Estradiol-16α-carboxylic acid esters as locally active estrogens

#The present invention relates to novel 16-α estradiol ester compounds and their use as locally active estrogens in the treatment of the symptomology of menopause.

#It is well recognized that pharmacologic estrogen administration (hormone replacement therapy, HRT) can alleviate most, if not all, of the symptomology associated with the menopause. These symptoms include, but are not limited to: bone loss associated with osteoporosis; heart disease associated with changes in blood lipids and lipoproteins; hot flashes; and vaginal dyspareunia.1 However, there are risks associated with estrogen administration in HRT as well as oral contraceptive use, and include an association with endometrial cancer, breast cancer, and stroke. Although for the most part, the therapeutic benefits of HRT outweigh the risks, nevertheless, while the risks are small, they do exist.2-4

#Estrogen therapy, directly and indirectly, affects a number of organs. Some of the outcomes associated with estrogen therapy are deleterious. Consequently, where possible, symptomology which could be ameliorated by local rather than systemic administration could limit the adverse side-effects of estrogen therapy. One such syndrome that can be treated directly, caused by estrogen deprivation or estrogen antagonists, is vaginal dyspareunia. It is a common disorder which affects a large proportion of women, approximately 40% within 10 years of the onset of the menopause.5 It is and important factor in the quality of life for women so afflicted, as it is associated with a severe physical and psychological impact. It is not only painful but it can dramatically influence a women's self image and lead to clinical depression.6 Another possible use of local estrogens includes topical administration to aging skin. The skin contains ER and it is an estrogen target organ.11-13 While topical application of estrogens to the vaginal mucosa has been used to treat vaginal dyspareunia of the menopause, these estrogens are adsorbed into the blood and result in significant blood levels of estrogens.7-10 Thus, this therapy may not be used where systemic estrogens are contraindicated.

#FIG. 1 provides an abbreviation key for the E2-16α-carboxy esters of the present invention. E16-(m+1),(n+1): where 16 is the position in the steroid nucleus from which the ester chain originates and the quantity (m+1) is the number of carbon atoms in the acid and (n+1), the alcohol portion of the chain containing the ester. e.g. E16-2,2; in the figure m and n=1.

#FIG. 2 depicts of the results of an in vivo systemic estrogenic assay (uterotrophic assay) as described in the experimental section. Immature female rats (22 days old) were injected with E16-1,1, E16-1,2 and E16-1,2F1 as well as E2 in sesame oil once daily for 3 days. On the fourth day the animals were killed, the uteri removed and weighed. The total dose is shown. Controls were injected with sesame oil. Error bars are±S.D. n=5. *P<0.05, **P<0.001 when compared to the control.

#FIG. 3 depicts the results of in vivo local estrogenic assay (vaginal assay). Castrated female mice were intravaginally administered E16-1,1, E16-1,2, E16-1,2F1 and E2 in a single dose.

#The present invention is directed to compounds according to the structure:

#Where R is H, a C1 to C5 alkyl, vinyl, CF3, CH2CH2F, CH2CHF2 and CH2CF3; and m is from 0-2. Preferably, R is H, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, pentyl, neo-pentyl, vinyl, CF3, CH2CH2F, CH2CHF2 and CH2CF3. Preferably, m is 0 and R is methyl, ethyl, CH2CH2F, CH2CHF2 or CH2CF3. More preferably, m is 0 and R is methyl, ethyl, CH2CH2F or CH2CHF2.

#The present invention also relates to pharmaceutical compositions according to the present invention comprising an effective amount of at least one compound as described above in combination with a pharmaceutically acceptable carrier, additive or excipient. Preferably, pharmaceutical compositions according to the present invention are formulated in topical dosage form, more preferably as vaginal creams, gels or suppositories for local delivery of the active compounds to the patient.