, pKD was calculated as the concentration of antagonist)/(CR-1), then the negative logarithm of the KD were combined with the values of RA2 for a larger set of values RA2.

Results

Effect of racemic oxybutynin and DEO, and their respective enantiomers on carbachol-induced reduction are summarized in the following percentage error) and slope (average mean-square error).

These results show that as S-OXY, and S-DEO are less effective antagonists of muscarinic receptors in the bladder compared with R - and racemic OXY, as well as R - and racemic DEO.

Effect of racemic oxybutynin and its enantiomers on potassium-induced contraction are summarized in the following table. 10. (The values are the magnitude of the reduction caused by 137,7 mm K+ after 60 min the effect of the compound divided by the magnitude of the reduction induced by prior exposure to drugs).

These results indicate that oxybutynin and its enantiomers, and also desethyloxybutynin and its enantiomers are equally effective antispasmodics smooth muscle of the bladder.

Conclusions

It is well known that the normal emptying of the bladder is mediated by cholinergic mechanisms, while the instability of the bladder observed in patients suffering from urinary incontinence, apparently, associated with neholinergichesky contractions of the bladder. Anderson (Andersson) and others (Neurourol Urodun 5, 579-586 (1986) showed in animals that are resistant to atropine muscle, eject urine, has vysokoshirotnoy to the receptor sites for calcium channel blockers diltiazem and verapamil, described above allows to conclude that (S)-oxybutynin and (S)-desethyloxybutynin have a therapeutic effect on involuntary urination, while (in contrast to R-isomers and racemates) they have very little influence on the mechanism of normal emptying of the bladder. Both compounds also demonstrate significant weak anticholinergic side effects compared with the corresponding R-isomer and the racemate. Special attention deserves no side effects on the cardiovascular system, which is a consequence of anticholinergic actions of racemic oxybutynin. We conclude that (S)-oxybutynin and (S)-desethyloxybutynin are an effective medication for the treatment of urinary incontinence in people with significantly reduced side effects in comparison with the racemate or pure R-enantiomers.

Methyl (R) - cyclohexyl-hydroxyindolacetic (IV)

To a mixture of (R)--cyclohexyl--hydroxypentadecanoic acid (III) (12.2 g, to 52.1 mmol) and K2CO3(10.8 g, 78.2 mmol) in 100 ml of acetone was bury at 0oC (ice bath) methyl iodide (Mi) (13,0 ml, 208 mmol). After adding the Mixture was filtered through a layer of celite and twice washed with acetone. The filtrate was concentrated to obtain a white suspension, which was diluted with water and extracted with heptane. The combined extracts were washed with water, brine, dried and concentrated to obtain the product (R)-IV (11.9 g, yield 92%) as a solid white color.

Methyl (S) - cyclohexyl-hydroxyindolacetic (IV).

Executing the above procedure from (S)-III (10.6 g, 45,3 mmol) was obtained (S)-IV (11.2 g, yield 100%) as a solid white color.

4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-butynyl(R)--cyclohexyl--hydroxyindolacetic (VI).

To a solution of (R)-IV (11.9 g, while 47.7 mmol) and 4-[N-ethyl-(4-methoxyphenyl)methylamino] -2-buten-1-ol (V) (of 9.30 g, and 39.9 mmol) in 120 ml of toluene was added NaOMe (0,222 g, 4,11 mmol). The reaction mixture was stirred with heating in a flask under reflux for 5 hours and with the help of Dean-stark took a total of 6 ml of solvent. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, brine, dried and concentrated. The residue was chromatographically on silica gel (elution 1, 2.5 and 5% Meon and CH2Cl2) to obtain the product (R)-IV (14.1 g, yield 79%) as oil.

4-[N-ethyl-(4-methoxyphenyl)methyl) - Rev.)-IV (4,24 g, yield 58%) and V (4,24 g, 18.2 mmol) was obtained (S)-VI (4,24 g, yield 58%) as oil.

Racemic 4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-butynyl(S)--cyclohexyl--hydroxyindolacetic.

Executing the above procedure, from racemic IV (2,98 g, 12,0 mmol) and V (2,48 g, 10.6 mmol) obtained racemic precursor DEO (2,05 g, yield 43%) as oil.

4-(ethylamino)-2-butynyl(R)--cyclohexyl--hydroxyindolacetic hydrochloric salt (VII) is HCl.

A solution of (R)-VI (14.0 g, and 31.2 mmol) and chloracidobacterium (4,0 ml, or 37.4 mmol) in 1,2-dichloroethane was stirred with heating in a flask under reflux for 1 hour. After cooling, the reaction mixture was concentrated and to the residue was added 200 ml of Meon. The reaction mixture was stirred with heating in a flask under reflux for 20 min and cooled to room temperature. The mixture was concentrated and the residue was chromatographically on silica gel (elution with 1% and then 50% of the Meon in CH2CL2then was mixed with ether to obtain the product (R)-(VII)-HC1 (8,93 g, yield 87%) as a solid brownish-yellow color. Solid brown-yellow color was subjected to further purification by recrystallization from EtOH/Et2O and after the receipt of (R)-DEO-HC1 (6,44 g) in the form of solid substances not quite white.

4-(ethylamino)-2-butynyl(S) - cyclohexyl-hydroxyindolacetic chloride-hydrogen salt (VII) is HCl.

Executing the above procedure from (S)-VI (11.4 g, and 25.4 mmol) was obtained (S)-DEO-HCl (5,27 g, yield 57%) as a solid substance not quite white.

Racemic 4-(ethylamino)-2-butynyl--cyclohexyl--hydroxyindolacetic hydrochloric salt.

Executing the above procedure from (a) predecessor (2.28 g, 5.08 mmol) received ()-DEO-HC1 (0,63 g) in the form of solid substances not quite white.

S-oxybutynin can be cooked in the same way by replacing 4-(diethylamino)-2-butyl-1-ol on the protected intermediate V.

4-[N-ethyl-(4-methoxyphenyl)methylamino] -2-buten-1-ol (V) used as an intermediate substance that is synthesized in the following way:

N-ethyl-4-methoxybenzylideneamino:

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 nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 min, then was cooled to 0oUsing an ice bath. Portions were added NaBH(OAc) (36,9 g, 174 mmol) and the reaction mixture by perevorot (10 g NaOH in 100 ml 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 chromatographically on silica gel (elution with 5% Meon in CH2Cl2then 50% of the Meon in CH2Cl2containing 4% EtN) to obtain the product (11.2 g, yield 59%) as oil.

4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-buten-1-ol (V):

A mixture of N-ethyl-4-methoxybenzylamine (13.3 g, of 80.6 mmol), paraformaldehyde (3,63 g), propargilovyh alcohol (6,33 g, 113 mmol) and CuCl (0,311 g) in 350 ml of 1,4-dioxane was stirred under heating in a flask under reflux for 30 minutes, the Reaction mixture was cooled to room temperature and concentrated. The residue was diluted with 200 ml of 50% NH4OH and was extracted with EtOAc. The combined extracts were washed with water, brine, dried and concentrated. The residue was chromatographically on silica gel (elution with 2.5% Meon in CH2Cl2then 5% of the Meon in CH2Cl2) to obtain the product V (15,1 g, yield 81%) as oil.

1. A method of treating urinary incontinence prevention related probability of occurrence of negative effects, which includes the introduction of a person in need of such treatment, a therapeutically effective alicemimi salt, containing at least 90% (wt. ) (S)-oxybutynin or (S)-desethyloxybutynin and 10% (wt. ) or less (R)-oxybutynin or (R)-desethyloxybutynin.

2. The method according to p. 1, which includes the introduction of a person in need of such treatment, a therapeutically effective amount of (S)-oxybutynin or its pharmaceutically acceptable salt, substantially free of the corresponding R enantiomer.

3. The method according to p. 1, which includes the introduction of a person in need of such treatment, a therapeutically effective amount of (S)-desethyloxybutynin or its pharmaceutically acceptable salt, substantially free of the corresponding R enantiomer.

4. The method according to any of paragraphs. 1-3, in which the corresponding compound is administered by inhalation or parenterally, transdermally, rectally or by mouth.

5. The method according to p. 4, in which the corresponding compound is administered orally.

6. The method according to p. 4, in which the corresponding compound is administered transdermally.

7. The active ingredient of medicaments for the treatment of urinary incontinence, representing a compound selected from the group comprising (S)-oxybutynin, (S)-desethyloxybutynin and 10% (wt. ) or less (R)-oxybutynin or (R)-desethyloxybutynin.

8. The active ingredient under item 7, characterized in that the said compound contains (S)-oxybutynin or its pharmaceutically acceptable salt.

9. The active ingredient under item 7, characterized in that the said compound contains (S)-desethyloxybutynin or its pharmaceutically acceptable salt.

10. The active ingredient according to any one of paragraphs. 7-9 for the drug, administered through inhalation or injected parenterally, transdermally, rectally or orally.

11. The active ingredient according to p. 10 for oral medication.

12. The active ingredient according to p. 10 for percutaneous drug.

13. Pharmaceutical dosage form for the treatment of urinary incontinence in the form of tablets or capsules, which comprises a therapeutically effective amount of a compound selected from the group comprising (S)-oxybutynin, (S)-desethyloxybutynin and their pharmaceutically acceptable salts, containing at least 90% (wt. ) (S)-oxybutynin or (S)-desethyloxybutynin and 10% (wt. ) or less (R)-oxybutynin or (R)-desethyloxybutynin, and a pharmaceutically acceptable carrier.

14. Pharmaceutical dosage fromclause from 0.5 to 100 mg of (S)-desethyloxybutynin.

16. Pharmaceutical dosage form for the treatment of urinary incontinence in the form of percutaneous delivery vehicles, which includes a therapeutically effective amount of a compound selected from the group comprising (S)-oxybutynin and (S)-desethyloxybutynin or their pharmaceutically acceptable salts, containing at least 90% (wt. ) (S)-oxybutynin or (S)-desethyloxybutynin and 10% (wt. ) or less (R)-oxybutynin or (R)-desethyloxybutynin, and a pharmaceutically acceptable carrier.

17. The pharmaceutical dosage form according to p. 16, where the specified pharmaceutically acceptable carrier includes power penetration.

18. The method of obtaining (S)-desethyloxybutynin that includes the following steps: (a) the interaction of methyl (S) - cyclohexyl-hydroxyindolacetic 4-[N-ethyl-(4-methoxyphenyl)methylamino] -2-buten-1-I in the presence of an anhydrous base to obtain (S)-4-[N-ethyl-(4-methoxyphenyl)methylamino] -2-butenyl-cyclohexyl-hydroxyindolacetic and (b) interaction of the specified (S)-4-[N-ethyl-(4-methoxyphenyl)methylamino] -2-butenyl-cyclohexyl-hydroxyindolacetic, consistently, with carbochlorination and methanol for the formation of (S)-4-(ethylamino] -2-butenyl--cyclohexyl--hydroxyindolacetic.

20. The method according to p. 19, comprising: (a) interaction of N-ethyl-4-methoxybenzylideneamino 2-propyne-1-I and paraformaldehyde in an inert solvent in the presence of copper chloride to obtain 4-[N-ethyl-(4-methoxyphenyl)methylamino] -2-buten-1-ol; (b) the interaction of methyl (S) - cyclohexyl-hydroxyindolacetic with the specified 4-[N-ethyl-(4-methoxyphenyl)methylamino] -2-buten-1-I in the presence of sodium methoxide in toluene to obtain (S)-4-[N-ethyl-(4-methoxyphenyl)methylamino] -2-butenyl-cyclohexyl-hydroxyindolacetic and (C) interaction of the specified (S)-4-[N-ethyl-(4-methoxyphenyl)methylamino] -2-butenyl-cyclohexyl-hydroxyindolacetic, consistently with chloracidobacterium in dichloromethane, then with methanol to education (S)-4-(ethylamino] -2-butenyl-cyclohexyl-hydroxyindolacetic.

21. The active ingredient of medicaments for the treatment of urinary incontinence, representing a compound selected from the group comprising (S)-oxybutynin, (S)-desethyloxybutynin and their pharmaceutically acceptable salts, containing at least 99% (wt. ) (S)-oxybutynin or (S)-desethyloxybutynin and 1% (wt. ) or less (R)-oxybutynin or (R)-desethyloxybutynin.

22. The active ingredient in p. 21, characterized in that upon ngredient by p. 21, characterized in that the said compound contains (S)-desethyloxybutynin or its pharmaceutically acceptable salt.

24. The active ingredient according to any one of paragraphs. 21-23 for the drug, administered through inhalation or injected parenterally, transdermally, rectally or orally.

25. The active ingredient in p. 24 for oral medication.

26. The active ingredient in p. 24 for percutaneous drug.

27. Pharmaceutical dosage form for the treatment of urinary incontinence in the form of tablets or capsules, which comprises a therapeutically effective amount of a compound selected from the group comprising (S)-oxybutynin, (S)-desethyloxybutynin and their pharmaceutically acceptable salts, where the compound containing at least 99% (wt. ) (S)-oxybutynin or (S)-desethyloxybutynin and 1% (wt. ) or less (R)-oxybutynin or (R)-desethyloxybutynin, and a pharmaceutically acceptable carrier.

28. The pharmaceutical dosage form according to p. 27, comprising from 0.5 to 100 mg of (S)-oxybutynin.

29. The pharmaceutical dosage form according to p. 27, comprising from 0.5 to 100 mg of (S)-desethyloxybutynin.

30. Pharmaceutical dosage form for the treatment of naderian the tion, selected from the group comprising (S)-oxybutynin and (S)-desethyloxybutynin or their pharmaceutically acceptable salts, containing at least 99% (wt. ) (S)-oxybutynin or (S)-desethyloxybutynin and 1% (wt. ) or less (R)-oxybutynin or (R)-desethyloxybutynin, and a pharmaceutically acceptable carrier.

31. The pharmaceutical dosage form according to p. 30, where specified pharmaceutically acceptable carrier includes power penetration.

Priority signs:

31.01.1995 for items that contain the features related to (S)-oxybutynin;

07.06.1995 for items that contain the features related to (S)-desethyloxybutynin.

 

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< / BR>
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< / BR>
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< / BR>
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