Sex steroid precursors alone or in combination with a selective estrogen receptor modulator and/or with estrogens and/or a type 5 cGMP phosphodiesterase inhibitor for the prevention and treatment of vaginal dryness and sexual dysfunction in postmenopausal women
View Patent ↗Novel methods for treating or reducing the likelihood of acquiring vaginal dysfunctions, more particularly vaginal dryness and dyspareunia, leading to sexual dysfunction and low sexual desire and performance , in susceptible warm-blooded animals including humans involving administration of a sex steroid precursor. Further administration of estrogen or selective estrogen receptor modulator, particularly those selected from the group consisting of Raloxifene, Arzoxifene, Tamoxifen, Droloxifene, Toremifene, Iodoxifene, GW 5638, TSE-424, ERA-923, and lasofoxifene, and more particularly compounds having the general structure: is specifically disclosed for the medical treatment and/or inhibition of development of some of these above-mentioned diseases. Pharmaceutical compositions for delivery of active ingredient(s) and kit(s) useful to the invention are also disclosed.
1. A method of treating or reducing the likelihood of acquiring a vaginal disease or condition caused by the atrophy of either or both the layer lamina propria and/or the layer muscularis of the vagina in postmenopausal women, said disease or condition selected from the group consisting of atrophic vaginitis, vaginal atrophy, narrowing of vaginal cavity and shortening of the vaginal cavity, said method comprising administering a sex steroid precursor selected from the group consisting of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-ene-3β3,17β-diol and 4-androsten-3,17-dione to a patient in need of said treatment, the method further comprising the step of administering to said patient a therapeutically effective amount of a selective estrogen receptor modulator for uterine and mammary gland protection against cancer as part of a combination therapy, without administering estrogen to said patient.
2. The method of claim 1 where the selective estrogen receptor modulator is acolbifene.
3. The method of claim 1 wherein the vaginal diseases or problems are selected from the group consisting of vaginal atrophy and atrophic vaginitis.
4. The method of claim 1 , wherein the sex steroid precursor is dehydroepiandrosterone.
5. The methods of any one of claims 1 , wherein the sex steroid precursor is administered intravaginally.
6. The methods of any one of claims 1 , wherein the sex steroid precursor is orally or percutaneously administered.
7. The method of any one of claims 1 , wherein the selective estrogen receptor modulator is orally, percutaneously or intravaginally administered.
8. A method of treating atrophic vaginitis or vaginal atrophy in postmenopausal women said method comprising administering a sex steroid precursor selected from the group consisting of dehydroepiandrosterone, dehydroepiandrosterone sulphate, androst-5-ene-3β,17β-diol and 4-androsten-3,17-dione in association with a therapeutically effective amount of a selective estrogen receptor modulator for uterine and mammary gland protection against cancer to a patient in need of such treatment, without administering estrogen to said patient.
9. The method of claim 8 , wherein the sex steroid precursor and the selective estrogen receptor modulator are administered intravaginally, orally or percutaneously.
10. The method of any one of claims 1 , wherein the selective estrogen receptor modulator has a molecular formula with the following features:
a) two aromatic rings spaced by 1 to 2 intervening carbon atoms, both aromatic rings being either unsubstituted or substituted by a hydroxyl group or a group converted in vivo to hydroxyl; and
b) a side chain possessing an aromatic ring and a tertiary amine function or salt thereof.
11. The method of claim 10 , wherein the selective estrogen receptor modulator has the following formula:
wherein R 1 and R 2 are independently hydrogen, hydroxyl or a moiety which is converted to hydroxyl in vivo;
wherein Z is a bivalent closing moiety;
wherein the R 100 is a bivalent moiety which distances L from the B-ring by 4-10intervening atoms;
wherein L is a bivalent or trivalent polar moiety selected from the group of —SO—, —CON—, —N<, and —SON<;
wherein G 1 is selected from the group consisting of hydrogen, a C 1 to C 5 hydrocarbon or a bivalent moiety which joins G 2 and L to form a 5-to 7-membered heterocyclic ring, and halo or unsaturated derivatives of the foregoing;
wherein G 2 is either absent or selected from the group consisting of hydrogen, a C 1 to C 5 hydrocarbon or a bivalent moiety which joins G 1 and L to form a 5-to 7- membered heterocyclic ring, and halo or unsaturated derivatives of the foregoing;
wherein G 3 is selected from the group consisting of hydrogen, methyl and ethyl.
12. The method of claim 10 , wherein the selective estrogen receptor modulator is an optically active compound having an absolute configuration S on carbon 2 or pharmaceutically acceptable salt thereof, said compound having the molecular structure:
wherein R 1 and R 2 are independently selected from the group consisting of hydroxyl and a moiety convertible in vivo to hydroxyl;
wherein R 3 is a species selected from the group consisting of saturated, unsaturated or substituted pyrrolidinyl, saturated, unsaturated or substituted piperidino, saturated, unsaturated or substituted piperidinyl, saturated, unsaturated or substituted morpholino, nitrogen-containing cyclic moiety, nitrogen-containing polycyclic moiety, and NRaRb, Ra and Rb being independently hydrogen, straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, and straight or branched C 2 -C 6 alkynyl.
13. The method of claim 12 , wherein said compound or salt substantially lacks (2R)-enantiomer.
14. The method of claim 12 , wherein the benzopyran derivative is a salt of an acid selected from the group consisting of acetic acid, adipic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, hydrochlorothiazide acid, hydroxy-naphthoic acid, lactic acid, maleic acid, methanesulfonic acid, methylsulfuric acid, 1,5-naphthalenedisulfonic acid, nitric acid, palmitic acid, pivalic acid, phosphoric acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, terephthalic acid, p-toluenesulfonic acid, and valeric acid.
15. The method of any one of claims 1 , wherein the selective estrogen receptor modulator is selected from the group consisting of Raloxifene, Arzoxifene(LY 353381), LY 335563, Tamoxifen, OH-Tamoxifen, Droloxifene, Toremifene, Idoxifen, Ospemifene, GW 5638, SERM 3339, TSE-424, ERA-923, Lasofoxifene(CP 336156), Levormeloxifene, Acolbifene(EM-1538), EM-652 and EM-800.
16. The method of any one of claims 1 , 8 , and 9 , wherein said selective estrogen receptor modulator is:
17. The method of any one of claims 1 , wherein the sex steroid precursor is dehydroepiandrosterone.
18. The method of claim 7 , wherein the selective estrogen receptor modulator has a molecular formula with the following features:
a) two aromatic rings spaced by 1 to 2 intervening carbon atoms, both aromatic rings being either unsubstituted or substituted by a hydroxyl group or a group converted in vivo to hydroxyl; and
b) a side chain possessing an aromatic ring and a tertiary amine function or salt thereof.
19. The method of claim 7 , wherein the selective estrogen receptor modulator has the following formula:
wherein R 1 and R 2 are independently hydrogen, hydroxyl or a moiety which is converted to hydroxyl in vivo;
wherein Z is a bivalent closing moiety;
wherein the R 100 is a bivalent moiety which distances L from the B-ring by 4-10 intervening atoms;
wherein L is a bivalent or trivalent polar moiety selected from the group of —SO—, —CON—, —N<, and —SON<;
wherein G 1 is selected from the group consisting of hydrogen, a C 1 to C 5 hydrocarbon or a bivalent moiety which joins G 2 and L to form a 5-to 7-membered heterocyclic ring, and halo or unsaturated derivatives of the foregoing;
wherein G 2 is either absent or selected from the group consisting of hydrogen, a C 1 to C 5 hydrocarbon or a bivalent moiety which joins G 1 and L to form a 5-to 7- membered heterocyclic ring, and halo or unsaturated derivatives of the foregoing;
wherein G 3 is selected from the group consisting of hydrogen, methyl and ethyl.
20. The method of claim 7 , wherein the selective estrogen receptor modulator is an optically active compound having an absolute configuration S on carbon 2 or pharmaceutically acceptable salt thereof, said compound having the molecular structure:
wherein R 1 and R 2 are independently selected from the group consisting of hydroxyl and a moiety convertible in vivo to hydroxyl;
wherein R 3 is a species selected from the group consisting of saturated, unsaturated or substituted pyrrolidinyl, saturated, unsaturated or substituted piperidino, saturated, unsaturated or substituted piperidinyl, saturated, unsaturated or substituted morpholino, nitrogen-containing cyclic moiety, nitrogen-containing polycyclic moiety, and NRaRb, Ra and Rb being independently hydrogen, straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, and straight or branched C 2 -C 6 alkynyl.
21. The method of claim 20 , wherein said compound or salt substantially lacks (2R)-enantiomer.
22. The method of claim 20 , wherein the benzopyran derivative is a salt of an acid selected from the group consisting of acetic acid, adipic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, hydrochlorothiazide acid, hydroxy-naphthoic acid, lactic acid, maleic acid, methanesulfonic acid, methylsulfuric acid, 1,5-naphthalenedisulfonic acid, nitric acid, palmitic acid, pivalic acid, phosphoric acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, terephthalic acid, p-toluenesulfonic acid, and valeric acid.
23. The method of claim 7 , wherein the selective estrogen receptor modulator is selected from the group consisting of Raloxifene, Arzoxifene(LY 353381), LY 335563, Tamoxifen, OH-Tamoxifen, Droloxifene, Toremifene, Idoxifen, Ospemifene, GW 5638, SERM 3339, TSE-424, ERA-923, Lasofoxifene(CP 336156), Levormeloxifene, Acolbifene(EM-1538), EM-652 and EM-800.
24. The method of claim 7 , wherein said selective estrogen receptor modulator is:
25. The method of claim 7 , wherein the sex steroid precursor is dehydroepiandrosterone.
26. The method of claim 5 , wherein the sex steroid precursor is dehydroepiandrosterone.
27. The method of claim 6 , wherein the sex steroid precursor is dehydroepiandrosterone.