Devices, of suitable form and size for insertion into the vagina of a female mammal, composed of a polymeric material which has, incorporated in it, a 1-substituted imidazole spermicide and a pharmaceutically acceptable chelating agent, and which release effective amounts of said spermicide while in place in the vaginal cavity, are useful as contraceptives.

BACKGROUND OF THE INVENTION 
The present invention relates to methods and devices for contraception 
which depend upon spermicidal activity of 1-substituted imidazoles 
applicable to the female mammal intravaginally. More specifically, the 
present invention concerns intravaginal inserts, such as diaphragms, 
rings, or cervical caps which contain, within the matrix of the material 
of which they are composed, a spermicide of the chemical class of 
1-substituted imidazoles and a pharmaceutically acceptable chelating 
agent, and which devices are capable of releasing an effective amount of 
said spermicide at a controlled rate in situ. 
Present methods of contraception suffer from a variety of well known 
defects. Systemically active drugs which alter the ovulatory cycle of the 
female, whether taken orally, or inserted in the uterus or vagina for slow 
release, cause a substantial number of side effects ranging from 
discomfort and menstrual irregularities to life threatening alterations in 
metabolism. Mechanical barriers, such as condoms and diaphragms, in their 
present form, are not ideally effective, and, more importantly, do not 
have maximum user acceptance because of the necessity of their being 
employed in the same psychological time frame as intercourse. Spermicidal 
preparations designed for intravaginal application are even less effective 
and less aesthetically acceptable than the aforesaid mechanical barrier 
devices. The goal of a contraceptive which is (a) effective (b) confined 
in its metabolic effects to contraception itself, and (c) can be employed 
at a time far psychologically removed from the sex act, has not been 
achieved in the prior art. 
Intravaginal devices for release of contraceptive materials are well known, 
and many designs have been described: for example, a vaginal contraceptive 
tampon is described in international application published under No. PCT 
80/00008 (claiming priority from U.S. application Ser. No. 888,578); a 
vaginal medicator in U.S. Pat. No. 3,885,564; a vaginal ring in U.S. Pat. 
No. 3,545,439; a diaphragm in U.S. Pat. No. 2,087,610, and a cervical cap 
in U.S. Pat. No. 2,836,177. 
Devices for the release of a progestational agent as the active ingredient 
have also been described: (WHO Special Programme of Research, Development 
and Research Training in Human Reproduction, Geneva, Switzerland: Journal 
of Steroid Biochemistry 11 (1B) 461 (1979); Burton, F. G., et al, 
Contraception 17 (3) 221 (1978); Gordon, N. R., et al, Saf. Health Plast. 
Nat'l. Tech. Conf. Soc. Plast Engr. 1977, 109. Victor, A., et al, 
Contraception, 16 (2) 125 (1977), Zanartu, et al, Steroids 21 (3) 325 
(1973); British patent application No. 2,616,064. However, the results 
have been unsatisfactory because of continuing problems with unwanted 
metabolic alterations and because of the difficulty of assuring proper 
release of the steroid (WHO study, supra). As systemic contraceptives, 
progestational compounds are subject to causing such side effects 
regardless of the mode of administration. 
Release of spermicides, because the effect is not systemic to the female 
host, is an inherently more desirable option. Devices which release 
spermicides of the surfactant type have also been described: Stone, et al, 
Am. J. Obstet. and Gynecol. 133 (6): 635 (1979), U.S. Pat. No. 4,031,202, 
British Pat. No. 1,329,619, European Pat. Nos. 9-417 and 9-518. However, 
surfactant spermicides are effective only at relatively high 
concentrations, and devices which remain in the vaginal cavity are 
incapable of releasing effective amounts over long periods. Furthermore, 
surfactants are not effective within the cervical mucus. Hence, 
effectiveness is impaired because the critical sperm pathway through the 
mucus to effect conception remains unimpaired. 
The present invention utilizes 1-substituted imidazole spermicides and a 
pharmaceutically acceptable chelating agent. Because of the effectiveness 
of these spermicides at low concentrations, intravaginal devices which 
incorporate them and a pharmaceutically acceptable chelating agent into 
the matrix of the device are capable of releasing effective quantities for 
a prolonged period to be absorbed by the cervical mucus. The devices and 
method of this invention thus permit a method of contraception which is 
esthetically more appealing and provides greater protection than the above 
known methods. 
SUMMARY OF THE INVENTION 
The present invention concerns a device of suitable configuration for 
vaginal insertion and long term retention in the female mammal, which is 
composed of an inert flexible polymeric material wherein the 
polymerization is effected in the presence of a 1-substituted imidazole 
spermicide or their pharmaceutically acceptable acid addition salts and a 
pharmaceutically acceptable chelating agent and wherein the resulting 
polymer is permeable to the release of said spermicide and chelating 
agent. 
This device is useful for effecting contraception. Accordingly, another 
aspect of the present invention concerns a method of contraception using 
said device and a method of contraception including removing the device 
prior to coitus. 
DETAILED DESCRIPTION 
Definitions: 
As used herein: 
"Spermicide" or "spermicidal" includes those agents which kill sperm, and 
also those which otherwise immobilize or render sperm ineffective in 
fertilization; 
"Inert" means material which does not dissolve in, or become absorbed by, 
the fluids or structures of the vaginal cavity, and maintains its 
structural and configurational integrity in the vaginal environment; 
The term "pharmaceutically acceptable chelating agent" refers to those 
chelating agents which do not have a deleterious effect on the subject 
using the composition. 
"Alkyl" refers to a branched or unbranched saturated hydrocarbon 
substituent containing two to twelve carbon atoms, such as, for example, 
ethyl, i-propyl, n-butyl, n-hexyl, n-octyl or n-dodecyl. 
"Lower Alkyl" refers to a straight or branched chain monovalent substituent 
consisting solely of carbon and hydrogen containing no unsaturation and 
having one to four carbon atoms. Examples of lower alkyl are methyl, 
ethyl, i-propyl, n-propyl, n-butyl, i-butyl and t-butyl. 
"Cycloalkyl" refers to a cyclic saturated monovalent substituent consisting 
solely of carbon and hydrogen and having five to seven carbon atoms in the 
ring. Examples of cycloalkyl are cyclopentyl, cyclohexyl and cycloheptyl. 
"Cycloalkylalkyl" refers to a cycloalkyl group as defined above attached to 
an alkylene chain of one to three carbon atoms. Non-limiting Examples of 
cycloalkylalkyl groups are cyclopentylmethyl, cyclohexylethyl and 
cyclohexyl-n-propyl. 
"Alkenyl" refers to a straight or branched chain monovalent substituent of 
two to twelve carbon atoms consisting solely of carbon and hydrogen 
containing olefinic unsaturation. Examples of alkenyl are ethenyl, 
n-butenyl, n-pentenyl, i-pentenyl, n-octenyl and n-dodecenyl. "Lower 
alkenyl" refers to alkenyl of two to four carbon atoms. Examples of "lower 
alkenyl" are ethenyl, propenyl and butenyl. 
"Phenyl-lower-alkyl" refers to phenyl ring attached to an alkylene chain of 
one to four carbon atoms. Examples of "phenyl-lower-alkyl" are benzyl, 
phenylethyl and 4-chlorophenylpropyl. "Phenyl-lower-alkenyl" refers to 
phenyl ring attached to a lower alkenylene chain. Examples of 
"phenyl-lower-alkenyl are phenylethenyl, phenylpropenyl and 
4-methoxyphenylbutenyl. 
"Lower alkoxy" refers to OR" wherein R" is lower alkyl as defined above. 
Examples of "lower alkoxy" are methoxy, ethoxy and i-propoxy. 
"Halo" refers to fluoro, chloro and bromo. 
"Pharmaceutically acceptable acid addition salt" means those salts which 
retain the spermicidal 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 inorganic 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. 
"Optionally substituted" means that the substrate may or may not be 
substituted in the phenyl or naphthyl moiety with 1-3 substituents 
selected from the group consisting of halo atoms, lower alkyl, lower 
alkoxy or trifluoromethyl. 
Article of Manufacture 
A. Configuration 
The device of the invention herein is intended to be insertable into, and 
retained in, the vagina for extended time periods, easily removable, 
comfortable, and non-interfering with intercourse. It is designed to 
remain in the vagina between menstrual periods, and to be disposable at 
the end of each use; to be self-inserted (unlike intrauterine devices 
which must be inserted by a physician) and to be of non-critical 
dimensions, so that it need not be fitted by a physician (as is the case 
with diaphragms).

DESCRIPTION OF THE DRAWING 
An exemplary embodiment of the configuration of the invention is a ring 
such as that shown in FIG. 1, which is 70-80 mm across and 4-10 mm in 
diameter, and flexible so as to be retained between the rear wall of the 
vagina and the upper edge of the pubic bone, as shown in FIG. 2. The 
insertion and removal of such a device may be done by hand by the user. 
Another embodiment of the configuration of the invention, exemplified in 
FIG. 3, is a diaphragm, which is essentially similar to the above ring in 
dimensions, properties and usability, except that the ring supports a 
membrane of thin flexible material. As the effectiveness of the device 
herein-described does not depend on its attributes as a mechanical 
barrier, this embodiment of the invention does not require fitting by a 
physician, as is the case with diaphragms in general. 
Another preferred embodiment, exemplified in FIG. 4, is a cervical cap. As 
is the case with diaphragm, the efficacy of this embodiment of the device 
does not depend on its properties as a barrier. Therefore, exact fit is 
not critical, and user insertion is feasible. The cap is held in place by 
suction, and may be removed by hand. 
FIG. 5 shows a cross-section of a "diaphragm" which comprises a single 
molded piece of polymeric material which holds the spermicide in the 
matrix of the polymer. 
The preceeding drawing depicts suitable embodiments of the device which are 
intended to be exemplary, and not limiting. Any device which consists as a 
whole, or in part, of a polymeric material capable of incorporating the 
spermicides and a pharmaceutically acceptable chelating agent described 
herein into the matrix of the polymer, and which will be retained in the 
vagina is encompassed by the invention. 
B. Composition of the Matrix 
The matrix which constitutes the structure and configuration of the device 
is composed of inert, flexible polymeric material which has been 
polymerized in the presence of, and as to include within itself, an 
effective amount of spermicide and a pharmaceutically acceptable chelating 
agent. The nature of the spermicide and a pharmaceutically acceptable 
chelating agent are further described hereinbelow. Additionally, if 
desired, polymerization may be carried out so as to incorporate other 
therapeutically active or contraceptive materials, as well as the 
spermicide, such as antifungal agents, antiviral agents, antibiotics, 
hormones, pH control agents, and the like. 
Various types of polymers, such as polyethylene, polyurethane, nylon, and 
silastics are suitably flexible and inert. Preparation and regulation of 
the physical properties of said polymeric materials are well known to 
those skilled in the art. Standard methods of preparation and property 
control for these polymers may for example, be found in the Modern 
Plastics Encyclopedia, published by McGraw-Hill, New York, N.Y., U.S.A. 
In the preferred embodiment, silastic polymers are employed, such as those 
described in U.S. Pat. No. 3,269,996. In a still more preferred 
embodiment, the silastic is a silicone elastomer such as Dow-Corning 382 
silicone elastomer (available from Dow Corning Corp.), polymerized in the 
presence of a catalyst. 
In a typical preparation, the spermicide 0.05%-10% by weight, preferably 
0.5%-5% and a pharmaceutically acceptable chelating agent such as EDTA 
0.05%-1% by weight, preferably 0.1%-0.75% are stirred into a paste 
containing the silicone elastomer and a suitable catalyst as essentially 
the balance of the mixture, and optionally, other therapeutically active 
or contraceptive ingredients. The mixture is placed into a mold suitable 
for the configuration such as those described above, and allowed to set. 
The proportion of catalyst to monomer will depend on the degree of 
flexibility desired, but will range from 10%-30% of the entire mixture, 
preferably about 20% for the uses described herein. 
Optional additional therapeutically active or contraceptive ingredients may 
include, without limitation, bacteria controlling agents, such as, for 
example, penicillins, tetracyclines, or streptomycins or their 
pharmaceutically acceptable salts; antiinflammatory agents, such as, for 
example, cortisone or prednisolone or their salts; estrogens or other 
hormones, such as, for example, estradiol; prostaglandins; or 
progesterone; or physiologically safe acids such as tartaric, citric or 
boric, which serve to lower the ambient pH and thus create a hostile 
environment for spermatoza. 
C. Spermicides 
The effectiveness of the device and method of contraception described 
herein depends upon the use, as a spermicide, of compounds of the class 
consisting of the 1-substituted imidazoles. 
Particularly useful classes of spermicides are 1-substituted imidazoles 
disclosed in U.S. Pat. No. 4,247,552 as well as the imidazoles described 
hereinbelow. 
Illustrative of 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): 
##STR1## 
wherein: (i) 
R is alkyl of one to twelve carbon atoms, phenyl or phenyl-lower-alkyl of 
one to four carbon atoms wherein the phenyl ring is optionally substituted 
by one or more lower alkyl of one to four carbon atoms, lower alkoxy of 
one to four carbon atoms, halo or trifluoromethyl; 
R.sup.2 together with R.sup.3 is ethylenedithio or propylenedithio wherein 
the alkylene chain is optionally substituted by one lower alkyl of one to 
four carbon atoms; and n is 1, 2 or 3; 
(ii) 
R is cycloalkyl of five to seven carbon atoms or cycloalkylalkyl of six to 
ten carbon atoms; 
R.sup.2 is hydrogen or lower alkyl of one to four carbon atoms; 
R.sup.3 is alkyl of two to twelve carbon atoms, cycloalkyl of five to seven 
carbon atoms or cycloalkylalkyl of six to ten carbon atoms; and n is 1, 2 
or 3; 
(iii) 
R is phenyl or phenyl-lower-alkyl of one to three carbon atoms wherein the 
phenyl ring is optionally substituted by one or more lower alkyl of one to 
four carbon atoms, lower alkoxy of one to four carbon atoms, halo or 
trifluoromethyl; 
R.sup.2 is hydrogen or lower alkyl of one to four carbon atoms; 
R.sup.3 is alkyl of one to twelve carbon atoms, phenyl-lower-alkyl of one 
to three carbon atoms wherein the phenyl ring is optionally substituted by 
one or more lower alkyl of one to four carbon atoms, lower alkoxy of one 
to four carbon atoms, halo, or trifluoromethyl; and 
n is 1, 2 or 3; 
(iv) 
R.sub.2 is alkyl of one to twelve carbon atoms; 
R.sup.2 is hydrogen or lower alkyl of one to four carbon atoms; 
R.sup.3 is hydrogen or alkyl of one to twelve carbon atoms; and 
n is 1, 2, 3 or 4; and 
(v) 
R and R.sup.4 are each alkyl of one to twelve carbon atoms, alkenyl of two 
to twelve carbon atoms, phenyl, phenyl-lower-alkyl of one to four carbon 
atoms or phenyl-lower-alkenyl of two to four carbon atoms wherein the 
phenyl ring is optionally substituted by one or more lower alkyl of one to 
four carbon atoms, lower alkoxy of one to four carbon atoms, halo, or 
trifluoromethyl; 
R.sup.2 is hydrogen or lower alkyl of one to four carbon atoms; 
R.sup.3 is X-R.sup.4 wherein X is oxygen or sulfur; and 
n is 1, 2 or 3. 
Within group (i) it is preferred that R is an alkyl group of one to twelve 
carbon atoms. Within this subgroup it is preferred that R is alkyl of five 
to ten carbon atoms and n is 1 or 2. Within this subgroup it is preferred 
that R.sup.2 together with R.sup.3 is ethylenedithio. Particularly 
preferred are 
1-[(3,3-ethylenedithio)-n-octyl]imidazole; 
1-[(3,3-ethylenedithio)-n-decyl]imidazole; 
1-[(3,3-ethylenedithio)-n-dodecyl]imidazole; 
1-[(2,2-ethylenedithio)-n-octyl]imidazole; 
1-[(2,2-ethylenedithio)-n-octyl]imidazole; 
1-[(2,2-ethylenedithio)-n-decyl]imidazole; and 
1-[(2,2-ethylenedithio)-n-dodecyl]imidazole. 
Within group (ii) it is preferred that R is cyclohexyl or cyclohexylalkyl. 
It is also preferred that when R.sup.3 is alkyl that R.sup.3 is alkyl of 
four to twelve carbon atoms. Particularly preferred are 
1-(2-cyclohexylmethyl-n-hexyl)imidazole; 
1-(2-cyclohexyl-n-hexyl)imidazole; 
1-[2-methyl-2-(cyclohexylmethyl)-n-hexyl)imidazole; 
1-[2-propyl-2-(cyclohexylmethyl)-n-pentyl]imidazole; 
1-(3-cyclohexylmethyl)-n-heptyl)imidazole; 
1-(4-cyclohexylmethyl)-n-octyl)imidazole; and 
1-[2-cyclohexylmethyl)-3-cyclohexyl-n-propyl]-imidazole. 
Within group (iii) it is preferred that R is phenyl-lower-alkyl optionally 
substituted by one or more lower alkyl of one to four carbon atoms, lower 
alkoxy of one to four carbon atoms, halo or trifluoromethyl. Preferred 
within this subgroup are 
1-[2-(2-(2-chlorophenyl)ethyl)-n-hexyl]imidazole; 
1-[2-(2-(4-chlorophenyl)ethyl)-n-hexyl]imidazole; 
1-[2-(2-(4-methylphenyl)ethyl)-n-hexyl]imidazole; 
1-(2-benzyl-n-heptyl)imidazole; 
1-[2-(2-phenylethyl-n-octyl)imidazole; and 
1-[2-(2-(4-methylphenyl)ethyl)-n-octyl]imidazole. 
Within group (iv) it is preferred that R is alkyl of four to twelve carbon 
atoms. Particularly preferred are 
1-(n-decyl)imidazole; 
1-(n-dodecyl)imidazole; 
1-(3-propyl-n-heptyl)imidazole; 
1-(2-propyl-n-octyl)imidazole; 
1-(4-n-butyl-n-octyl)imidazole; and 
1-(3-n-pentyl-n-nonyl)imidazole. 
Within groups (v) it is preferred that R is alkyl of three to eight carbon 
atoms. It is particularly preferred within this subgroup that R.sup.4 is 
phenyl or phenyl-lower-alkyl wherein the phenyl ring is optionally 
substituted by one or more lower alkyl of one to four carbon atoms, lower 
alkoxy of one to four carbon atoms, halo or trifluoromethyl. Particularly 
preferred is 
1-[2-(2,4-dichlorobenzyloxy)-n-octyl]imidazole. 
Compounds of formula (I) as defined in group (i) are prepared by the 
methods disclosed in U.S. Pat. No. 4,359,475 incorporated herein by 
reference. Compounds wherein R is alkyl may be prepared by the above 
disclosed methods, but substituting the appropriate alkyl halo ketones for 
the aryl halo ketones. The alkyl halo ketones are prepared by the methods 
described in U.S. Pat. No. 4,078,071 and U.S. Pat. No. 4,359,475 using the 
appropriate alkyl starting material. 
The compounds described in groups (ii), (iii) and (iv) are prepared, for 
example, by the following reaction sequence: 
##STR2## 
wherein R' is a lower alkyl group, e.g., an ethyl group, and R, R.sup.2, 
and R.sup.3, are as defined above and W is a leaving group. 
In the above sequence, the alkylation steps may, of course, be carried out 
in any order, and either RW, R.sup.2 W, or R.sup.3 W may be added first. 
The conversion of the acid of formula (IV) to the acid of formula 
(IV.sub.a) wherein R.sup.2 is lower alkyl may be carried out as depicted 
by employing a dianion (e.g., the dilithium derivative) of the acid of 
formula (IV), or by alkylation of an ester derivative of the compound of 
formula (IV) (e.g., a t-butyl ester) with R.sup.3 W followed by 
hydrolysis. The required reaction conditions for the malonic ester 
synthesis are well-known to those skilled in the art and are described, 
for example, in Organic Chemistry by Robert T. Morrison and Robert N. Boyd 
(2nd ed.) pp. 918-921 and the Merck Index (9th ed.) p. ONR-57. 
The compound of formula (IV) or (IVa) is then reduced to the corresponding 
compound of formula (II) wherein n is 1, (II.sub.1), using an appropriate 
reducing agent, such as, for example, borane-tetrahydrofuran complex or 
lithium aluminum hydride. The reducing agent, e.g., borane-tetrahydrofuran 
is added to a solution of the acid of formula (IV) or (IVa) in a solvent 
such as tetrahydrofuran at -20.degree. to 30.degree. C., preferably at 
-0.degree. to 10.degree. C. and stirred for 5 minutes to 1 hour, 
preferably for 15 minutes to 30 minutes and then allowed to warm to room 
temperature. 
Those compounds wherein R.sup.2 and R.sup.3 are both hydrogen may be 
prepared from RCH(COOR').sub.2 by decarboxylation followed by 
hydrogenation as described supra or directly from RCH.sub.2 COOH by 
hydrogenation. 
The intermediates of the formulas RW, R.sup.2 W and R.sup.3 W (wherein 
R.sup.2 is lower alkyl) are commercially available, i.e. from Aldrich 
Chemical Co., or can be prepared by methods well known in the art. The 
hydroxy group of the corresponding alcohols may be converted to a suitable 
leaving group, W, by the methods described hereinafter, or the above 
intermediates may be prepared by methods analogous to the methods depicted 
in the above reaction sequence. Another method of preparing compounds RW 
or R.sup.3 W wherein R and/or R.sup.3 are cyclohexyl is by hydrogenation 
of the analogous phenyl compound by, e.g. catalytic hydrogenation, 
discussed hereinafter. 
Compounds of formula (II) wherein n is greater than 1, may be prepared by 
homologation of compounds of formula (II.sub.1). 
The halide or sulfonate of the alcohol of formula (II.sub.1) (n is 1) 
(i.e., compounds of formula III) is converted to the corresponding nitrile 
by reaction with, for example, sodium cyanide in dimethylformamide. The 
mixture is heated to 50.degree. to 100.degree. C., preferably to 
60.degree. to 90.degree. C. for 1 to 24 hours, preferably overnight. The 
nitrile derivative is hydrolyzed by heating the reaction mixture to reflux 
for 1 to 24 hours, preferably overnight in the presence of a strong acid, 
e.g., aqueous sulfuric acid. Reduction as described above gives the 
alcohol of formula (II.sub.2) This sequence can, of course, be repeated, 
resulting in a compound of formula II wherein n is 3 (II.sub.3). 
The conversion of compounds of formula (II) to compounds of formula (III) 
may be accomplished by treating a compound of formula (II) with either a 
halogenating agent, such as, for example, thionyl bromide or 
N-bromosuccinimide/triphenylphosphine or with an appropriate sulfonyl 
halide, for example, a sulfonyl chloride, optionally in an inert solvent, 
such as, for example, dichloromethane, or tetrahydrofuran in the presence 
of a base, for example, a tertiary amine, such as, for example, pyridine 
or triethylamine. The base may also be used as the solvent, for example, 
pyridine. The reaction is carried out at a temperature of about 
-20.degree. C. to about 50.degree. C., preferably 0.degree. C. to 
25.degree. C. and over a period of 5 minutes to 24 hours preferably, 30 
minutes to overnight. Thereafter, the compound of formula (III) is 
converted to the final product of formula (I), by treating compound of 
formula (III) with at least one mole of imidazole per mole of compound of 
formula (III), preferably an excess (e.g. 1.1 to 5 moles imidazole per 
mole of compound of formula (III)). The reaction takes place in the 
absence of solvent (above the melting point of the mixture) or in an inert 
organic solvent such as dimethylformamide (DMF), acetonitrile, 
tetrahydrofuran, dimethylsulfoxide (DMSO) and the like; preferably, 
dimethylformamide, at a temperature between about 0.degree. to 170.degree. 
C., most preferably from about 50.degree. to 150.degree. C. Alternatively, 
the reaction may be carried out using a salt of imidazole, for example, an 
alkali metal salt, preferably a sodium salt, in the same solvents, at a 
temperature from about 0.degree. to 150.degree. C., preferably from about 
20.degree. to about 110.degree. C. 
The compound of formula (I) wherein R and/or R.sup.3 is cyclohexyl may also 
be prepared by catalytically hydrogenating the corresponding phenyl 
imidazole compound wherein the phenyl ring is optionally substituted by 
lower alkyl. This compound, dissolved in an inert solvent, is hydrogenated 
using a catalyst such as rhodium on alumina at a pressure of about three 
to four atmospheres and a temperature of about 60.degree. to 80.degree. C. 
Compounds of formula (I) as defined in group (v) are prepared according to 
the methods described in U.S. Pat. Nos. 3,658,813, 3,717,655, 3,839,574, 
4,045,568, 4,055,652, 4,059,705, 4,078,071, 4,123,542, 4,213,991 all 
patents incorporated herein by reference. 
Chelating Agents 
The compounds having chelating action and useful as efficacy promoters in 
this invention were investigated by incorporating the chelating agent in, 
for example, a vaginal ring containing a 1-substituted imidazole in order 
to examine increase or decrease of spermicidal/spermatostatic activity of 
the 1-substituted imidazole. The mechanism of promotion effect has not so 
far been clarified, but it seems likely that the absorption mechanism of 
the cervical mucus may be changed through the chelating action and 
affinity to the mucous membrane possessed by these efficacy promoters. 
Although the mechanism of action of the efficacy promoter to increase the 
absorption by the cervical mucus may be speculated as mentioned above such 
a mechanism action is still no more than mere estimation and it is only 
sufficient to employ a compound having chelating action capable of bonding 
to at least calcium ions or magnesium ions. More specifically, the 
chelating ligands with effective chelating action, may be, for example, 
acid groups such as carboxylic acid group, sulfonic acid group, and 
phosphoric acid group, phenolic hydroxyl group, hydroxyl group, imino 
group, carbonyl group, amino group, and the like. Further, compounds 
having chelating action with these chelating ligands, include organic 
compounds having at least one acid group, such as carboxylic acid groups, 
thiocarboxylic acid groups, sulfonic acid groups or phosphoric acid 
groups, organic acid compounds having in addition, phenolic hydroxyl 
groups or organic compounds having at least 2 carbonyl groups. Organic 
compounds having at least one carboxylic acid group, sulfonic acid group 
or phosphoric acid group, include such compounds as monocarboxylic-, 
sulfonic-phosphoric-compounds or keto-carboxylic-, sulfonic-, 
phosphoric-compounds having carbonyl groups, hydroxy- or 
amino-carboxylic-, sulfonic-, phosphoric-compounds having hydroxyl groups 
or amino groups and polyacid compounds having two or more carboxylic acid 
groups, sulfonic acid groups or phosphoric acid groups. These compounds 
may also be classified as aliphatic compounds, alicyclic compounds, 
aromatic compounds and heterocyclic compounds. Further, keto-enol type 
tautomeric isomers may be classified either as compounds having carbonyl 
groups or as compounds having hydroxyl groups. Examples of chelating 
agents encompassed by this invention are polyacid compounds such as oxalic 
acid, malonic acid, succinic acid, fumaric acid, aconitic acid, pimellic 
acid, sebacic acid, suberic acid, azelaic acid, acridinic acid, 
allylmalonic acid, mesaconic acid, brassylic acid, dodecanolic acid, 
methylmalonic acid, ethylmalonic acid, phthalic acid, terephthalic acid, 
homophthalic acid, phenylsuccinic acid, phenylmalonic acid, 
phenylenediacetic acid, 1,3-naphthalenedicarboxylic acid, iminodiacetic 
acid, .beta.-alaninediacetic acid, hydrochelidonic acid, 
1,2-cyclohexanedicarboxylic acid, anthranylinoacetic acid, oxanylic 
acid-o-carboxylic acid, tricarballylic acid, 
1,3-diamino-propanetetraacetic acid, hydroxyethyliminodiacetic acid, 
ethylenediaminediacetic acid, ethylenediaminedipropionic acid, 
hydroxyethylethylenediaminetriacetic acid, ethylenediaminetetraacetic 
acid, ethyleneglycol-bis(.beta.-aminoethyl ether) N,N'-tetraacetic acid, 
trans-cyclohexanediamine-tetraacetic acid, diaminopropanoltetraacetic 
acid, diethylenetriaminepentaacetic acid, 
ethylenediamine-di-o-hydroxyphenylacetic acid, 
triethylenetetraminehexaacetic acid, nitrilotriacetic acid, 
nitrilotripropionic acid and the like. Examples of hydroxy-acid compounds 
or phenolic hydroxyl group-acid compounds are lactic acid, citric acid, 
isocitric acid, malic acid, glyceric acid, tartaric acid, oxyacetic acid, 
dihydroxylethylglycinepantothenic acid, pantoic acid, mevalonic acid, 
iduronic acid, saccharic acid, phospheneolpyruvic acid, 2-phosphoglyceric 
acid, 3-phosphoglyceric acid, glycero-3-phosphoric acid, 
glucose-1,6-diphosphoric acid, fructose-1,6-diphosphoric acid, 
.alpha.-oxybutyric acid, 8-oxybutyric acid, gluconic acid, 
.alpha.-oxyisobutyric acid, glucuronic acid, galacturonic acid, leusinic 
acid, oxyglutamic acid, diethooxalic acid, strolactinic acid, phenyllactic 
acid, naphthylglycolic acid, phenylhydroacrylic acid, benzylic acid, 
mandelic acid, salicylic acid, 2,5-dihydroxybenzoic acid, 
2,3-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, 
tetra-oxyhexahydrobenzoic acid, shikimic acid, melilotic acid, 
hexahydrosalicyclic acid, o-, m-, p-phenolsulfonic acid, 
1,2-hydroxybenzene-3,5-disulfonic acid, 1-naphthyl-2-sulfonic acid, 
1-naphthol-3,6-disulfonic acid, 4-amino-phenol-2-sulfonic acid, and the 
like. Exemplary carbonyl-acid compounds are glyoxalic acid, glyoxylylactic 
acid, acetoacetic acid, oxaloacetic acid, a-ketobutyric acid, acetopyruvic 
acid, pyuruvic acid, .alpha.-ketoglutaric acid, .beta.-ketoglutaric acid, 
.alpha.-ketomalonic acid, .alpha.-ketovaleric acid, .beta.-ketovaleric 
acid, benzoylformic acid, benzoylglylcolic acid, benzoylpropionic acid, 
benzoylbutric acid, levulinic acid, .beta.-ketocapric acid, phenylpyruvic 
acid, oxanylic acid, and the like. Typical examples of monoacid compounds 
are butyric acid, isovaleric acid, caproic acid, caprylic acid, capric 
acid, undecylic acid, lauric acid, myrystic acid, palmitic acid, stearic 
acid, eicosanic acid, arachidonic acid, linoleic acid, linolenic acid, 
phenylthioacetic acid, phenylpropionic acid, .gamma.-phenylbutyric acid, 
acetylsalicyclic acid, anisic acid, phenylphosphoric acid and the like. A 
compound containing phenolic hydroxyl groups may be, for example, 
salicylic acid as mentioned above. Amino-acid compounds may include amino 
acids such as quinaldic acid, kynurenic acid, glycine, alanine, proline, 
hydroxyproline, phenylalanine, phenylglycine, tyrosine, cystine, cysteic 
acid, .epsilon.-aminocaproic acid, aspartic acid, glutamine, glutamic 
acid, leucine, isoleucine, serine, valine, threonine, methionine, 
p-hydroxyphenylglycine, alginine, tryptophan, hystidine, lysine, 
.gamma.-carboxyglutamic acid, kynurenine and the like. Further, organic 
compounds having at least two carbonyl groups, may be preferably employed 
as enamine derivatives between amino acids (e.g. glycine, lysine, leusine, 
serine, phenylalanine, glutamic acid, thyrosine, phenylglycine, 
p-hydroxyphenyl-glycine, proline, hydroxyproline) and diketo compounds 
(e.g. acetylacetone, propionylacetone, butyroylacetone, 
3-phenylacetylacetone, methylacetonacetate, ethylacetoacetate, 
ethyldiacetoacetate, propylacetoacetate, methoxyethylacetoacetate, 
ethoxyethylacetoacetate, diethyl ethoxymethylene-malonate, dibutyl 
ethoxymethylmalonate, and the like). In addition, the above diketo 
compounds per se may also be employed as absorption promoters. These 
absorption promoters are generally used in the form of alkali metal salts 
such as sodium salts or potassium salts, or ammonium salts, but they may 
also be esterified to the extent that water solubility is not impaired. In 
some of the absorption promoters, for example, polyacid compounds such as 
ethylenediamine-tetraacetic acid (EDTA) or 
ethyleneglycol-bis(.beta.-aminoethyl ether)N,N'-tetraacetic acid (EGTA), a 
part of the acid groups may be protected by esterification or be converted 
to other derivatives. In particular, in case of EDTA, one of the 
carboxylic groups may be converted to ethylester. 
It is preferred that the chelating agent is selected from the group 
consisting of polyacid derivatives of ethylenediamine, enamine derivatives 
of amino acids, and compunds containing hydroxy or phenolic hydroxy group 
and carboxy groups. Particularly preferred are polyacid derivatives of 
etheylenediamine with ethylene-diaminetetraacetic acid (EDTA) being the 
most preferred. 
Method of Contraception 
The method of the present invention comprises effecting contraception using 
the article of manufacture described hereinabove. In this aspect of the 
invention, the device described herein is inserted and retained in the 
vaginal cavity in such a manner that an effective concentration of 
spermicide is maintained in the cervical mucus during and for at least 24 
hours after removal of the device. 
In the method of the present invention, the ability of the unique 
combination of the spermicide and pharmaceutically acceptable chelating 
agent to be absorbed by and maintained at effective levels in the cervical 
mucus permit insertion at any time during the menstrual cycle to as little 
as one hour before intercourse. Because the spermicide is absorbed at 
effective concentrations into the cervical mucus, the device of the 
present invention may be removed up to 24 hours prior to intercourse. This 
presents a distinct advantage over known devices and would be preferable 
to females with small vaginas and to partners who object to the presence 
of intrauterine devices during intercourse. An additional advantage of the 
present method of contraception is the sustained effective concentration 
of the spermicide in the cervical mucus for up to 24 hours after removal 
of the device. This provides greater freedom for the partners in that the 
protection is maintained during multiple coital acts. 
The device of the present invention may be inserted, if so desired, at 
least as much as 36 days before intercourse and may be removed, if so 
desired, up to 24 hours before to immediately thereafter. It is 
contemplated that the device would be removed during menstruation, and 
that ordinarily its total residence time in the vagina would not be 
greater than one month. The device may be used repeatedly until the 
internal concentration of spermicide and chelating agent is decreased 
below an effective level. 
The following examples are intended to illustrate, but not to limit, the 
invention: 
EXAMPLE I 
Six white, soft, elastic cervical rings were prepared, each of weight 0.5 
g., outer diameter 2.3 cm, inner diameter 1.5 cm, and thickness 0.3 cm. 
The rings were made from: 
1-(2-(2,4-dichlorobenzyloxy)-n-octyl)imidazole malate: 0.01 g 
EDTA: 2.5 mg 
Dow Corning Silicone 382 elastomer: 0.6 g 
Catalyst M (stannous octoate): 5 drops 
The procedure was as follows: 
The spermicide and EDTA was mixed well with the elastomer, and to the 
resultant mixture was added the catalyst with thorough mixing with a 
spatula. The resultant paste was carefully transferred to molds by small 
increments to avoid trapping of air. The molds were then allowed to stand 
overnight at room temperature for the elastomer to cure, whereafter smooth 
white rings were obtained from the molds. 
(Silicone 382 elastomer is an opaque viscous elastomer base composed of 
polydimethylsiloxane and silica filler.) 
EXAMPLE II 
A ring prepared as in Example 1 was placed intravaginally in a female 
stumptailed macaque (maintained in an estrogen-dominated physiological 
state by subcutaneously implanted silastic capsules of estradiol. Cervical 
mucus in such an animal continuously possesses the mucus characteristics 
only seen around the time of ovulation in normal macaques). 
The ring was maintained in place for eight days, and then removed. 
Twenty-four hours after ring removal, the female was mated, and poscoital 
analysis revealed the following: 
______________________________________ 
% Forward 
Sperm Motility 
Progression 
______________________________________ 
Vaginal Fluid 
Sperm Conc. 
No. .times. 10.sup.6 
158 70 4 
Cervical Mucus 
Sperm Con. 
(Per Grid) 
300 0 0 
______________________________________ 
These results are indicative of the contraceptive effects achievable in the 
cervical mucus with devices according to the invention.