NZ194619A - Use of 1-substituted imidazoles as contraceptives - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 94619 % 1946 1 9 <i ■ a a iitiiiiit Priority Datsfs): Complete Specification Filed: Class: Pub'rication Date: . .. 24. AUK .19B.4, .. !?£.i P.O. .Journal, I^o i 1 H I SHU'I N.Z. NO.

NEW ZEALAND Patents Act, 1953 COMPLETE SPECIFICATION "USE OF 1-SUBSTITUTED IMIDAZOLES FOR PREPARATION OF CONTRACEPTIVE COMPOSITIONS" WE, SYNTEX (U.S.A.) INC., a corporation organized and existing under the laws of the State of Delaware, United States of America, of 3401 Hillview Ave, Palo Alto, California 94304, United States of America, do hereby declare the invention, for which we pray that a Patent may be granted to us , and the method by which it is to be performed, to be particularly described in and by the following statement t (fn11nwpd bv 3a} 1946 19 ~1C{- USE OF 1-SUBSTITUTED IMIDAZOLES FOR PREPARATION OF CONTRACEPTIVE COMPOSITIONS BACKGROUND OF THE INVENTION It has long been known that a variety of chemical 15 agents when introduced into the vaginal canal as suitable compositions will interfere with mammalian sperm cells and prevent their ability to effect conception, either by reducing the motility of such cells (i.e. a spermatostatic effect), or by cytotoxicity (i.e. a 20 spermatocidal effect). In general, the types of agents most widely used for such purpose are alkylphenoxypolyethoxyethanols, quaternary ammonium compounds and organomercurial compounds. Recently a series of 1,2-benzisothiazole derivatives having 25 spermatocidal activity was described in U.S. 4,093,730.

However, only one such spermicide, poly(ethylene glycol)p-nonylphenyl ether (INN name: nonoxynol). is in general use in the U.S. However, this material has a high failure rate and is generally regarded as less than 30 ideal.

Furthermore, such spermatostatic and spermatocidal compounds for vaginal administration show little if any effect upon spermatic cells when administered systemically to the male mammal.

The present invention relates to a group of -10140 / 1945Q FF 1946 19 spermicides which appears to be more potent than that conventionally in use, and to have the additional property of effectiveness when administered to the sperm-producing male as well as when administered 5 intravaginally. In addition, the spermicides of the invention seem to be more reliable than the conventional product.

DESCRIPTION OF THE INVENTION The present invention concerns the use, for the 10 preparation of spermicidal, contraceptive compositions, of a compound selected from a group of 1-substituted imidazole derivatives, previously described for their anti-fungal, anti-bacterial and anti-protozoal activity. See, e.g. U.S. Patent 4,123,542. It has now been found, 15 surprisingly, that this class of compounds interferes with mammalian sperm and inhibits their ability to effect conception, either by reducing'their motility (spermatostatic activity) or by incapacitating their normal cellular function or by killing them 20 (spermatocidal activity). The compounds are generally non-toxic to the host.

In one aspect, the present invention is concerned with the use of the 1-substituted imidazoles contained herein as spermatostats or spermicides. 25 In another aspect, the present invention is concerned with formulation and preparation of compositions useful for contraception containing 1-substituted imidazoles or salts thereof suitable for vaginal administration.

In a third aspect, the present invention is concerned with the formulation and preparation of compositions useful for contraception containing 1-substituted imidazoles or salts thereof suitable for oral administration, in particular, oral administration to the male mammal. 1914 0 / 19150 FF 10 i 9 4 619 In a fourth aspect, the present invention is concerned with the formulation and preparation of compositions useful for contraception containing 1-substit'uted imidazoles or salts thereof suitable for parenteral administration, in particular parenteral administration to the male mammal.

In all of the above aspects, the 1-substituted imidazole may be used as the free base or as a pharmaceutically acceptable acid addition salt. Pharmaceutically acceptable acid addition salts are salts of the subject bases which retain the pharmaceutical properties of the free bases and which are neither biologically or otherwise undesirable, formed with, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; or organic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

It has been found that a wide variety of classes of known 1-imidazole compounds previously described as exhibiting anti-fungal, anti-bacterial and/or anti-protozoal activity, exhibit the aforementioned remarkable spermatostatic and spermatocidal effects, both in the male and female mammal. The classes of 1-substituted imidazoles forming a part of the present invention are those represented by the following general structural formula (as well as pharmaceutically acceptable acid addition salts thereof) and/or described 19440 / 19450 FF ! ^ y Vf in the issued patents listed hereinbelow: Compounds of the formula R3 R1—C— (CH ) —A i 2 n (I) 1 2 wherein R and R are independently alkyl(1-12C), cycloalkyl(3-7C), alkenyl(2-12C) , optionally substituted phenyl, optionally substituted phenyl lower alkyl(1-4C) or optionally substituted phenyl lower alkenyl(2-4C); wherein 11 substituted" means phenyl substituted by 1-3 15 groups selected from the set consisting of halo atoms and lower alkyl (1-4C), lower alkoxy(1-4C), cyano, nitro and trifluoromethyl groups; is hydrogen or lower alkyl (1-4C), X is O or S, and n is an integer from 1-4; or a pharmaceutically acceptable acid addition salt thereof. 20 a preferred embodiment of the present invention is the set of compounds of formula I wherein R-1- and R^ are each independently alkyl(1-12C) cycloalkyl (3-7C) or optionally substituted phenyl or optionally substituted phenyl lower alkyl (1-4C) wherein "substituted" means 25 phenyl substituted with 1 or 2 lower alkyl (1-^4C) or one or two halo substituents; R^ is hydrogen, and n=l or 2, and pharmaceutically acceptable salts thereof.

An even more preferred embodiment is comprised of compounds showing one of the following combinations 30 of substituents: (a) R-*- is alkyl or cycloalkyl R^ is alkyl, optionally substituted phenyl, or optionally substituted benzyl,R^ is hydrogen and n is 1 or 2; l 2 (b) R is optionally substituted phenyl, R is optionally substituted benzyl, R3 is hydrogen and n is 1; 19440 / 101 GO IT 194619 (c) R1 is optionally substituted phenethyl, R^ is optionally substituted phenyl, R^ is hydrogen and n is 1; and (d) is optionally substituted benzyl, R2 is optionally substituted phenyl or benzyl, R^ is hydrogen and n is 2; and, in (a) - (d), the pharmaceutically acceptable acid ' addition salts thereof.

* ^ One especially preferred group of compounds in this set is that wherein R-*- is alkyl having from 3 to 7 carbon atoms, more preferably from 4 to 6 carbon atoms, and most preferably 5 carbon atoms, R2 is optionally substituted phenyl, preferably phenyl substituted with halo or lower alkyl, R^ is hydrogen and n is 2; and the 15 pharmaceutically acceptable acid addition salts thereof.

A second especially preferred group of compounds is that wherein R1 is alkyl having from 4 to 8 carbon atoms, R2 is optionally substituted benzyl, R^ is hydrogen and n is 1, and the pharmaceutically acceptable and addition salts thereof.

A particularly preferred embodiment of the present invention is a compound selected from the set consisting of 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, "l-[2-(4-chlorobenzylthio)-n-octyl]imidazole nitrate, [3- (2,4-dichlorophenylthiojj^^heptyl ] imidazole oxalate, 9440 / 19450 FF I1 ■ tf 1-(2-ethylthio-n-tetradecyl)imidazole oxalate , 1-[3-(4-tert-butylphenylthio)-n-octyl]imidazole oxalate, 1- (3-n-decyloxy-3-cyclohexyl-n-propyl)imidazole 5 oxalate; and the pharmaceutically acceptable acid addition salts thereof.

The preparation of the above compounds is set forth in U.S. patents 3,717,655, 3,839,574, 3,658,813, 10 4,055,652, 4,078,071, 4,045,568, 4,059,705, and 4,123,542. Inclusive of representative compounds within this class are sulconazole, i.e. l-[2-(4-chlorobenzylthio)-2-(2,4-dichlorophenyl)ethyl]imida zole, miconazole, i.e., 1-[2-(2,4-dichlorobenzyloxy)-2-(2,4-15 dichlorophenyl)ethyl]imidazole, econazole, i.e., 1—[2— (4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)-ethyl]-imidazole, orconazole, i.e., 1-[2-(2,6-dichlorobenzyl-oxy)-2- (4-chlorophenyl)ethyl]imidazole, and 1—[2— allyloxy-2-(2,4-dichlorophenyl)-ethyl]imidazole. 20 With respect to use of the above compounds as spermicides in preparation and formulation of contraceptive compositions, excipients and techniques familiar to those skilled in the art are employed. Suitable pharmaceutical carriers and their use in 25 formulations are described in "Remington's Pharmaceutical Sciences" by E. W. Martin.(Edition 15(1975); Mack Publishing Co., N.Y.). Such compositions will, in all cases, contain an effective amount of the active compound, together with a suitable amount of carrier so 30 as to prepare the proper dosage form for proper administration to the subject.

In the aspect of the present invention concerning the formulation and preparation of compositions containing the above cited compounds suitable for vagine.1 administration, a variety of configurations are standard 1.9 4 40 / 194 50 FF- 1 94619 **• in the art, for example, vaginal suppositories, vaginal tablets, vaginal creams, vaginal spray-foams, vaginal soluble waffles, vaginal sponges, and the like, as well as slow release formulations such as implants. Each of these compositions would contain an effective amount of the active ingredient in a pharmaceutically acceptable non-toxic carrier or excipient normally employed for such formulations. Typical excipients for solid formulations are, for example, starch, glucose, lactose, mannitol, magnesium stearate, talc, cellulose, magnesium carbonate, sodium bicarbonate, citric acid, and the like. For semi-solid formulations such as suppositories, excipients such as polyalkylene glycols, modified vegetable oils or ' soft gelatin capsules containing, e.g., vegetable oil, mineral oil or polyalkylene glycol formulations may be used. For liquid or liquid-type formulations such as creams, jellies, foams, and the like, there may be used water, saline solution, aqueous dextrose, glycerol, higher alcohols, mineral oil, lanolin, gums of vegetable origin, polyalkylene glycols and propellants such as those of the Freon type. The compositions may contain i substantially between j 0.1 and 10.0 percent by weight of the active ingredient, preferably between about 0.5 and 2.0 percent by weight, and may, if desired, contain other 25 active ingredients.

A single dose consists of an amount of said composition which provides a dose in the range of 1 mg to 100 mg of active substance for each vaginal administration for a typical adult human subject, or 30 °*° 14 mg to 1.4 mg per kg of body weight.

In the aspect of the present-invention concerning the formulation and preparation of compositions containing the above cited compounds suitable for oral administration, final formulations may include tablets, 35 pills, capsules, powders, sustained release formulations, 19410 / 19450 FF ' 946 I 9 solutions, suspensions, elixirs, and the like. Carriers can be selected from the various oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. 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, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like.

The compositions may contain betweenf S Stfn^%a^ai^d 95% by weight of the active ingredient, so as to provide r suBstantially an effective dosage range of between 0.1 and about 100.0 mg active ingredient per kg body weight per day preferably 0.1 to 10 mg/kg per day, either in one dose or distributed over several doses. The exact regimen will necessarily be dependent upon the particular compound employed, the nature of the subject, and the like. As a rule, to ensure complete lack of motility of the spermatic cells, it is prudent to administer the compound to the male mammal at least 24 hours prior to coitus, preferably daily for a period of 3 to 7 days prior to coitus.

In the aspect of the present invention concerning the formulation and preparation of compositions containing the above cited compounds suitable for parenteral administrations, compositions may consist of solutions or suspensions ready for injection, dry products suitable for solution or suspension immediately prior to injection or emulsions. A more recent method of parenteral administration is via a slow-release subcutaneous implant type of formulation such as those generally known in the art, particularly those that are 19440 / 19450 FF !9461 9 biosoluble or biodegradeable. In this method only one administration need be made to supply active ingredient for an extended period, e.g., one month. See, e.g., U.S. 3,279,996 and 4,096,239.

Typical exipients for solid formulations include, for example, magnesium stearate, starch, lactose, gelatin, and the like; for liquid formulations there may be mentioned, for example, polyalkylene glycols, water, oils of vegetable origin and low boiling solvents such as isopropanol and hydrogenated naphthalenes.

The percentage of active ingredients in the . . r substantially composition may range from) 0.1 "to 10% in liquid formulations, and from|"SU^,Stan^l^1^o 95% in solid compositions suitable for solution or suspension immediately prior to injection. Formulations suitable for implantation are in the range of 0.1-10% active ingredient. The preferred content of active ingredient will depend on the exact mode of administration, since parenteral administration includes intramuscular, subcutaneous and intravenous routes. ! .In the aspect of the present invention concerning a method of contraception employing compositions and/or compounds as herein described, either the male or female or both is/are the recipient(s) of said compositions and/or compounds.

Appropriate amounts of compositions suitable for intravaginal administration are applied to the female, either in a single (preferred) or repeated dose preferably within 12 hours before intercourse. For example, such application is by means of a syringe, when the composition is a cream or jelly, by means of an aerosol device when the composition is a foam, or by hand <• r appropriate applicator when a waffle or tablet.

For application to the male, the composition may be i-n9ested orally, preferably at least 24 hours before, but --9MARI982 1044 0 / 19450 FF 1 o within 1 week before intercourse, and may be taken daily preferably in the form of daily unit dosage forms combining an appropriate amount of the active ingredient. A suitable amount of the active ingredient 5 sufficient to prevent conception according to the method of the invention is described below. In the alternative, a subcutaneous implant may be used to supply the subject compound on a continuous basis over a period of weeks or months.

The exact method to be employed will, of course, depend on the subject to be treated, the particular compound used, the type of composition selected, and the judgment of the prescribing physician.

The following examples are illustrative of the methods and compositions of the present invention. They should not be construed as limitative thereof in any manner.

EXAMPLE 1 The following illustrates formulations for vaginal administration. The specific active ingredient utilized is 1-[3-(4-chlorophenylthio)-n-octyl]imidazole oxalate, although any 1-substituted imidazole referred to above may be utilized. a) Water soluble vaginal cream Ingredients % w/w Active ingredient 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 hydroxyanisole 0.01 Purified water qs ad 100.0 3.94.40 / ID 150 I-'F 1946 1 9 ^ rv P9 MAR 1982 All ingredients except the active ingredient, water, and 10% of the Polysorbate 60 are mixed and treated to 70-80°C., 85% of the required water is separately heated to 70-80°C. The remaining Polysorbate 60 and 10% of the water are dissolved together at 50-60°C/ and the active ingredient dissolved therein.

The heated water is then added to the heated emulsifying ingredients using a bomomixer at medium speed, with a final increase to high speed for 1 minute after mixing is complete. The homomixer is removed and mixing continued gently until the mixture congeals and cools to room temperature; whereupon the active ingredient, previously dissolved as described above, is added, and gentle mixing continued for 20-30 minutes. The remaining 5% of water is then used to rinse the vessels containing the premixed active ingredient and the rinse added to the total mixture. Mixing is continued and further water added if necessary.

For each application approximately 1 gm of the cream is vaginally administered to an adult human female with a suitable syringe. b) Vaginal jelly Ingredients Active ingredient Tragacanth Acacia Glycerin Boric acid Ricinoleic acid p-hydroxybenzoic acid, propyl ester Purified water qs ad % w/w 1.00 3.00 0.53 5. 00 3.00 0.75 0.05 100.0 The tragacanth and acacia are intermixed thoroughly ith the glycerin; ricinoleic acid and active ingredient are then added to the mixture. The p-hydroxybenzoate and boric acid are dissolved in water (with heating if 10110 / 104 DO r F J 94619 necessary), and the solution is added to the prior mixture, with stirring and warming to dissolve. The mixture becomes gelatinous upon cooling.

For each application approximately 1 gram of the 5 jelly is vaginally administered to an adult human female with a suitable syringe. c) Vaginal suppository Ingredients % w/w Active ingredient 1.0 Polyethylene glycol 4000 20.0 Butylated hydroxyanisole 0.01 Polyethylene glycol 1000 qs ad 100.0 The Polyethylene glycol solids are mixed and heated to 70-80°C and the BHA dissolved in the mixture. After 15 cooling to 45°C, the active ingredient is suspended in the above mixture by stirring. The suspension is poured into molds which are of sufficient size to form suppositories of about 3 gm each, and cooled. d) Effervescent vaginal tablets Ingredients % w/w Active ingredient i.O Anhydrous citric acid .0 Sodium bicarbonate .0 Polyethylene glycol 6000 .0 Lactose qs ad 100.0 The above ingredients are combined and granulated using methanol as the solvent. The formulation is then dried and formed into tablets containing 20 mg of active compound with an appropriate tableting medicine. 30 e) Vaginal spray-foam Ingredients % w/w Active ingredient 2.0 Emulsion base 90.0 Propellant 12/114 (40:6jCU-^ 8.0 19440 / 10450 FF Cm 194619 The emulsion base is made up according to the following % w/w composition: myristic acid 1.33 stearic acid .33 cetyl alcohol 0.50 lanolin 0.20 isopropyl myristate 1.33 +' triethanolamine 3. 33 glycerin 4.70 polyvinyl pyrrolidine 0.34 purified water 82.93 The ingredients of the emulsion base, except for the water, are mixed in a stainless steel container kept at 70-80°C « 80% of the water to be used is also heated to 70-80qCand mixed during heating with a homomixer at moderate speed. After complete addition, the speed of mixing is increased for several minutes. The mixture is then cooled to room temperature and a solution containing the active ingredient in the remaining 20% water is added with continuous mixing. The preparation is placed in an appropriate spray can, topped with the propellant mixture, and sealed.

For each application approximately 0.5 gm of the foam are vaginally administered. f) Vaginal soluble waffle • Ingredients % w/w Active ingredient 1.0 Starch 10.0 Water soluble lanolin qs ad 100.0 y The above ingredients are thoroughly mixed and pressed into 0.8 gm waffles with a suitable press.

EXAMPLE 2 The following pharmaceutical compositions are representative of those which may be used for oral or 10440 / 19450—EF 9 parenteral administration to a male mammal. The active ingredient illustrated is the same as for that in Example 1 although any active ingredient referred to above may be utilized. a) Oral formulation tablet Ingredients Parts by Weight Active ingredient 200 Magnesium stearate 3 Starch 3 0 Lactose 116 Polyvinylpyrrolidone 3 The above ingredients are combined and granulated using methanol as the solvent. The formulation is then dried and formed into tablets containing 200 milligrams of active 15 compound with an appropriate tableting machine. b) Parenteral formulation for intravenous use - composition of 100 ml of solution: Ingredients Active ingredient 2.0 g Propylene glycol 20 g Polyethylene glycol 20 g Polysorbate 80 1 g 0.98 Saline solution qs ad 100 ml The active ingredient is dissolved in propylene glycol, 25 polyethylene glycol 400 and Polysorbate 80. A sufficient quantity of 9.9% saline solution is then added with stirring to provide 100 ml of the IV solution which is filtered through a 0.2 micron membrane filter and packaged under sterile condi tions. c) Implant formulation Ingredients % w/w Active ingredient 2.0 Polyethylene glycol 6000 5.0 Cholesterol qs ad 100.0 19440 / 19400 FF 1 946 1 The ingredients are mixed and compressed into pellets of approximately 2 mm (diameter) x 8 mm.

EXAMPLE 3 The following example illustrates the spermatostatic and spermatocidal activity of the 1-substituted imidazole derivatives of the invention when contacted directly with semen. This is representative of the effect for female contraception.

Semen is collected from a male dog and divided into aliquots. The test compound is dissolved in distilled water at concentrations of 1, 10 and 100 micrograms/ml. These solutions of test compound are mixed with semen in the ratio of 1 part test solution to 3 parts semen (v/v). They are then examined microscopically (a) immediately and (b) after 1 hour. The results are tabulated in the following chart. The parameters measured were minimum concentration of test compound (after admixture of test solution with semen) necessary to achieve (i) instant kill, (ii) greater than 75% kill after one hour, and (iii) zero motility after one hour.

Minimum dosage (pg/ml) causing Zero Instant 75% kill Motility Test Compound . Kill (1 hour) (1 hour) 1-[2-(4-chlorobenzylthio)-2- 25 - 2.5 (2,4-dichlorophenyl)ethyl]-imidazole nitrate 1-[2-(2,6-dichlorophenylthio)- - 25 2.5 4-(4-chlorophenyl)n-butyl]-imidazole nitrate 1-[2-(2,4-dichlorobenzyloxy)- - 25 2.5 2-(2,4-dichlorophenyl)-ethyl]imidazole nitrate 1-t2-n-heptylthio-2-(2,4- - 25 2.5 dichlorophenyl)ethyl] imidazole nitrate 19440 / 19450 FF f O fi fy V ffl 1-[3-(n-octylthio)-n-octyl]- 25 2.5 2.5 imidazole oxalate 1-[3-(4-chlorophenylthio)-n- 25 - 0.25 octyl]imidazole oxalate 1-[2-(4-methoxybenzylthio)-2- - 25 2.5 (2,4-dichlorophenyl)ethyl]-imidazole nitrate 1-[2-(2,4-dichlorobenzyloxy)- - 25. 2.5 4-(4-chlorophenyl)-n-butyl]imidazole nitrate 1-[2-(4-chlorobenzyloxy)-2- 25 - 0.25 (2,4-dichlorophenyl)ethyl]-imidazole nitrate 1-(3-n-dodecylthio-n-butyl)- - 25 2.5 imidazole oxalate 1-[3-(4-chlorobenzylthio)-n- - 25 2.5 octyl]imidazole nitrate 1-(3-n-hexyloxy-n-octyl)- 25 - 2.5 imidazole oxalate 1-(2-n-octylthio-n-octyl)- - 25 2.5 imidazole oxalate 1- [3-(4-chlorobenzyloxy)-n- 25 2. 5 0. 25 octyl]imidazole oxalate 1-f3-(2,4-dichlorobenzyloxy)- 25 - 2.5 n-octyl]imidazole oxalate 1-[2-(4-chlorophenylthio)-4- - 2.5 2.5 (4-chlorophenyl)-n-butyl]-imidazole nitrate 1-(3-(2-chlorobenzylthio)-4- 25 - ' 2.5 (4-chlorophenyl)-n-butyl]-imidazole nitrate 1-[2-(2,4-dichlorobenzyloxy)- 25 2.5 0.25 n-octyl]imidazole oxalate 1-[2-(4-chlorobenzylthio)-n- 25 - 0.25 octyl]imidazole nitrate 1-[3-(2,4-dichlorophenyl- 25 - 0.25 thio)-n-heptyl]imidazole oxalate 10440 / 19450'FF J. t •17- 1-[2-(2,4-dichlorophenyl- 25 thio)-2-methyl-n-hexyl]-imidazole nitrate 1- (2-ethylthio-n-tetradecyl)-imidazole oxalate 1-[3-(4-chlorophenylthio)- 3- (2,4-dichlorophenyl)-n-propyl]imidazole 1-[4-(4-chlorophenylthio)- 4- (2,4-dichlorophenyl)-n-butyl]imidazole oxalate 1-[3-(4-tert-butylphenyl- 25 thio)-n-octyl]imidazole oxalate 1-[4-(4-chlorobenzyloxy)-4-(2,4-dichlorophenyl) -n-butyl]imidazole nitrate 1-[3-(n-hexylthio)-3-(2, 4- 25 dichlorophenyl)-n-propyl]-imidazole oxalate 1-[2-(4-chlorobenzylthio)-3- (n-butylthio)-n-propyl]-imidazole 1-[4-(2,4-dichlorobenzyl-oxy)-4-(4-chlorophenyl)-n-butyl]imidazole nitrate 1-(3-n-decyloxy-3-cyclo-hexyl-n-propyl)imidazole oxalate 2.5 25 2.5 2.5 2.5 2.5 0. 25 2.5 2.5 0. 25 EXAMPLE 4 The following experiment illustrates the spermatostatic effect of a typical 1-substituted imidazole derivative, sulconazole nitrate, 1-[2-(4-chlorobenzylthio)-2-(2,4-dichlorophenyl)ethyl]- imidazole nitrate, when administered orally at various dosages to male dogs (approximately 10 kg) daily for a period of 6 weeks. After the 6 week treatment period 19440 / 19450 FF \ // semen was collected from each dog. The entire ejaculate, including both initial spermatozoa rich and prostatic secretion fractions were collected from the dogs into pre-warmed (37°C) collection tubes. Immediately after 5 collection the tubes were sealed and placed in a 37°C water bath. After 60 minutes from collection the ejaculate was well mixed by repeated inversion. A drop was withdrawn and placed on a pre-warmed slide and the motility of spermatozoa were immediately assessed 10 microscopically. Motility was scored on a scale of 0 to 5, the high score representing high motility. Motility was assessed as the total impression of motility within the optical field rather than by assessing motility of individual spermatozoa. The results were as follows: 15 Dosage Motility Rating Group No. (rng/dog/day) (average for group) at 60 min. 1 0 3.7 2 100 1.7 3 330 0 20 4 1000 0 The formulations utilized for the above study were as follows: Ingredient . wt. (mg) per capsule Sulconazole nitrate 100 330 250 Compressible sugar 280 220 300 Polyvinylpyrrolidone 7.6 11 11 Capsule size No. 1 No. 0 No. 0 The ingredients were combined and granulated using methanol as the solvent. The formulation is then dried and the capsules filled. For the 1000 mg/dog/day dose, four 250 mg capsules were utilized. 10440 / 10150 FF

Claims (1)

1. WHAT WE CLAIM IS: - 19 - 19461 1. A contraceptive composition containing as active ingredient a contraceptively effective amount of a compound of the formula R- r1—h- A <ch^„^0 wherein and R2 are each independently alkyl(1-12C), cycloalkyl (3-7C), alkenyl(2-12C), 2Q optionally substituted phenyl, optionally substituted phenyl lower alkyl(1-4C) or optionally substituted phenyl lower alkenyl(2-4C); wherein "substituted" means phenyl substituted by 1 to 3 substituents selected from the group consisting of halo atoms and 15 lower alkyl (1-4C), lower alkoxy (1-4C), cyano, nitro, and trifluoromethyl groups; R3 is hydrogen or lower alkyl (1-4C), X is 0 or S, and n is an integer from 1 to 4, or a pharmaceutically acceptable acid addition salt thereof. 20 2- The composition of Claim 1 wherein R^ and R2 are each independently alkyl (1-12C), cycloalkyl(3-7C), optionally substituted phenyl or phenyl lower alkyl wherein "substituted" means phenyl substituted with one or two lower alkyl(1-4C) or one or two halo substituents; 25 R3 is hydrogen and n - 1 or 2. 3. The composition of Claim 1 wherein the compound is selected from the group consisting of: 1- (3-n-octylthio-n-octyl)imidazole oxalate; 30 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; 19440 / 19450 FF & % *27APR!S8*'1 194619 10 -2 0- 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-ter t-butylphenylthio)-n-octyl]imida zole oxalate; and 1-(3-n-decyloxy-3-cyclohexyl-n-propyl)imidazole oxalate. 4 . The composition of Claim l wherein said composition is formulated for vaginal administration. 5 . The composition of Claim 1 wherein said composition is formulated for oral administration. 6, The composition of Claim 1 wherein said composition is formulated for parenteral administration. 7-. The composition of Claim 1 wherein said composition contains 0.1 mg to 100 mg of the active ingredient per kg body weight per dose. ■fcV The use, for the preparation of contraceptive compositions, of a compound of the formula 15 20 25 30 R X k2 35 4-(ch2>,HQ wherein R1 and R^ are each independently alkyl (1-12C) , cycloalkyl (3-7C)^tf£|||fj§pW2-12C) , -21- 1946)9 optionally substituted phenyl, optionally substituted phenyl lower alkyl C1-4C) or optionally substituted phenyl lower alkenyl C2-4C), wherein "substituted" means phenyl substituted by 1 to 3 substituents selected from the group consisting of halo atoms and lower alkyl C1-4C), lower alkoxy (1-4C), cyano 3 nitro, and trifluoromethyl groups; R is hydrogen or lower alkyl CJ.-4C) ; X is O or S; and n is an integer from 1 to 4, or a pharmaceutically acceptable acid addition salt thereof. 12 9. The use claimed in Claim 8 wherein R and R are each independently alkyl (1-22C) , cycloalkyl (3-7C) , optionally substituted phenyl or optionally substituted phenyl lower alkyl wherein "substituted" means phenyl substituted with one or two 3 lower alkylC1-4C) or one or two halo substituents; R is hydrogen and n = 1 or 2. 10. The use claimed in Claim 8 wherein the compound is selected from the group consisting of: 1-C3-n-octylthio-n-octyl)imidazole oxalate; 1-[3-C4-chlorophenylthio)-n-octyl]imidazole oxalate; -1-12- ( 4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl] -imidazole nitrate; 1-[3-(4-chlorobenzyloxy)-n-octyl]imidazole oxalate; 1-[2- C4-chlorophenylthio)-4-(4-chlorophenyl)-n-butyl] -imidazole nitrate; _L- [2- C2,4-dichlorobenzyloxy) -n-octyl] imidazole oxalate; 1-[2-C4—chlorobenzylthio)-n-octylJ imidazole nitrate; 1-[3-(2,4-dichlorophenylthio)-n-heptyl]imidazole oxalate; 1-(2-ethylthio-n-tetradecyl)imidazole oxalate; 1-13-(4-tert-butylphenylthio)-n-octyllimidazole oxalate; 194619 22 and 1-C3-n-dec?yloxy-3-cyclohexyl-n—propyl) imidazole oxalate. f 11. The use claimed in Claim 8 wherein such compositions are administered vaginally. 12. The use claimed in Claim 8 wherein such compositions are administered orally. 13. The use claimed in Claim 8 wherein such compositions are administered parentally. 14. The use claimed in Claim 8 wherein such compositions are administered in a dose containing 0.1 mg to 100 mg of active ingredient per kg body weight. SYNTEX (U.S.A.) INC By Their Attorneys HENRY HUGHES LIMITED V