WO2010054758A1 - Synergistic pharmaceutical combination comprising an estrogen receptor antagonist and a progestin - Google Patents
Synergistic pharmaceutical combination comprising an estrogen receptor antagonist and a progestin Download PDFInfo
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- WO2010054758A1 WO2010054758A1 PCT/EP2009/007801 EP2009007801W WO2010054758A1 WO 2010054758 A1 WO2010054758 A1 WO 2010054758A1 EP 2009007801 W EP2009007801 W EP 2009007801W WO 2010054758 A1 WO2010054758 A1 WO 2010054758A1
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- estrogen receptor
- receptor antagonist
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/32—Antioestrogens
Definitions
- Synergistic pharmaceutical combination comprising an estrogen receptor antagonist and a progestin
- the present invention relates to the coadministration of an estrogen receptor antagonist and a progestin to treat gynecological diseases resulting from abnormal growth of uterine tissue, such as endometriosis or uterine fibroids.
- Endometriosis is a disease in women of reproductive age characterized by the ectopic growth of uterine tissue in the abdominal cavity. This uterine tissue remains hormone responsive, such as cyclical bleeding and estrogen-dependent growth. The ectopic growth triggers abdominal pain leading to a loss in quality of life, and immune system activation. Frequently, endometriosis leads to infertility in affected women.
- Uterine fibroids or uterine leiomyomata is a disease in women of reproductive age characterized by benign tumor-like growth of the myometrial layer of the uterus, and deposition of fibroid tissue on the uterine wall.
- estrogen receptor antagonist e.g. antiestrogens (e.g. WO2003/045972 and W01998/007740) or selective estrogen receptor modulators (SERMs, e.g. WO2001 /68634).
- SERMs selective estrogen receptor modulators
- SERMs have a tissue-specific partial agonism that allows beneficial estrogen agonist effects on bone with estrogen antagonistic effects on the uterus.
- the SERM raloxifene ([6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl] 4-(2- piperidinoethoxy)phenyl] ketone) which is a uterine antagonist, has been shown to be efficacious in treating uterine leiomymata in postmenopausal women (Palomba, S., Sammartino, A., Di Carlo, C, Affinito, P., ZuIIo, F., and Nappi, C. (2001 ). Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women. Fertil Steril 76, 38-43).
- Progestins have been shown to effectively reduce endometriotic symptoms, be it by local application of levonorgestrel in an intrauterine device (Bahamondes, L., Petta, C. A., Femandes, A., and Monteiro, I. (2007).
- levonorgestrel-releasing intrauterine system in women with endometriosis, chronic pelvic pain and dysmenorrhea. Contraception 75, S134-139) or by systemic application of the progestin dienogest (Schindler, A. E., Christensen, B., Henkel, A., Oettel, M., and Moore, C. (2006).
- hormone-dependent gynecological diseases e.g. endometriosis or uterine fibroids
- hormone-dependent gynecological diseases e.g. endometriosis or uterine fibroids
- progestin can be treated by the combination of an estrogen receptor antagonist with a progestin.
- the estrogen receptor antagonist to be used can be Fulvestrant, Raloxifene, Tamoxifene, Toremifene, Arzoxifene, CHF-4227, Lasofoxifene, LY-2066948, LY- 2120310, Ospemifene, Sivifene, TAS-108, Bazedoxifene acetate (1- ⁇ 4-[2-(Azepan-1- yl)ethoxy]benzyl ⁇ -2-(4-hydroxyphenyl)-3-methyl-1 H-indol-5-ol acetate), Afimoxifene, Enclomiphene, Fispemifene, Acolbifene, EM-652, Droloxifene, GW-7603, Centchromane, Levormeloxifene, ICI-164384, A-007, PSK-3471 , BL-3040, CH- 4893237, SRI-16158, SRI 16137, Rad-1901 , i
- any compound can be used that interacts with the progesterone receptor and shows agonistic activity on biological endpoints of the natural hormone, progesterone (P4) ' s action.
- the progestin used in this invention can be any progestin from the group of Desogestrel, Dienogest, Drospirenone, Gestodene, Levonorgestrel, Medroxyprogesterone, Medroxyprogesterone acetate, Megestrol acetate, Nomegestrol, Norethindrone acetate, Norethynodrel, Norethisterone, Norethisterone acetate, Norgestimate, Norgestrel, NorLevo, Progesterone, SH-329, SH-461 , SH- 543, Tibolone, Trimegestone, Cyproterone, Nestorone , Nomegestrol acetat, Org- 201745, Org-42669, Org-47241 , Org-32818, Tanaproget, AP-1081 , ETI-411 , FPMA, NSP-808, Eltanolone, Etonorgestrel, Tosagestin, TX
- Combinations preferably comprises of drospirenon and apeledoxifene acetate (1- ⁇ 4- [2-(Azepan-1 -yl)ethoxy]benzyl ⁇ -2-(4-hydroxyphenyl)-3-methyl-1 H-indol-5-ol acetate), drospirenon and (+)-3-(4-Hydroxyphenyl)-2-[4-(2-piperidin-1 -ylethoxy)phenyl]-4- (trifluoromethyl)-2H-chromen-7-ol, drospirenon and a steroidal estrogen receptor antagonist, levonorgestrel and apeledoxifen, levonorgestrel and (+)-3-(4- Hydroxyphenyl ⁇ - ⁇ -piperidin-i-ylethoxyJphenyll ⁇ - ⁇ rifluoromethyl ⁇ H-chromen- 7-ol, levonorgestrel and a steroidal estrogen receptor antagonist, dienogest and apeledoxifen, die
- This combination is able to
- the combination shows a synergistic effect as it is superior to antiestrogens and SERMs that cause ovarian stimulation, to SERMs devoid of ovarian stimulation as described in WO2004/009086 because it harnesses the proven effects of the progestin on endometriotic lesions, and is superior to progestin-only treatments because of the anti-uterotrophic effect of the antiestrogen.
- This combination can also be used to treat leiomyomata of the uterus.
- the progestin and the estrogen receptor antagonist can be administered simultaneously, consecutively and partly simultaneaously and partly consecutively. It is also possible, that there are application free days between the administration of the progestin and the estrogen receptor antagonist.
- a simultaneous application means an application of both active ingredients in a fixed combination as well as an application in separated dosage forms as long as both active ingredients are administered at the same day.
- a consecutive administration means the administration of both active ingredients in different dosage forms and on different days.
- the number of administration free days can be between 1 and 28, especially 7, 14 and 21.
- Raloxifene, Bazedoxifene, and compounds A, B and C were tested in this assay and found to elevate estrogen levels by a factor of 2 or higher. This is indicative of ovarian stimulation, an effect which is unwanted.
- Addition of the progestin gestoden alleviated the antiestrogen-evoked rise in estradiol levels.
- To control for antiestrogenic activity in vivo uteri are prepared and weighed after necropsy (after 10 days). The experiment shows that the addition of gestodene alleviates the stimulation of E2 levels, but does not impair antiuterotrophic activity of the SERM or antiestrogen.
- Table 2 Restoration of estrogen levels to baseline evoked by a 10-day-treatment with SERMs and Antiestrogens by a progestin.
- Premenopausal women suffering from endometriosis are treated with a daily dose of 1-100 mg of (+)-3-(4-Hydroxyphenyl)-2-[4-(2-piperidin-1-ylethoxy)phenyl]-4- (trifluoromethyl)-2H-chromen-7-ol, and a daily dose of 2-4 mg Dienogest for three to six months.
- women show amenorrhea and improved pelvic pain sensation.
- Laparoscopic examination of endometriotic lesions will show atrophy/ shrinking of lesions.
- Premenopausal women suffering from endometriosis are treated for several treatment cycles first for twentyfour days with a daily dose of 1 -100 mg of 11£-Fluoro- 17 ⁇ -methyl-7 ⁇ -5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentylestra-1 ,3,5(10)- triene-3,17£-diol (compound B), combined with a daily dose of 0,1-0,3 mg Levonorgestrel, followed by a 4 day interval without treatment.
- This treatment cycle is repeated three to six times.
- women show amenorrhea and improved pelvic pain sensation. Laparoscopic examination of endometriotic lesions will show atrophy/ shrinking of lesions.
- Premenopausal women suffering from endometriosis are treated for several treatment cycles first for six days with a daily dose of between 1 and 100 mg of apeledoxifene acetate, combined with a daily dose of 0,05 mg gestodene, followed by a 5 day treatment with the same dose of apeledoxifene acetate combined with 0,07 mg Gestodene, followed by treatment for 10 days with the same dose of apeledoxifene acetate combined with 0,1 mg Gestodene.
- This treatment cycle is repeated three to six times.
- women show amenorrhea and improved pelvic pain sensation. Laparoscopic examination of endometriotic lesions will show atrophy/shrinking of lesions.
- Fig. 1 Estrogen increase by Bazedoxifene, and alleviation by gestoden
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Abstract
The present invention relates to the coadministration of an estrogen receptor antagonist and a progestin to treat gynecological diseases resulting from abnormal growth of uterine tissue, such as endometriosis or uterine fibroids.
Description
Synergistic pharmaceutical combination comprising an estrogen receptor antagonist and a progestin
The present invention relates to the coadministration of an estrogen receptor antagonist and a progestin to treat gynecological diseases resulting from abnormal growth of uterine tissue, such as endometriosis or uterine fibroids.
Endometriosis is a disease in women of reproductive age characterized by the ectopic growth of uterine tissue in the abdominal cavity. This uterine tissue remains hormone responsive, such as cyclical bleeding and estrogen-dependent growth. The ectopic growth triggers abdominal pain leading to a loss in quality of life, and immune system activation. Frequently, endometriosis leads to infertility in affected women.
Uterine fibroids or uterine leiomyomata is a disease in women of reproductive age characterized by benign tumor-like growth of the myometrial layer of the uterus, and deposition of fibroid tissue on the uterine wall.
Evidence suggests that both processes of ectopic uterine growth are characterized by inappropriate stimulation of endometrial or fibroid tissue by estrogen.
A variety of publications have described estrogen receptor antagonist e.g. antiestrogens (e.g. WO2003/045972 and W01998/007740) or selective estrogen receptor modulators (SERMs, e.g. WO2001 /68634).
Whereas pure antiestrogens have an estrogen antagonist effect in all tissues, including bone and cardiovascular system (where estrogen agonist action is beneficial), SERMs have a tissue-specific partial agonism that allows beneficial estrogen agonist effects on bone with estrogen antagonistic effects on the uterus.
The SERM raloxifene ([6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl] 4-(2- piperidinoethoxy)phenyl] ketone) which is a uterine antagonist, has been shown to be efficacious in treating uterine leiomymata in postmenopausal women (Palomba, S., Sammartino, A., Di Carlo, C, Affinito, P., ZuIIo, F., and Nappi, C. (2001 ). Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women. Fertil Steril 76, 38-43). The clinical use, however, of both antiestrogens and SERMs for the treatment of premenopausal women is limited by their stimulation of the ovaries, leading to elevated estrogen levels (Palomba, S., Orio, F., Jr., Morelli, M., Russo, T.,
Pellicano, M., Zupi, E., Lombardi, G., Nappi, C, Panici, P. L., and ZuIIo, F. (2002). Raloxifene administration in premenopausal women with uterine leiomyomas: a pilot study. J Clin Endocrinol Metab 87, 3603-3608). One approach to solve this problem has been to identify SERM compounds that do not cause ovarian stimulation (e.g. WO2004/009086; Geiser, A. G., Hummel, C. W., Draper, M. W., Henck, J. W., Cohen, I. R., Rudmann, D. G., Donnelly, K. B., Adrian, M. D., Shepherd, T. A., Wallace, O. B., et al. (2005). A new selective estrogen receptor modulator with potent uterine antagonist activity, agonist activity in bone, and minimal ovarian stimulation. Endocrinology 146, 4524-4535). The clinical feasibility of this approach has yet to be demonstrated.
Progestins have been shown to effectively reduce endometriotic symptoms, be it by local application of levonorgestrel in an intrauterine device (Bahamondes, L., Petta, C. A., Femandes, A., and Monteiro, I. (2007). Use of the levonorgestrel-releasing intrauterine system in women with endometriosis, chronic pelvic pain and dysmenorrhea. Contraception 75, S134-139) or by systemic application of the progestin dienogest (Schindler, A. E., Christensen, B., Henkel, A., Oettel, M., and Moore, C. (2006). High-dose pilot study with the novel progestogen dienogestin patients with endometriosis. Gynecol Endocrinol 22, 9-17). Furthermore, oral contraceptives consisting of estrogens and progestins have been used to treat endometriotic symptoms, and a combination of estrogens and progestins has been claimed to prevent endometriosis due to their induction of an amenorrhoeic state (WO 2000/07599)
It was now found, that the addition of a progestin alleviates the stimulation of ovarian function evoked by estrogen receptor antagonist treatment. Thus hormone- dependent gynecological diseases, e.g. endometriosis or uterine fibroids, can be treated by the combination of an estrogen receptor antagonist with a progestin.
The estrogen receptor antagonist to be used can be Fulvestrant, Raloxifene, Tamoxifene, Toremifene, Arzoxifene, CHF-4227, Lasofoxifene, LY-2066948, LY- 2120310, Ospemifene, Sivifene, TAS-108, Bazedoxifene acetate (1-{4-[2-(Azepan-1- yl)ethoxy]benzyl}-2-(4-hydroxyphenyl)-3-methyl-1 H-indol-5-ol acetate), Afimoxifene, Enclomiphene, Fispemifene, Acolbifene, EM-652, Droloxifene, GW-7603, Centchromane, Levormeloxifene, ICI-164384, A-007, PSK-3471 , BL-3040, CH- 4893237, SRI-16158, SRI 16137, Rad-1901 , i i/ff-Fluoro^σ-tδ^methylS-p^.δ.δ.δ-
pentafluoropentyl)sulfanyl]propylamino)pentyl]estra-1 ,3,5(10)-triene-3,17yff-diol (compound A, see WO1998/007740), 11jff-Fluoro-17σ-methyl-7σ-5-[methyl(8,8,9,9,9- pentafluorononyl)amino]pentylestra-1 ,3,5(10)-triene-3,17/?-diol (compound B, see WO2003/045972) or (+)-3-(4-Hydroxyphenyl)-2-[4-(2-piperidin-1 -ylethoxy)phenyl]-4- (trifIuoromethyl)-2H-chromen-7-ol (compound C) (WO2001/68634).
As Gestagen or progestin, any compound can be used that interacts with the progesterone receptor and shows agonistic activity on biological endpoints of the natural hormone, progesterone (P4)'s action.
The progestin used in this invention can be any progestin from the group of Desogestrel, Dienogest, Drospirenone, Gestodene, Levonorgestrel, Medroxyprogesterone, Medroxyprogesterone acetate, Megestrol acetate, Nomegestrol, Norethindrone acetate, Norethynodrel, Norethisterone, Norethisterone acetate, Norgestimate, Norgestrel, NorLevo, Progesterone, SH-329, SH-461 , SH- 543, Tibolone, Trimegestone, Cyproterone, Nestorone , Nomegestrol acetat, Org- 201745, Org-42669, Org-47241 , Org-32818, Tanaproget, AP-1081 , ETI-411 , FPMA, NSP-808, Eltanolone, Etonorgestrel, Tosagestin, TX-525.
Combinations preferably comprises of drospirenon and bazedoxifene acetate (1-{4- [2-(Azepan-1 -yl)ethoxy]benzyl}-2-(4-hydroxyphenyl)-3-methyl-1 H-indol-5-ol acetate), drospirenon and (+)-3-(4-Hydroxyphenyl)-2-[4-(2-piperidin-1 -ylethoxy)phenyl]-4- (trifluoromethyl)-2H-chromen-7-ol, drospirenon and a steroidal estrogen receptor antagonist, levonorgestrel and bazedoxifen, levonorgestrel and (+)-3-(4- Hydroxyphenyl^-^^-piperidin-i-ylethoxyJphenyll^-^rifluoromethyl^H-chromen- 7-ol, levonorgestrel and a steroidal estrogen receptor antagonist, dienogest and bazedoxifen, dienogest and (+)-3-(4-Hydroxyphenyl)-2-[4-(2-piperidin-1- ylethoxy)phenyl]-4-(trifluoromethyl)-2H-chromen-7-ol or dienogest and a steroidal estrogen receptor antagonist.
This combination is able to
- block estrogen-mediated growth of ectopic endometrium by the estrogen receptor antagonist
- reduce ovarian stimulation (as evoked by the estrogen receptor antagonist) by the addition of the progestin and
- seize the clinically proven effects of the progestin on both endometriotic lesions and pelvic pain
By this, the combination shows a synergistic effect as it is superior to antiestrogens and SERMs that cause ovarian stimulation, to SERMs devoid of ovarian stimulation as described in WO2004/009086 because it harnesses the proven effects of the progestin on endometriotic lesions, and is superior to progestin-only treatments because of the anti-uterotrophic effect of the antiestrogen.
This combination can also be used to treat leiomyomata of the uterus.
The progestin and the estrogen receptor antagonist can be administered simultaneously, consecutively and partly simultaneaously and partly consecutively. It is also possible, that there are application free days between the administration of the progestin and the estrogen receptor antagonist. A simultaneous application means an application of both active ingredients in a fixed combination as well as an application in separated dosage forms as long as both active ingredients are administered at the same day. A consecutive administration means the administration of both active ingredients in different dosage forms and on different days. The number of administration free days can be between 1 and 28, especially 7, 14 and 21.
The following examples further describes the invention without limiting it.
Example 1 (Biological assay):
To assess ovarian stimulation by antiestrogens, and its reversal by a progestin, adult HanWistar rats are controlled for their ovarian cycle by vaginal smear. On the day of estrus, serum samples are collected by retroorbital bleeding, followed by a ten-day treatment with 0,3 or 3 mg/kg/day of the antiestrogen or SERM dissolved in oleum arachidis/ ethanol (9+1 v/v). After ten days, another serum sample is collected, and estrogen levels are measured by RIA (commercially available at Beckman Coulter/DSL-4400) performed according to manufacturer's instructions.
Raloxifene, Bazedoxifene, and compounds A, B and C were tested in this assay and found to elevate estrogen levels by a factor of 2 or higher. This is indicative of ovarian stimulation, an effect which is unwanted. Addition of the progestin gestoden,
alleviated the antiestrogen-evoked rise in estradiol levels. To control for antiestrogenic activity in vivo, uteri are prepared and weighed after necropsy (after 10 days). The experiment shows that the addition of gestodene alleviates the stimulation of E2 levels, but does not impair antiuterotrophic activity of the SERM or antiestrogen.
Table 1 Compounds tested
Table 2: Restoration of estrogen levels to baseline evoked by a 10-day-treatment with SERMs and Antiestrogens by a progestin.
The results are displayed in Fig. 1 and 2 of the drawings.
Example 2:
Premenopausal women suffering from endometriosis are treated with a daily dose of 1-100 mg of (+)-3-(4-Hydroxyphenyl)-2-[4-(2-piperidin-1-ylethoxy)phenyl]-4- (trifluoromethyl)-2H-chromen-7-ol, and a daily dose of 2-4 mg Dienogest for three to six months. During treatment, women show amenorrhea and improved pelvic pain sensation. Laparoscopic examination of endometriotic lesions will show atrophy/ shrinking of lesions.
Example 3:
Premenopausal women suffering from endometriosis are treated for several treatment cycles first for twentyfour days with a daily dose of 1 -100 mg of 11£-Fluoro-
17σ-methyl-7σ-5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentylestra-1 ,3,5(10)- triene-3,17£-diol (compound B), combined with a daily dose of 0,1-0,3 mg Levonorgestrel, followed by a 4 day interval without treatment. This treatment cycle is repeated three to six times. During treatment, women show amenorrhea and improved pelvic pain sensation. Laparoscopic examination of endometriotic lesions will show atrophy/ shrinking of lesions.
Example 4:
Premenopausal women suffering from endometriosis are treated for several treatment cycles first for six days with a daily dose of between 1 and 100 mg of bazedoxifene acetate, combined with a daily dose of 0,05 mg gestodene, followed by a 5 day treatment with the same dose of bazedoxifene acetate combined with 0,07 mg Gestodene, followed by treatment for 10 days with the same dose of bazedoxifene acetate combined with 0,1 mg Gestodene. This treatment cycle is repeated three to six times. After the first treatment cycle, women show amenorrhea and improved pelvic pain sensation. Laparoscopic examination of endometriotic lesions will show atrophy/shrinking of lesions.
Drawings
Fig. 1 : Estrogen increase by Bazedoxifene, and alleviation by gestoden
Fig.2 Anti-uterotrophic action of Bazedoxifene acetate and combination of Bazedoxifene acetate and Gestoden
Claims
1. Pharmaceutical combination consisting of estrogen receptor antagonists and progestins.
2. Pharmaceutical combination according to claim 1 wherein the estrogen receptor antagonist is an antiestrogen.
3. Pharmaceutical combination according to claim 1 wherein the estrogen receptor antagonist is a SERM.
4. Pharmaceutical combination according to claim 1 wherein the estrogen receptor antagonists is Fulvestrant, Raloxifene, Tamoxifene, Toremifene, Arzoxifene, CHF-4227, Lasofoxifene, LY-2066948, LY-2120310, Ospemifene, Sivifene, TAS-108, Bazedoxifene or Bazedoxifene acetate, Afimoxifene, Enclomiphene, Fispemifene, Acolbifene, EM-652, Droloxifene, GW-7603, Centchromane, Levormeloxifene, ICI-164384, A-007, PSK-3471 , BL-3040, CH-4893237, SRM 6158, SRI 16137, Rad-1901 , 11£-Fluoro-7σ-[5-(methyl3- [(4,4,5,5,5-pentafluoropentyl)sulfanyl]propylamino)pentyl]estra-1 ,3,5(10)- triene-3,17#-diol, 11/?-Fluoro-17σ-methyl-7σ-5-[methyl(8,8,9,9,9- pentafluorononyl)amino]pentylestra-1 ,3,5(10)-triene-3,17/?-diol or (+)-3-(4- Hydroxyphenyl)-2-[4-(2-piperidin-1-ylethoxy)phenyl]-4-(trifluoromethyl)-2H- chromen-7-ol.
5. Pharmaceutical combination according to claim 1 wherein the progestin is Desogestrel, Dienogest, Drospirenone, Gestodene, Levonorgestrel, Medroxyprogesterone, Medroxyprogesterone acetate, Megestrol acetate, Nomegestrol, Norethindrone acetate, Norethynodrel, Norethisterone, Norethisterone acetate, Norgestimate, Norgestrel, NorLevo, Progesterone, SH-329, SH-461 , SH-543, Tibolone, Trimegestone, Cyproterone, Nestorone , Nomegestrol acetat, Org-201745, Org-42669, Org-47241 , Org-32818, Tanaproget, AP-1081 , ETI-411 , FPMA, NSP-808, Eltanolone, Etonorgestrel, Tosagestin or TX-525.
6. Pharmaceutical combination according to claim 1 wherein drospirenone and bazedoxifene or bazedoxifene acetate, drospirenon and (+)-3-(4- Hydroxyphenyl)-2-[4-(2-piperidin-1-ylethoxy)phenyl]-4-(trifluoromethyl)-2H- chromen-7-ol, drospirenone and a steroidal estrogen receptor antagonist, levonorgestrel and bazedoxifen, levonorgestrel and (+)-3-(4-Hydroxyphenyl)- 2-[4-(2-piperidin-1-ylethoxy)phenyl]-4-(trifluoromethyl)-2H-chromen-7-ol, levonorgestrel and a steroidal estrogen receptor antagonist, dienogest and bazedoxifen, dienogest and (+)-3-(4-Hydroxyphenyl)-2-[4-(2-piperidin-1- ylethoxy)phenyl]-4-(trifluoromethyl)-2H-chromen-7-ol or dienogest and a steroidal estrogen receptor antagonist are combined.
7. Use of an estrogen receptor antagonist in combination with a progestin for the manufacture of a medicine to treat endometriosis or fibroids.
8. Use according to claim 7 where the estrogen receptor antagonist is an antiestrogen.
9. Use according to claim 7 where the estrogen receptor antagonist is a SERM.
10. Use according to claim 7 where at least one of the following estrogen receptor antagonists are used: Fulvestrant, Raloxifene, Tamoxifene, Toremifene, Arzoxifene, CHF-4227, Lasofoxifene, LY-2066948, LY-2120310, Ospemifene, Sivifene, TAS-108, bazedoxifene or bazedoxifene acetate, Afimoxifene, Enclomiphene, Fispemifene, Acolbifene, EM-652, Droloxifene, GW-7603, Centchromane, Levormeloxifene, ICI-164384, A-007, PSK-3471 , BL-3040, CH-4893237, SRM 6158, SRI 16137, Rad-1901 , 11£-Fluoro-7σ-[5-(methyl3- [(4,4,5,5,5-pentafluoropentyl)sulfanyl]propylamino)pentyl]estra-1 ,3,5(10)- triene-3,17,ff-diol, 11#-Fluoro-17σ-methyl-7σ-5-[methyl(8,8,9,9,9- pentafluorononyl)amino]pentylestra-1 ,3,5(10)-triene-3,17/?-diol or (+)-3-(4- Hydroxyphenyl)-2-[4-(2-piperidin-1-ylethoxy)phenyl]-4-(trifluoromethyl)-2H- chromen-7-ol.
11. Use according to claim 7 where at least one of the following progestins are used: Desogestrel, Dienogest, Drospirenone, Gestodene, Levonorgestrel, Medroxyprogesterone, Medroxyprogesterone acetate, Megestrol acetate, Nomegestrol, Norethindrone acetate, Norethynodrel, Norethisterone, Norethisterone acetate, Norgestimate, Norgestrel, NorLevo, Progesterone, SH-329, SH-461 , SH-543, Tibolone, Trimegestone, Cyproterone, Nestorone , Nomegestrol acetat, Org-201745, Org-42669, Org-47241 , Org-32818, Tanaproget, AP-1081 , ETI-411 , FPMA, NSP-808, Eltanolone, Etonorgestrel, Tosagestin or TX-525.
12. Use according to claim 7 wherein the following estrogen receptor antagonist and progestin combinations are used: drospirenon and bazedoxifene or bazedoxifene acetate, drospirenon and (+)-3-(4-Hydroxyphenyl)-2-[4-(2- piperidin-1-ylethoxy)phenyl]-4-(trifluoromethyl)-2H-chromen-7-ol, drospirenon and a steroidal estrogen receptor antagonist, levonorgestrel and bazedoxifen, levonorgestrel and (+)-3-(4-Hydroxyphenyl)-2-[4-(2-piperidin-1- ylethoxy)phenyl]-4-(trifluoromethyl)-2H-chromen-7-ol, levonorgestrel and a steroidal estrogen receptor antagonist, dienogest and bazedoxifene or bazedoxifene acetate, dienogest and (+)-3-(4-Hydroxyphenyl)-2-[4-(2- piperidin-1 -ylethoxy)phenyl]-4-(trifluoromethyl)-2H-chromen-7-ol or dienogest and a steroidal estrogen receptor antagonist.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102008057230A DE102008057230A1 (en) | 2008-11-11 | 2008-11-11 | Synergistic pharmaceutical combination with an estrogen receptor antagonist and a progestin |
| DE102008057230.6 | 2008-11-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2010054758A1 true WO2010054758A1 (en) | 2010-05-20 |
Family
ID=41606625
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2009/007801 Ceased WO2010054758A1 (en) | 2008-11-11 | 2009-10-31 | Synergistic pharmaceutical combination comprising an estrogen receptor antagonist and a progestin |
Country Status (6)
| Country | Link |
|---|---|
| AR (1) | AR074297A1 (en) |
| DE (1) | DE102008057230A1 (en) |
| PA (1) | PA8847901A1 (en) |
| TW (1) | TW201022251A (en) |
| UY (1) | UY32235A (en) |
| WO (1) | WO2010054758A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011029782A1 (en) * | 2009-09-11 | 2011-03-17 | Bayer Schering Pharma Aktiengesellschaft | Substituted (heteroarylmethyl) thiohydantoins as anticancer drugs |
| WO2013131105A1 (en) * | 2012-03-02 | 2013-09-06 | Sri International | Synergistic anti-proliferation activity of tas-108 with mtor inhibitors against cancer cells |
| CN104370796A (en) * | 2014-11-21 | 2015-02-25 | 扬子江药业集团有限公司 | Preparation method of bazedoxifene acetate polycrystalline type B |
| WO2017010515A1 (en) * | 2015-07-14 | 2017-01-19 | ノーベルファーマ株式会社 | ESTROGEN RECEPTOR β PARTIAL AGONIST HAVING ESTROGEN RECEPTOR α INHIBITORY EFFECT, AND THERAPEUTIC AGENT FOR GYNECOLOGICAL DISORDERS USING SAME |
| JP2017522375A (en) * | 2014-07-02 | 2017-08-10 | ザビエル・ユニバーシティ・オブ・ルイジアナＸａｖｉｅｒ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｌｏｕｉｓｉａｎａ | Boron-based prodrug strategy for increased bioavailability and lower required dose for drug molecules containing at least one phenol (or aromatic hydroxyl) group |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998007740A1 (en) * | 1996-08-20 | 1998-02-26 | Schering Aktiengesellschaft | 7α-(κ-AMINOALKYL)ESTRATRIENES, PROCESS FOR PREPARING THE SAME, PHARMACEUTICAL PREPARATIONS CONTAINING SAID 7α-(κ-AMINOALKYL)ESTRATRIENES AND THEIR USE FOR PREPARING MEDICAMENTS |
| WO1999024027A2 (en) * | 1997-11-06 | 1999-05-20 | American Home Products Corporation | Anti-estrogen plus progestin containing oral contraceptives |
| WO2000007599A1 (en) * | 1998-08-07 | 2000-02-17 | William Leroy Heinrichs | Prevention of endometriosis signs or symptoms |
| GB2352716A (en) * | 1999-07-29 | 2001-02-07 | Lilly Co Eli | Crystalline form of arzoxifene |
| WO2001068634A1 (en) * | 2000-03-15 | 2001-09-20 | Schering Aktiengesellschaft | 4-fluoroalkyl-2h-benzopyrans with anti-estrogenic activity |
| WO2003045972A1 (en) * | 2001-11-27 | 2003-06-05 | Schering Aktiengesellschaft | 17α-ALKYL-17β-OXY-ESTRATRIENES AND INTERMEDIATES FOR THE PRODUCTION THEREOF, AND USE OF SAID 17α-ALKYL-17β-OXY-ESTRATRIENES FOR PRODUCING MEDICAMENTS AND PHARMACEUTICAL PREPARATIONS |
| WO2003063859A1 (en) * | 2002-01-14 | 2003-08-07 | Nordic Bioscience A/S | Suppression of cartilage degradation via the estrogen receptor |
| WO2003099292A1 (en) * | 2002-05-24 | 2003-12-04 | Akzo Nobel N.V. | Treatment of post-menopausal complaints in breast cancer patients comprising tibolone and a serm |
| WO2004009086A1 (en) * | 2002-07-22 | 2004-01-29 | Eli Lilly And Company | Selective estrogen receptor modulators containing a phenylsulfonyl group |
| WO2007144151A1 (en) * | 2006-06-13 | 2007-12-21 | Bayer Schering Pharma Aktiengesellschaft | Step-down estrogen regimen for women receiving estrogen therapy |
-
2008
- 2008-11-11 DE DE102008057230A patent/DE102008057230A1/en not_active Withdrawn
-
2009
- 2009-10-31 WO PCT/EP2009/007801 patent/WO2010054758A1/en not_active Ceased
- 2009-11-06 AR ARP090104296A patent/AR074297A1/en unknown
- 2009-11-09 PA PA20098847901A patent/PA8847901A1/en unknown
- 2009-11-10 UY UY0001032235A patent/UY32235A/en not_active Application Discontinuation
- 2009-11-11 TW TW098138262A patent/TW201022251A/en unknown
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998007740A1 (en) * | 1996-08-20 | 1998-02-26 | Schering Aktiengesellschaft | 7α-(κ-AMINOALKYL)ESTRATRIENES, PROCESS FOR PREPARING THE SAME, PHARMACEUTICAL PREPARATIONS CONTAINING SAID 7α-(κ-AMINOALKYL)ESTRATRIENES AND THEIR USE FOR PREPARING MEDICAMENTS |
| WO1999024027A2 (en) * | 1997-11-06 | 1999-05-20 | American Home Products Corporation | Anti-estrogen plus progestin containing oral contraceptives |
| WO2000007599A1 (en) * | 1998-08-07 | 2000-02-17 | William Leroy Heinrichs | Prevention of endometriosis signs or symptoms |
| GB2352716A (en) * | 1999-07-29 | 2001-02-07 | Lilly Co Eli | Crystalline form of arzoxifene |
| WO2001068634A1 (en) * | 2000-03-15 | 2001-09-20 | Schering Aktiengesellschaft | 4-fluoroalkyl-2h-benzopyrans with anti-estrogenic activity |
| WO2003045972A1 (en) * | 2001-11-27 | 2003-06-05 | Schering Aktiengesellschaft | 17α-ALKYL-17β-OXY-ESTRATRIENES AND INTERMEDIATES FOR THE PRODUCTION THEREOF, AND USE OF SAID 17α-ALKYL-17β-OXY-ESTRATRIENES FOR PRODUCING MEDICAMENTS AND PHARMACEUTICAL PREPARATIONS |
| WO2003063859A1 (en) * | 2002-01-14 | 2003-08-07 | Nordic Bioscience A/S | Suppression of cartilage degradation via the estrogen receptor |
| WO2003099292A1 (en) * | 2002-05-24 | 2003-12-04 | Akzo Nobel N.V. | Treatment of post-menopausal complaints in breast cancer patients comprising tibolone and a serm |
| WO2004009086A1 (en) * | 2002-07-22 | 2004-01-29 | Eli Lilly And Company | Selective estrogen receptor modulators containing a phenylsulfonyl group |
| WO2007144151A1 (en) * | 2006-06-13 | 2007-12-21 | Bayer Schering Pharma Aktiengesellschaft | Step-down estrogen regimen for women receiving estrogen therapy |
Non-Patent Citations (3)
| Title |
|---|
| PALOMBA STEFANO ET AL: "Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women", FERTILITY AND STERILITY, vol. 76, no. 1, July 2001 (2001-07-01), pages 38 - 43, XP002567171, ISSN: 0015-0282 * |
| PALOMBA STEFANO ET AL: "Raloxifene administration in premenopausal women with uterine leiomyomas: A pilot study", JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM, vol. 87, no. 8, August 2002 (2002-08-01), pages 3603 - 3608, XP002567170, ISSN: 0021-972X * |
| SPRITZER P M ET AL: "Effects of norethisterone acetate and tamoxifen on serum prolactin levels, uterine growth and on the presence of uterine immunoreactive prolactin in estradiol-treated ovariectomized rats", BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH, vol. 28, no. 1, 1995, pages 125 - 130, XP009129124, ISSN: 0100-879X * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011029782A1 (en) * | 2009-09-11 | 2011-03-17 | Bayer Schering Pharma Aktiengesellschaft | Substituted (heteroarylmethyl) thiohydantoins as anticancer drugs |
| WO2013131105A1 (en) * | 2012-03-02 | 2013-09-06 | Sri International | Synergistic anti-proliferation activity of tas-108 with mtor inhibitors against cancer cells |
| JP2017522375A (en) * | 2014-07-02 | 2017-08-10 | ザビエル・ユニバーシティ・オブ・ルイジアナＸａｖｉｅｒ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｌｏｕｉｓｉａｎａ | Boron-based prodrug strategy for increased bioavailability and lower required dose for drug molecules containing at least one phenol (or aromatic hydroxyl) group |
| CN104370796A (en) * | 2014-11-21 | 2015-02-25 | 扬子江药业集团有限公司 | Preparation method of bazedoxifene acetate polycrystalline type B |
| CN104370796B (en) * | 2014-11-21 | 2016-09-14 | 扬子江药业集团有限公司 | A kind of preparation method of bazedoxifene acetate polymorph b |
| WO2017010515A1 (en) * | 2015-07-14 | 2017-01-19 | ノーベルファーマ株式会社 | ESTROGEN RECEPTOR β PARTIAL AGONIST HAVING ESTROGEN RECEPTOR α INHIBITORY EFFECT, AND THERAPEUTIC AGENT FOR GYNECOLOGICAL DISORDERS USING SAME |
| US10369159B2 (en) | 2015-07-14 | 2019-08-06 | Nobelpharma Co., Ltd. | Estrogen receptor β partial agonist having estrogen receptor α inhibitory effect, and gynecological disease therapeutic agent using same |
| AU2016294185B2 (en) * | 2015-07-14 | 2021-10-14 | National University Corporation Tottori University | Estrogen receptor β partial agonist having estrogen receptor α inhibitory effect, and therapeutic agent for gynecological disorders using same |
Also Published As
| Publication number | Publication date |
|---|---|
| PA8847901A1 (en) | 2010-06-28 |
| DE102008057230A1 (en) | 2010-05-12 |
| TW201022251A (en) | 2010-06-16 |
| UY32235A (en) | 2010-06-30 |
| AR074297A1 (en) | 2011-01-05 |
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