JP2002114681A - Therapeutic agent for anorthosis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new therapeutic agent for anorthosis, having an excellent effect on the anorthosis, useful as a medicine especially slightly affecting on the heart. SOLUTION: This therapeutic agent for anorthosis comprises a spirooxathiolane quinuclidine derivative, its acid addition salt, especially 2- methylspiro(1,3-oxathiolane-5,3')quinuclidine hydrochloric acid addition salt as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a therapeutic agent for erectile dysfunction, comprising a spirooxathiolanquinuclidine derivative and an acid addition salt thereof as an active ingredient. The preparation of the present invention has an excellent effect on erectile dysfunction, and is particularly useful as a medicine having little effect on the heart.

[0002]

2. Description of the Related Art Erectile dysfunction refers to a state in which effective erection cannot be obtained during sexual intercourse and sexual intercourse cannot be performed satisfactorily, and is regarded as one of so-called sexual dysfunctions. The penis erection is usually controlled by smooth muscle cells that compress the arteries and prevent blood from flowing too much into the corpus cavernosum, but a chemical that relaxes smooth muscle cells when sexually aroused. Is promoted, and as a result,
The arteries expand and the blood increases, filling the corpus cavernosum with blood. At the same time, swelling of the tissue squeezes the veins, preventing blood outflow and erecting the penis. Erectile dysfunction refers to a condition in which the system does not function for any reason. Erectile dysfunction can be divided into organic, psychogenic, mixed, and others. As a cause, erectile dysfunction tends to increase with age, but this is due to the increase in underlying diseases such as heart disease, diabetes, hypertension, hyperlipidemia, arteriosclerosis, and The use of medications such as antihypertensives, antidepressants, and hypoglycemics that are taken in the treatment can also be a cause. Other factors include smoking, lack of exercise, uneven eating, excessive alcohol consumption,
These include stress, pelvic trauma, and surgery affecting the pelvic plexus. Epidemiological studies in the United States report that 50% of people in their 50s and 70's do not have satisfactory sexual intercourse due to some impairment, such as erectile dysfunction, and 70% in their 70s. In Japan, the number of erectile dysfunction patients is estimated to be about 9 million, which is a major problem.

[0003] Treatment of erectile dysfunction includes non-invasive treatments such as discontinuation of the causative drug, psychotherapy, oral medicine, negative pressure erection, and cavernous injection, prosthesis surgery, and arterial / venous surgery. However, the latter is very rarely applied. Oral medications recently approved as non-invasive treatments are contraindicated in patients taking nitrates such as nitroglycerin because of their effects on the heart, and because sexual activity itself places a strain on the heart. Therefore, it is hard to say that it is desirable. Erectile dysfunction can be easily treated before intercourse,
Desirable are those that show an immediate effect and do not last an erection for a long time of 4 hours or more. In particular, it is necessary that there is no side effect on the heart and the like, but a method satisfying these has not yet been established.

[0004]

In view of the above situation, the present inventors have conducted an intensive search for compounds that have an immediate erectile action and have few side effects on the heart and the like. It has been found that a spirooxathiolanquinuclidine derivative or an acid addition salt thereof, which is known as a therapeutic agent, produces an erectile effect. Accordingly, an object of the present invention is to provide a therapeutic agent for erectile dysfunction, comprising a spirooxathiolanquinuclidine derivative or an acid addition salt thereof as an active ingredient.

[0005]

The present invention relates to a therapeutic agent for erectile dysfunction, comprising a spirooxathiolanquinuclidine derivative and an acid addition salt thereof as an active ingredient. The preparation of the present invention has an excellent effect on erectile dysfunction, and is particularly useful as a medicine having little effect on the heart.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION A spirooxathiolanquinuclidine derivative and an acid addition salt thereof, which are active ingredients of the preparation of the present invention, are represented by the following general formula (I).

[0007]

Embedded image Wherein R ¹ and R ² may be the same or different and are each hydrogen, alkyl, cyclopentyl, cyclohexyl, aryl or diarylmethylol, or alkyl substituted with one or more aryl groups. is there.)

In the present invention, alkyl refers to methyl, ethyl, propyl, isopropyl, butyl, s-butyl and t-butyl.
It means lower alkyl having 1 to 6 carbon atoms such as butyl, amyl and hexyl. Examples of aryl include phenyl, tolyl, xylyl, diphenyl and diphenylmethyl.

The spirooxathiolanquinuclidine derivative and the acid addition salt thereof used in the present invention are disclosed in JP-A-61-280.
It is a known compound disclosed in JP-A-497, which is efficiently absorbed by oral or parenteral administration. In addition, the toxicity is about ₅₀ mg / ₅₀ mg / day by oral administration to mice.
kg is known (JP-A-61-280497). The spirooxathiolanquinuclidine derivatives used in the present invention include the following compounds. (1) 2-methylspiro (1,3-oxathiolane-5,
3 ′) quinuclidine (2) 2-diphenylmethylspiro (1,3-oxathiolane-5,3 ′) quinuclidine (3) 2-methyl-2-phenylspiro (1,3-oxathiolane-5.3 ′) quinuclidine ( 4) cis-2-methylspiro (1,3-oxathiolane-
5, 3 ') Quinuclidine hydrochloride addition salt

These compounds have geometric isomers, enantiomers, diastereomers or racemates. In the present invention, any of these may be used. Acid addition salts include hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, lactic acid, tartaric acid,
There are acid addition salts with inorganic or organic acids such as succinic acid and maleic acid. Among these compounds, it is preferable to use 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine hydrochloride addition salt, particularly preferably a cis form,
Alternatively, it is preferable to use a compound that is a mixture of a cis-isomer and a trans-isomer and contains a large amount of the cis-isomer.
As the spirooxathiolane quinuclidine derivative or an acid addition salt thereof which is the active ingredient of the present invention, 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine hydrochloride, especially a cis-form thereof, may be used. preferable.

The spirooxathiolanquinuclidine derivative of the present invention can be produced according to the method described in JP-A-61-280497. For example, formula (II)
As shown in the above, 3-hydroxy-3-mercaptomethylquinuclidine is reacted with a carbonyl compound represented by the formula R ¹ —CO—R ² (R ¹ and R ² represent the same groups as described above). The compound can be easily produced by isolating the target compound from the reaction mixture. The reaction formula is as follows. As a method for isolating optical isomers or other isomers from the obtained compound, for example,
A method described in JP-A-61-280497 or JP-A-2-22280 can be used.

[0012]

Embedded image

The therapeutic agent for erectile dysfunction of the present invention can be orally or parenterally administered to humans and animals as a safe and excellent drug. When administered for the treatment of a disease, the compound used as an active ingredient of the present invention is used as a main component and is used alone or in combination with a pharmacologically acceptable carrier for pharmaceutical preparations. Or a pharmaceutical composition suitable for rectal administration, such as a capsule,
It is administered in the form of tablets, powder packaging, granules, injections, ointments, creams, aerosols, emulsions, lotions, suppositories and the like. Further, the present invention can be applied in a form of being attached to a contraceptive device such as a condom.

[0014] Formulations suitable for oral use include, for example, solid compositions such as capsules, tablets, powders, granules, troches and liquid compositions such as syrups and suspensions. In the present invention, oral preparations such as capsules, tablets, granules and the like are produced according to a conventional method using, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, inorganic salts and the like. In this type of preparation, a binder, a disintegrating agent, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a flavor, and the like can be used as appropriate in addition to the excipients. As a binder,
Examples include starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol and the like. Examples of the disintegrant include starch, hydroxypropyl starch, sodium carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, and low-substituted hydroxypropylcellulose. Examples of the surfactant include sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80, and the like. Examples of the lubricant include talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol and the like. Further, as the fluidity promoter, light anhydrous silicic acid, dried aluminum hydroxide gel,
Examples include synthetic aluminum silicate and magnesium silicate.

Further, when administered orally, a suspension,
It can also be administered as an emulsion, syrup or elixir, and these various dosage forms may contain flavoring agents, coloring agents and the like. These dosage forms preferably contain 1 to 95% by weight of the active ingredient compound.

Formulations suitable for parenteral administration include, for example, injections. This parenteral preparation is manufactured according to a conventional method, and generally uses distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. as a diluent. be able to. Further, if necessary, a bactericide, a preservative, and a stabilizer may be added. In addition, this parenteral preparation is
After filling into a vial or the like, the mixture is frozen, water is removed by a usual freeze-drying technique, and a liquid preparation can be prepared again from the freeze-dried product immediately before use. Further, if necessary, an isotonic agent, a stabilizer, a preservative, a soothing agent and the like may be appropriately added. As an injection, for example, it may be dissolved in normal injection water or the like in the form of a salt, or in a form of an injectable form such as a suspension or emulsion in a mixture of medically acceptable oils or liquids. Can be. In this case, an antibacterial agent such as benzyl alcohol, an antioxidant such as ascorbic acid, a buffer, a reagent for adjusting osmotic pressure, a solubilizing agent and the like may be contained. This injection contains 0.1 to 5% by weight of the active ingredient compound.
It is desirable to include it, and it can be used in the form of intravenous, arterial, intramuscular or subcutaneous injection.

Formulations suitable for topical or rectal administration include, for example, ointments, creams, aerosols, emulsions, lotions, suppositories and the like. The ointment is prepared by a conventional method by adding a commonly used base and the like. Furthermore, Azone
(Generic name Laurocapram) and the like. In these dosage forms, it is desirable to contain 0.5 to 30% by weight of the active ingredient compound. Suppositories may contain commonly used carriers for preparations, for example, polyethylene glycol, lanolin, cocoa oil, fatty acid triglyceride, and the like, and desirably contain 1 to 95% by weight of the active ingredient compound.

In addition, these pharmaceutical compositions are released by a known method so that the active ingredient is released rapidly, slowly or slowly after administration to a patient. It can be formulated as follows.

The dose of the preparation of the present invention is appropriately set depending on the form of the preparation, the method of administration, the purpose of use, and the age, weight, and condition of the patient to which the preparation is applied, and is not constant. The amount of the active ingredient contained in the above is suitably in the range of about 10 mg to about 1 g per adult. The amount of the active ingredient in the preparation is appropriately set according to the dose.

[0020]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which are merely illustrative and do not limit the present invention.

[0021]

Example 1 Erectile-promoting action of the drug of the present invention Male Wistar rats (9 to 12 weeks old) (Charles River Japan) were administered with sodium pentobarbital (20 mg / kg intraperitoneal administration + 40 mg / kg subcutaneous administration) ( (Dynabot Co., Ltd.) and held in a dorsal position. Rectal temperature was maintained at 38 ° C. during the measurement. The penis was exposed from the foreskin, and a 25G needle (Termo) connected to a polyethylene tube (Natsume Seisakusho) was inserted into the right or left cavernous body. The other end of the polyethylene tube was connected to a pressure transducer (Statham), and the change in pressure was recorded using a polygraph (Nihon Kohden). Via a polyethylene tube indwelled in the femoral vein, cis-2-methylspiro (1,3-oxathiolan-5,5) prepared according to the method of JP-A-61-280497.
3 ') Intravenous administration of quinuclidine hydrochloride addition salt at 10 mg / kg,
Changes in penile pressure were observed. The results are shown in FIG. As a result, cis-2-methylspiro (1,3-oxathiolane-
5, 3 ') After administration of quinuclidine hydrochloride addition salt, the pressure in the penis increased to about 2.2 times (base pressure 13 mmHg, maximum pressure 28 mmHg) before administration, and it was confirmed that the pressure continued to be higher than before administration for about 15 minutes thereafter Was done. Therefore, it was revealed that the compound as the active ingredient of the present invention has an erection-promoting action.

[0022]

Example 2 Erection-promoting action of the drug of the present invention (for electrical stimulation)
According to) Wistar male rats (9-12 weeks old) (Charles River Japan) were anesthetized with sodium pentobarbital (20 mg / kg ip + 40 mg / kg subcutaneous) (Dynabot) Was fixed to. Rectal temperature was maintained at 38 ° C. during the measurement. An incision was made in the midline of the abdomen, and the bladder and seminal vesicles were set aside to expose the cavernous nerve. The nerve was separated from the surrounding connective tissue and mounted on a platinum bipolar electrode (Unique Medical).
The penis was exposed from the foreskin, and a 25G needle (Termo) connected to a polyethylene tube (Natsume Seisakusho) was inserted into the right or left cavernous body. The other end of the polyethylene tube was connected to a pressure transducer (Statham), and the change in pressure was recorded using a polygraph (Nihon Kohden).
Using an electric stimulator, a square wave (voltage
The cavernous nerve was stimulated under the conditions of 6, 8, or 10 V), 20 Hz, and 20 seconds, and the change in penile pressure was measured. Thereafter, the cis-cell was passed through a polyethylene tube placed in the femoral vein.
Intravenous administration of 10 mg / kg of 2-methylspiro (1,3-oxathiolane-5,3 ') quinuclidine hydrochloride addition salt, approximately 4 minutes later, the same stimulation as before administration was given, and changes in penile pressure were observed. did. 10 V before administration of cis-2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine hydrochloride addition salt
Table 1 shows the percentage of response at each stimulation voltage before and after administration, where the change in penile pressure (difference between baseline and maximum response) when stimulating was 100%. As a result, after administration of cis-2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine hydrochloride addition salt, an increase in internal pressure of up to about twice as much as before administration of the same stimulation intensity was observed. Therefore, it was revealed that the compound as the active ingredient of the present invention promotes the erectile reaction.

[0023]

[Table 1]

[0024]

Example 3 Effects on Blood Pressure and Heart Rate Under anesthesia, 5 to 6 Wistar male rats (9 to 12 weeks old, Charles River Japan) were cis-2
-30 mg / kg of methyl spiro (1,3-oxathiolane-5,3 ') quinuclidine hydrochloride or distilled water as a solvent was orally administered, and the blood pressure was measured via a pressure transducer (Statham) placed in the abdominal aorta. And a strain pressure amplifier (Nihon Kohden). The heart rate was measured by a signal derived from a blood pressure pulse wave using an instantaneous heart rate unit (Nihon Kohden). The results are shown in FIGS. As a result, no significant difference was observed in the mean blood pressure and the heart rate between the cis-2-methylspiro (1,3-oxathiolane-5,3 ') quinuclidine hydrochloride addition salt 30 mg / kg administration group and the solvent administration group. Therefore, it was clarified that the compound as the active ingredient of the present invention did not affect blood pressure or heart rate.

[0025]

Example 4 Preparation of Pharmaceutical Preparation Production Example 1: Capsules A capsule having the following composition was prepared by a conventional method. Cis-2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine hydrochloride addition salt 10 g low-substituted hydroxypropylcellulose (L-HPC) 20 g crosslinked sodium carboxymethylcellulose (crosslinked CMC-Na) 5 g magnesium stearate 2 g lactose 100 g No. 3 capsule was filled with 200 mg of each of the following compositions, and cis-
500 capsules containing 20 mg of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine hydrochloride addition salt in one capsule were obtained.

Production Example 2: Tablet A tablet having the following composition was produced by a conventional method. Cis-2-methylspiro (1,3-oxathiolane-5,3 ') quinuclidine hydrochloride addition salt 20 g low-substituted hydroxypropylcellulose (L-HPC) 10 g crystalline cellulose 15 g hydroxypropylmethylcellulose (HPMC) 10 g magnesium stearate 1 g lactose 100g Prepared so that the total weight per tablet is 150mg.
660 tablets each containing 30 mg of 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine hydrochloride addition salt were obtained.

Production Example 3: Ointment An ointment containing 20% of cis-2-methylspiro (1,3-oxathiolane-5,3 ') quinuclidine hydrochloride having the following composition was produced by a conventional method. Cis-2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine hydrochloride addition salt 2 g plasticy base hydrophilic 10 g

Production Example 4: Injection A 0.5% injection having the following composition was produced by a conventional method. Cis-2-methylspiro (1,3-oxathiolane-5,3 ') quinuclidine hydrochloride addition salt 1 g glucose 10 g distilled water for injection 200 ml

[0029]

Industrial Applicability According to the present invention, there is provided a therapeutic agent for erectile dysfunction comprising a spirooxathiolanquinuclidine derivative and an acid addition salt thereof as an active ingredient. The preparation of the present invention has an excellent effect on erectile dysfunction, and is particularly useful as a medicine having no effect on the heart.

[Brief description of the drawings]

FIG. 1 shows the erection-promoting effect of the preparation of the present invention in Example 1.

FIG. 2 shows mean blood pressure of rats after administration of the preparation of the present invention and a solvent in Example 3.

[Explanation of symbols]

 ：: Solvent administration group ●: Formulation administration group of the present invention

FIG. 3 shows the heart rate of rats after administration of the preparation of the present invention and a solvent in Example 3.

[Explanation of symbols]

 ：: Solvent administration group ●: Formulation administration group of the present invention

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C071 AA04 BB02 CC01 CC11 CC21 EE22 FF06 GG01 LL01 4C086 AA01 AA02 CB31 GA13 GA16 MA01 MA04 NA06 NA14 ZA81 ZC01

Claims (3)

[Claims] 1. A therapeutic agent for erectile dysfunction, comprising a spirooxathiolanquinuclidine derivative represented by the following general formula (I) or an acid addition salt thereof as an active ingredient. Embedded image Wherein R ¹ and R ² may be the same or different and are each hydrogen, alkyl, cyclopentyl, cyclohexyl, aryl or diarylmethylol, or alkyl substituted with one or more aryl groups. is there.) 2. The spirooxathiolane quinuclidine derivative acid addition salt is 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine hydrochloride addition salt.
The therapeutic agent as described above. 3. The 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine hydrochloride addition salt is a cis form.
The therapeutic agent according to claim 2.