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Selective estrogen receptor modulators for the treatment of vasomotor symptoms

Selective estrogen receptor modulators for the treatment of vasomotor symptoms description/claims

“Vasomotor symptoms”, i.e., hot flashes, night sweats, vaginal dryness, sleep disturbances, nausea and mood swings commonly affect women around menopause. In fact, a majority of postmenopausal women will experience vasomotor symptoms with a significant percentage of these women continuing to suffer symptoms for more than five years (Psychosom. Med. 1965, 27, 266; Med. Gynecol. Soc. 1969, 4, 268). Women who have undergone bilateral oophorectomy, radiotherapy or treatment with GnRH (gonadotropin releasing hormone) agonists are particularly prone to experiencing hot flashes (Br. J. Obstet. Gynaecol. 1977, 84, 769). Men have also been reported to experience vasomotor symptoms following treatment with a GnRH agonist (N. Engl. J. Med. 1981, 305, 663) or after orchidectomy (Urology 1980, 16, 620).

In spite of being identified as an ailment of menopause for hundreds of years, the precise mechanism underlying the cause of vasomotor symptoms is not clear. However, a link with declining estrogen levels (due to natural menopause or otherwise) is widely accepted. Interestingly, women with low estrogen levels due to ovarian dysgenesis generally do not suffer from vasomotor symptoms unless they are first given hormone replacement therapy (HRT) and then have it discontinued (Clin. Endocrinol. (Oxf) 1985, 22, 293), suggesting that estrogen withdrawal may be an underlying cause of vasomotor instability. HRT is currently a preferred standard treatment for vasomotor symptoms and is effective in >80% of women who initiate treatment, which again is supportive of an estrogenic role in the etiology thereof.

Hot flashes (flushes) are characterised by a warming sensation that begins in the chest and moves towards the neck and head, and are often accompanied by sweating, palpitations and cutaneous flashing. The episodes last from 30 seconds to 10 minutes. The hot flash event itself is thought to be centrally mediated resulting from a transient lowering of the thermoregulatory set point in the hypothalamus (for a review, see: Can. J. Physiol. Pharmacol. 1987, 65, 1312). Regulation of the thermoregulatory process may involve catecholamines, estrogen, testosterone, opioids and serotonin, among others (for a review, see: Mayo. Clin. Proc. 2002, 77, 1207). In fact, compounds that modulate the signaling pathway of each of these hormones/neurotransmitters have been evaluated for the treatment of hot flashes. See, e.g., Ann. Intern. Med. 2000, 132, 788; Br. Med. J. 1974, i, 409; Maturitas, 1978, 1, 21; Med. J. Aust. 1986, 144, 369; Fertil. Steril. 1985, 43, 401; Br. J. Obstet. Gynaecol. 1981, 88, 919; J. Clin. Endocrinol. Metab; 1984, 58, 578; Clin. Endocrinol. 1985, 22, 293; Maturitas 2000, 36, 155; J. Clin. Oncol 2002, 20, 1583; JAMA 2003, 289, 2827; Lancet 2000, 356, 2059; N. Engl. J. Med. 1994, 331, 347; Obstet. Gynecol. 1984, 63, 1; Obstet. Gynecol. 1999, 94, 225; Br. J. Obstet. Gynecol. 1998, 105, 904; Neurology 2000, 54, 2161; Obstet. Gynecol. 1998, 72, 688; J. Clin. Oncol. 1998, 16, 495; J. Clin. Oncol. 2001, 19, 2739; and J. Nutr. 2001, 131 (11, supl), 3095s.

In spite of the apparent large number of treatments for hot flashes, all the current therapies suffer from poor efficacy, are associated with unacceptable side effects or are contraindicated for certain patient populations. For example, HRT is not recommended for women with a history of breast cancer, uterine cancer, ovarian cancer, or venous thromboembolism. Recent data also suggests HRT may not be suitable for women with coronary artery disease. Non-hormonal treatments generally are not fully efficacious (e.g. clonidine) and/or cause adverse effects (e.g., venlafaxine, gabapen tin).

Many publications have appeared within the last ten years disclosing selective estrogen receptor modulators (SERMs), e.g., U.S. Pat. Nos. 5,484,795, 5,484,798, 5,510,358, 5,998,401 and WO 96/09040. Many of these SERMs, generally speaking, have been found to have a beneficial estrogen agonist activity in the bone and cardiovascular systems with a concomitant beneficial estrogen antagonist activity in the breast. A small, particularly useful subset of such compounds has also been found to have an estrogen antagonist effect or to have a non-estrogenic effect in the uterus. However, the actual use of a SERM in the treatment of vasomotor symptoms has also been hampered by problems with efficacy, e.g., during Phase III clinical studies of raloxifene for the treatment/prevention of post-menopausal osteoporosis, raloxifene was associated with a slight increased incidence of hot flash compared to placebo and tamoxifen is known to induce hot flashes in more than 50% of patients (Arch. Intern. Med. 1991, 151, 1842).

There, therefore, remains an unmet medical need for vasomotor symptom therapies that overcome the liabilities of current treatments. In particular, there is a need for a medication that possesses the positive attributes of previously disclosed SERMs such as raloxifene (i.e., positive effects on bone, uterus, breast and cardiovascular system) but also alleviates vasomotor symptoms.

The present invention relates to a compound of formula I:

wherein:

m is 0, 1 or 2;

n is 1, 2, 3 or 4;

R is H or methyl provided that if m is 1 or 2, then R must be H and that if m is 0, then R must be methyl;

R1 is H, SO2(n-C4-C6 alkyl) or COR2;

X is O or NR3.

X1 is O, CH2 or C═O;

R6 is H or F or R6 combines with X1 to form a moiety of the formula:

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