JPH0234924B2 - IMIDAZOORUJUDOTAIOFUKUMUHININNYUYONASOSEIBUTSU - Google Patents

Description

[Detailed description of the invention]

When inserted into the vaginal canal in appropriate compositions, a variety of chemicals have been shown to reduce the intrinsic motility of mammalian sperm cells (i.e., sperm immobilization) or to be cytotoxic (i.e., spermicidal). It has long been known that both inhibit mammalian sperm cells and reduce the fertilization potential of said mammalian sperm cells. Generally, the most widely known chemicals for such purposes are alkylphenoxypolyethoxyethanols, quaternary ammonium compounds, and organomercury compounds. Recently, a series of 1,2-benziisothiazole derivatives with spermicidal activity have been disclosed in US Pat. No. 4,093,730. However, only one such spermicide, poly(ethylene glycol) p-nonylphenyl ether {INN name: nonoxynol},
Commonly used in the United States. but,
This material has a high failure rate and is generally considered substandard. Furthermore, such sperm immobilizing and spermicidal compounds for intravaginal administration have little, if any, effect on sperm cells when administered systemically to male mammals. The present invention relates to a group of spermicides that appear to be more potent than commonly used spermicides, and which have a more effective effect when administered intravaginally as well as when administered to sperm-producing males. The present invention relates to the use of compounds selected from the group of 1-substituted imidazole derivatives, which have antifungal, antibacterial and antigenic properties, for the preparation of spermicide and pregnancy regulator compounds. It has been previously reported to have insecticidal effects.
See, eg, US Pat. No. 4,123,542. It is now surprisingly possible that compounds of this class act by reducing the motility of mammalian sperm, or by incapacitating their normal cellular functions, or by killing them (spermicidal activity). ) were found to inhibit mammalian spermatozoa and prevent their ability to fertilize. The compounds are generally non-toxic to the recipient. The present invention relates in one aspect to the use of the 1-substituted imidazoles contained therein as sperm immobilizing agents or spermicides. In another aspect, the present invention relates to the preparation and formulation of compositions useful for contraception containing 1-substituted imidazoles or salts thereof suitable for intravaginal administration. Furthermore, from a third aspect, the present invention relates to the manufacture and formulation of compositions useful for contraception containing 1-substituted imidazoles or salts thereof suitable for oral administration, particularly to male mammals. . Furthermore, from a fourth aspect, the present invention provides parenteral administration,
The present invention relates to the preparation and formulation of compositions useful for contraception containing 1-substituted imidazoles or salts thereof suitable for parenteral administration, particularly to male mammals. From a fifth aspect, the invention relates to a method of contraception using compounds and/or compositions as described in the invention. In all aspects above, the 1-substituted imidazoles are free bases or pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable salts are salts of the subject bases that retain the pharmaceutical properties of the free base, and further, the salts are preferably formed by other than biological methods, such as with acids such as .
i.e. inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acids; or acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, malic, maleic, fumaric, tartaric acids. , citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-
Organic acids such as toluenesulfonic acid, salicylic acid, etc. The many known 1-imidazole compounds described above as exhibiting antifungal, antibacterial and/or antiprotozoal effects have significant sperm immobilizing and spermicidal effects in both male and female mammals. It was found that the effect was shown to be effective. The 1-substituted imidazoles forming part of the present invention include compounds represented by the following general formulas (and pharmaceutically acceptable acid addition salts thereof) and/or the compounds disclosed in the following patent specifications: That is, the following formula () or a pharmaceutically acceptable acid addition salt thereof. In the above formula (), R ¹
and R ² are each independently an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, unsubstituted or substituted phenyl (substituted phenyl includes a halogen atom and 1 to 4 carbon atoms) a lower alkyl group having
1 selected from lower alkoxy groups having 1 to 4 carbon atoms, and trifluoromethyl groups;
or unsubstituted or substituted phenyl (substituted phenyl is a halogen atom and a lower alkyl group having 1 to 4 carbon atoms, 1 to 4 carbon atoms); an alkyl group having 1 to 4 carbon atoms substituted with phenyl substituted with 1 to 3 groups selected from R ³ and trifluoromethyl; is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, X is an oxygen atom or a sulfur atom, and n is an integer from 1 to 4. A preferred embodiment of the present invention has the above formula {wherein R ¹
and R ² are each independently an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 4 carbon atoms, or an unsubstituted or substituted phenyl group (substituted phenyl is an alkyl group having 1 to 4 carbon atoms). or by 2 lower alkyl or 1
or phenyl lower alkyl (C _1-4 ) (which phenyl may be substituted by 1 or 2 lower alkyl having 1 to 4 carbon atoms); optionally substituted with one or two halo substituents), R ³ is a hydrogen atom, and n is 1 or 2}
and pharmaceutically acceptable salts of the compounds. Further preferred embodiments are compounds exhibiting one of the following combinations of substituents, and combinations thereof ((a)
consisting of a pharmaceutically acceptable acid addition salt of the compound in (d)): (a) R ¹ is alkyl or cycloalkyl;
R ² is alkyl, substituted or unsubstituted phenyl,
or substituted or unsubstituted benzyl, R ³
is a hydrogen atom and n is 1 or 2; (b) R ¹ is substituted or unsubstituted phenyl;
R ² is substituted or unsubstituted benzyl,
R ³ is a hydrogen atom, n is 1; (c) R ¹ is substituted or unsubstituted funinethyl, R ²
is substituted or unsubstituted phenyl, R ³ is a hydrogen atom, and n is 1; and (d) R ¹ is substituted or unsubstituted benzyl, and R ² is substituted or unsubstituted phenyl or benzyl. ,
R ³ is a hydrogen atom, and n is 2. A particularly preferred group of compounds in this set are those in which R ¹ is alkyl having 3 to 7 carbon atoms, more preferably 4 to 6 carbon atoms, most preferably 5 carbon atoms, and R ² is substituted or unsubstituted. Substituted phenyl, preferably phenyl substituted with a halogen atom or lower alkyl, R ³
is a hydrogen atom and n is 2, and pharmaceutically acceptable acid addition salts thereof. A second particularly preferred group of compounds is such that R ¹ is alkyl having 4 to 8 carbon atoms, R ² is substituted or unsubstituted benzyl, R ³ is hydrogen and n is 1. and their pharmaceutically acceptable acid addition salts. Particularly preferred embodiments of the present invention include 1-[3-(n-octylthio-n-octyl]imidazole oxalate, 1-[3-(4-chlorophenylthio)-n-
Octyl]imidazole oxalate, 1-[2-(4-chlorobenzyloxy)-2
-(2,4-dichlorophenyl)ethyl]imidazole nitrate, 1-[3-(4-chlorobenzyloxy)-n
-Octyl]imidazole oxalate, 1-[2-(4-chlorophenylthio)-4-
(4-chlorophenyl)-n-butyl]imidazole nitrate, 1-[2-(2,,4-dichlorobenzyloxy)-n-octyl]imidazole oxalate, 1-[2-(4-chlorobenzylthio) -n-
Octyl]imidazole nitrate, 1-[3-(2,4-dichlorophenylthio)
-n-heptyl]imidazole oxalate, 1-(2-ethylthio-n-tetradecyl)imidazole oxalate, 1-[3-(4-tert-butylphenylthio)
-n-octyl]imidazole oxalate, and 1-(3-n-decyloxy-3-cyclohexyl-n-propyl)imidazole oxalate, and pharmaceutically acceptable acid additions thereof. It's salt. The preparation of the above compounds is described in US Pat. No. 3,717,655;
No. 3839574, No. 3658813, No. 4055652, No.
No. 4078071, No. 4045568, No. 4059705 and No.
It is stated in No. 4123542. Representative compounds within this class include sulconazole, 1-[2-(4-chlorobenzylthio)-2-(2,4-dichlorophenyl)ethyl]imidazole, miconazole, , that is, 1-[2-(2,4-
dichlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl]imidazole, econazole, i.e. 1-[2-(4-
chlorobenzyloxy)-2-(2,4-dichlorophenyl)-ethyl]imidazole, orconazole, i.e. 1-[2-
(2,6-dichlorobenzyloxy))-2-(4
-chlorophenyl)ethyl]imidazole, and 1-[2-allyloxy-2-(2,4-dichlorophenyl)-ethyl]imidazole. For the use of the compounds described above as spermicides in the preparation and formulation of contraceptive compositions, excipients and techniques well known to those skilled in the art are employed. Suitable pharmaceutical carriers and their use in formulations include E.
“Remington’S Pharmaceutical” by W. Martin
Science” (15th edition (1975); Matsuku Publishing, New York). Such a composition is
In all cases, the formulation contains an effective amount of active compound together with the appropriate amount of carrier to prepare a suitable dosage form for the desired administration to the recipient. The present invention relates to the formulation and preparation of compositions containing the above-mentioned compounds suitable for intravaginal administration, in a variety of forms, such as vaginal suppositories, vaginal tablets, vaginal creams, vaginal sprays - foams, vaginally soluble watsufules, vaginal Slow release agents for the active ingredient, such as sponges and the like, as well as implants, are typical in the art. Each of these compositions contains an effective amount of a pharmaceutically acceptable non-toxic carrier or excipient commonly used for such formulations. Typical excipients for solid formulations are, for example, starch, glucose, lactose, mannitrate, magnesium stearate, talc, cellulose, magnesium carbonate, sodium bicarbonate, citric acid, and the like. For semisolid formulations such as suppositories, excipients such as polyalkylene glycols, modified vegetable oils or soft gelatin capsules containing, for example, vegetable oils, mineral oils or polyalkylene glycols are used. For liquid or liquid-type formulations such as creams, jellies, and foams, liquid blowing agents of the water, saline, aqueous dextrose, glycerol, higher alcohols, mineral oils, lanolin, gums of vegetable origin, polyalkylene glycols, and Freon types may be used. Can be used. The pharmaceutical composition contains 0.1 to 10.0% by weight,
It preferably contains 0.2 to 2.0% by weight of active ingredient, and optionally other active ingredients. A single dose consists of an amount of said composition resulting in a dose ranging from 1 mg to 100 mg for a single intravaginal administration for an average adult, or from 0.014 mg to 1.4 mg of active ingredient per kg of body weight. . In the present invention, which relates to the preparation and formulation of compositions containing the above-mentioned compounds suitable for oral administration, the final formulation may include tablets, pills, capsules, powders, sustained release agents, solutions, suspensions, etc. Includes suspensions, elixirs, etc. The carrier is petroleum, animal oil,
Choose from a variety of oils, including vegetable oils, synthetic oils (peanut oil, soybean oil, mineral oil, sesame oil, etc.).
Water, saline, aqueous dextrose and glycols are preferred liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, wheat, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, Examples include dry skim milk, glycerol, propylene glycol, water, and ethanol. The composition may contain from about 5% to 95% by weight of active ingredient, so that about 0.1 mg/Kg body weight per day, either in a single dose or divided into several doses. or about 100.0
mg, preferably between 0.1 and 10 mg per kg body weight per day. The precise regimen will necessarily depend on the particular compound used, the characteristics of the recipient, etc. Generally, to ensure complete immobilization of sperm cells, it is advisable to administer the compound to a male mammal daily for at least 24 hours before intercourse, and preferably for 3 to 7 days before intercourse. In the present invention, which relates to the preparation and formulation of compositions containing the above-mentioned compounds suitable for parenteral administration, the compositions may be prepared as solutions or suspensions ready for injection, solutions or suspensions or emulsions ready for injection. It is a suitable dry product. More recent methods of parenteral administration include slow and sustained release of the active ingredient, such as implantable formulations commonly known to those skilled in the art, especially biosoluble or bioreleasable implantable formulations. This method uses a subcutaneous implant. In this way, only one administration is required to supply the active ingredient for an extended period of time, for example one month. This method is described, for example, in U.S. Patent No.
See Nos. 3279996 and 4096239. Typical excipients for solid formulations include, for example, magnesium stearate, starch, lactose,
gelatin, and for liquid formulations, low boiling solvents such as polyalkylene glycols, water, oils of vegetable origin and isopropanol and hydrogenated naphthalenes. The percentage of active ingredient within the composition ranges from about 0.1 to 10% in liquid formulations and from about 50% to 95% in solid compositions suitable for solution or suspension just prior to injection. There is.
Formulations suitable for implantation are in the range of 0.1-10% active ingredient. The preferred content of active ingredient depends on the mode of administration. This is because parenteral administration includes intramuscular, subcutaneous and intravenous routes. In the present invention, which relates to methods of contraception using the compositions and/or compounds described herein, either the female or male sex or both sexes are the receptors for the compositions and/or compounds. A suitable amount of the composition suitable for intravaginal administration is preferably administered once or (preferably) within 12 hours before sexual intercourse.
Applied to females either in repeated doses. For example, such application may be carried out by syringe if the composition is a cream or jelly, by an aerosol device if the composition is in the form of a foam, or by hand or by a suitable applicator if the composition is in the form of a foam or tablet. For male applications, the compositions are administered orally within one week, preferably 24 hours, before sexual intercourse, and are further administered daily in a daily dosage form combined with an appropriate amount of the active ingredient. preferable. Preferred amounts of active ingredient sufficient to prevent fertilization for the method of the invention are set out below. In other methods, subcutaneous implants are used and the compound is delivered continuously to the applicant over a period of weeks or months. The method to be used will, of course, depend on the person to whom it is administered,
This will depend on the particular compound used, the type of composition chosen and the judgment of the prescribing physician. The following examples illustrate the methods and compositions of the invention.
However, it should be understood that this in no way limits the scope of the invention. Example 1 A formulation for intravaginal administration will be described below. The active ingredient used is 1-[3-(4-chlorophenylthio)-n-octyl]imidazole oxalate, although any of the 1-substituted imidazoles mentioned above can be used. a Water-soluble cream ingredients W/W% Active ingredients 1.0 Cetostearyl alcohol 12.0 Polysorbate 60 2.0 Sorbitan monostearate 2.0 Mineral oil 2.0 Propylene glycol 4.0 Benzyl alcohol 1.0 Butylated oxyanisole 0.01 Purified water Appropriate amount 100.0 Active ingredients, All ingredients except water and 10% polysorbate 60 are mixed and further heated to 70-80°C. Separately heat 95% of the required water to 70-80°C.
Combine the remaining polysorbate60 and 10% water to 50~
Melt at 60 ° C and dissolve the active ingredients in them. Next, heated water is added to the heated emulsified ingredients using a homomixer, and after completing the mixing,
The speed is finally increased to perform high speed operation for 1 minute. Remove the homomixer, then continue to mix gently until the mixture solidifies, then cool to room temperature; then add the pre-dissolved active ingredient as described above and continue mixing gently for 20-30 minutes. . Then, using the remaining 5% water,
The vessel containing the premixed active ingredients is washed and the wash water is added in full mix. Continue mixing and add more water if necessary. Approximately 1 gm of cream for each application is administered intravaginally to adults (females) using a suitable syringe. b Vaginal jelly ingredients W/W% Active ingredients 1.00 Gum tragacanth 3.00 Gum arabic 0.53 Glycerin 5.00 Boric acid 3.00 Ricinoleic acid 0.75 Propyl p-oxybenzoic acid 0.05 Appropriate amount of purified water 100.0 Completely mix gum tragacanth and gum arabic with glycerin. , then add ricinoleic acid and active ingredient to the mixture. The p-oxybenzoate and boric acid are dissolved in water (with heating if necessary), then water is added to the above mixture and dissolved with stirring and heating. The mixture gels upon cooling. For each application, approximately 1 g of jelly is administered intravaginally to an adult (female) via a suitable syringe. c Vaginal suppository ingredients W/W% active ingredient 1.0 Polyethylene glycol 400 20.0 Butylated oxyanisole 0.01 Polyethylene glycol 1000 appropriate amount total amount 100.0 Polyethylene glycol solids are mixed, then heated to 70-80°C, and further BHA is added to the mixture. dissolve. Cool to 45° C. and suspend the active ingredient in the mixture by stirring. The suspension is poured into molds large enough to form suppositories of approximately 3 gm each and then cooled. d Boiling Vaginal Tablet Ingredients W/W% Active Ingredients 1.0 Citric Anhydride 35.0 Sodium Bicarbonate 15.0 Polyethylene Glycol 6000 20.0 Lactose Appropriate Total Amount 100.0 The above ingredients are combined and granulated using methanol as a solvent. The granules are then dried and formed into tablets containing 20 mg of active ingredient using a suitable tablet press. e Vaginal spray foam ingredient W/W% Active ingredient 2.0 Emulsion base material 90.0 Propellant 12/114 (40:60) 8.0 Emulsion base material has the following composition (w/w%)
Manufactured according to. Myristic acid 1.33 Stearic acid 5.33 Cecyl alcohol 0.50 Lanolin 0.20 Isopropyl myristate 1.33 Triethanolamine 3.33 Glycerin 4.70 Polyvinyl pyrrolidone 0.34 Purified water 82.93 The components of the emulsion base excluding water are 70 to 80
Mix in a stainless steel container kept at °C. 80% of the water to be used is also heated to 70-80°C and then during heating it is mixed at an appropriate speed using a homomixer. After complete addition, increase the mixing speed for a few minutes. The mixture is then cooled to room temperature and the remaining solution containing the active ingredient dissolved in 20% water is added with continuous mixing. The preparation is loaded into a suitable spray gun, the surface is covered with liquid blowing agent and then sealed. Approximately 0.5 gr of foam is administered intravaginally for each application. f Vaginally soluble Watsuful ingredients W/W% Active ingredient 1.0 Starch 10.0 Water-soluble lanolin Appropriate amount Total amount 100.0 The above ingredients are thoroughly mixed and then pressurized appropriately to form a 0.8 gm Watsuful. Example 2 The following composition is representative of a composition used for oral or parenteral administration to male mammals. The active ingredients described are the same as those of Example 1, but any other active ingredients mentioned above can be used. a Oral Tablet Ingredients Parts by Weight Active Ingredients 200 Magnesium Stearate 3 Starch 30 Lactose 116 Polyvinylpyrrolidone 3 The above ingredients are combined and then granulated using methanol as a solvent. The granules are then dried and formed into tablets containing 200 mg of active ingredient using a suitable tablet press. b. Parenteral preparation for intravenous composition with 100 ml of solution Active ingredients 2.0 g Propylene glycol 20 g Polyethylene glycol 20 g Polysorbate 80 1 g 0.98 saline appropriate volume 100 ml Active ingredient dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80 do. A sufficient amount of 0.98% saline is then added with stirring to obtain 100 ml of the IV solution, which is passed through a 0.2 micron membrane filter and filled into containers under aseptic conditions. c Implant formulation ingredients W/W% active ingredient 2.0 Polyethylene glycol 6000 5.0 Cholesterol Appropriate amount Total amount 100.0 The ingredients are mixed and then compressed into pellets approximately 2 mm (diameter) x 8 mm. Example 3 The following example illustrates the sperm immobilizing and spermicidal effects of the 1-substituted imidazole derivatives of the invention when in direct contact with semen. This example shows the effect on female contraception. Semen is collected from male dogs and then divided into aliquots. The test compounds are dissolved in distilled water and these solutions of test compounds at concentrations of 1, 10 and 100 μg/ml are mixed with the semen in a ratio of 1 part test solution to 3 parts semen (v/v). Then the mixture is immediately
(a) and 1 hour later (b) Microscopic observation is performed. The results are shown in the table below. The measured characteristic values are the tests necessary to achieve immediate spermicidal (i), spermicidal rate of 75% or more after 1 hour (ii), and complete immobilization (motility 0) after 1 hour (iii). was the lowest concentration of the compound (after mixing the semen and test solution).

[Table] Midazole oxalate

[Table] Octyl imidazole oxalate

[Table] Dazole oxalate Example 4 The following example shows how to treat a male dog (approximately 6
A typical 1-substituted imidazole derivative, sarconazole, when administered orally at various concentrations in Kg)
This shows the sperm immobilization effect of nitrate, that is, 1-[2-(4-chlorobenzylthio)-2-(2,4-dichlorophenyl)ethyl]imidazole nitrate. After a 6-week treatment period, semen was collected from each dog. Whole semen, including both the early sperm rich fraction and the prostatic secretion fraction, was collected from multiple dogs and placed into prewarmed (37°C) collection tubes. Immediately after collection, the tube was sealed and placed in a 37°C water bath. 60 minutes after collection, the semen was thoroughly mixed by repeated inversion. A drop was removed and placed on a prewarmed slide, and sperm motility was immediately assessed using a microscope. Motility was scored on a scale of 0 to 5. High scores indicate high motility. Motility was assessed as an overall impression of motility within the optical field rather than by assessing the motility of individual sperm. The result is as follows;

[Table] The formulations used in the above test were as follows.

[Table] Capsule size No.1 No.0 No.
0
The ingredients were combined and granulated using methanol as the solvent. The formulation was then dried and filled into capsules. 1000mg per day per dog
Four 250 mg capsules were used for the dose.

Claims (1)

[Claims] 1. An effective amount of the following formula () as an active ingredient: A composition useful for contraception, comprising a compound represented by: or a pharmaceutically acceptable acid addition salt thereof. In the above formula (), R ¹ and R ² are each independently an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, unsubstituted or substituted phenyl (the substituted phenyl is a halogen phenyl substituted with 1 to 3 groups selected from atoms and lower alkyl groups having 1 to 4 carbon atoms, lower alkoxy groups having 1 to 4 carbon atoms, and trifluoromethyl groups ), or unsubstituted or substituted phenyl selected from a halogen atom and a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, and a trifluoromethyl group an alkyl group having 1 to 4 carbon atoms substituted with phenyl substituted by 1 to 3 groups, and R ³ is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms; , X is an oxygen atom or a sulfur atom, and n is an integer from 1 to 4. 2 an alkyl group in which R ¹ and R ² each independently have 1 to 12 carbon atoms, 3 to 7;
a cycloalkyl group having 1 carbon atoms, or an unsubstituted or substituted phenyl group (the substituted phenyl has 1
phenyl substituted by 1 to 3 groups selected from 1 to 2 lower alkyl groups having 1 to 4 carbon atoms or 1 to 2 halogen substituents), and R The composition according to claim 1, wherein ³ is a hydrogen atom and n is 1 or 2. 3 The compound is 1-(3-n-octylthio-n-octyl)imidazole oxalate, 1-[3
-(4-chlorophenylthio)-n-octyl]
Imidazole oxalate, 1-[2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl]imidazole nitrate, 1-[3-
(4-chlorobenzyloxy)-n-octyl]
Imidazole nitrate, 1-[2-(4-chlorophenylthio)-4-(4-chlorophenyl)-n
-Butyl]imidazole nitrate, 1-[2-
(2,4-dichlorobenzyloxy)-n-octyl]imidazole nitrate, 1-[2-(4-chlorobenzylthio)-n-octyl]imidazole nitrate, 1-[3-(2,4-dichlorophenylene) (ruthio)-n-heptyl]imidazole oxalate,
1-(2-ethylthio-n-tetradecyl)imidazole oxalate, 1-[3-(4-tert-butylphenylthio)-n-octyl]imidazole oxalate, 1-(3-n-decyloxy The composition according to claim 1, wherein the composition is selected from the group consisting of -3-cyclohexyl-n-propyl)imidazole oxalate. 4. The composition of claim 1, wherein the composition is formulated for vaginal administration. 5. The composition of claim 1, wherein the composition is formulated for oral administration. 6. The composition of claim 1, wherein the composition is formulated for parenteral administration. 7. A composition according to claim 1, wherein said composition contains from 0.1 mg to 100 mg of active ingredient per kg body weight per dose.