Methods for Assessing, Improving, or Maintaining Urogenital Health in Postmenopausal Women

专利摘要:
PURPOSE: Provided are methods for improving or maintaining urogenital health using an estrogen agonist / antagonist. In postmenopausal women, conditions such as urinary and vaginal infections; incontinence; and vaginal dryness can be treated using the same. Also, methods of assessing vaginal health are provided. CONSTITUTION: The estrogen agonist/antagonist is used in the manufacture of a medicament for improving or maintaining urogenital health; lowering vaginal pH; treating a urinary tract infection; treating vaginal dryness; treating vaginal itching; treating undesired vaginal spasms; treating vaginitis; treating a vaginal yeast or bacterial infection; treating vulvar atrophy; treating urethrocele, cystocele, rectocele, or enterocele prolapse; treating urinary or anal incontinence; treating undesired urinary frequency or urgency; or increasing the frequency or intensity or orgasms in a female patient. The estrogen agonist/antagonist is a compound of formula(I).
公开号:KR20020030035A
申请号:KR1020010063744
申请日:2001-10-16
公开日:2002-04-22
发明作者:웨슬리 워렌 데이；앤드류 조지 리；데이비드 드웨인 톰슨
申请人:데이비드 존 우드；화이자 프로덕츠 인크.；
IPC主号:

专利说明:

How to analyze, promote or maintain urogenital health in postmenopausal women {Methods for Assessing, Improving, or Maintaining Urogenital Health in Postmenopausal Women}
[1] The present invention relates to methods of promoting or maintaining urogenital health using estrogen agonists / antagonists. Urinary and vaginal infections in postmenopausal women; incontinence; And symptoms such as vaginal dryness can be treated using the methods of the invention. The invention also relates to a method for analyzing vaginal health.
[2] Menopause occurs naturally in women in the United States of age 50-51 years. As the ovary ages, the pituitary gland's response to gonadotropins (follicle stimulating hormone [FSH] and progesterone [LH]) is reduced, initially shortening the follicle (and thus shortening the menstrual cycle), Less ovulation, less progesterone production, more irregular menstrual cycles. Eventually, the follicles become unresponsive and do not produce estrogens. The transitional phase at which the female reproductive phase ends, begins before menopause. This is referred to as menopause or myopathy, but most people call it menopause.
[3] Early menopause refers to ovarian failure caused by unknown causes that occur before age 40. This may be associated with smoking, living in high mountains, or malnutrition. Artificial menopause can result from ovarian resection, chemotherapy, radiation of the pelvis, or any method that impairs ovarian blood supply or ovarian function.
[4] Menopausal symptoms range from asymptomatic to severe. 75% of women in the menopausal cycle are affected by febrile redness and sweating due to vasomotor instability. Most suffer from recessive scarring for at least one year and 25 to 50% for at least five years. Women feel warmth or heat and can sometimes be severely sweated. The skin, especially the head and neck, becomes red and warm. You may feel chilled after scarletness, which can last from 30 seconds to 5 minutes. Vascular motor symptoms of recessive scarlet occur concurrently with the operation of the LH pulse, but suggest that hypothalamic control of the LH pulse is independent of scarlet hypothalamic control, since the increase in LH is not always associated with recessive scarletness. This irrelevance is confirmed by the development of recessive scarletness in women who have damaged the pituitary gland and do not secrete LH and / or FSH.
[5] Estrogen reduction causes severe changes in the lower genital tract; For example, the vaginal mucosa and vulva skin become thinner, the normal bacterial phase changes, and the labia minora, clitoris, uterus and ovary become smaller. Inflammation of the vaginal mucosa (atrophic vaginitis) can make the mucous membrane strawberry-like and cause urinary and urinary insufficiency, vaginal dryness and sexual dysphoria. Women can lose pelvic muscle tension and develop incontinence, cystitis and vaginitis.
[6] Normal vaginal secretions include vulvar secretions from sebaceous glands, sweat glands, bastoline glands and skin glands; Seeping out of the vaginal wall; Exfoliated vaginal and cervical cells; Cervical mucosa; Endometrial and fallopian tubes; And microorganisms and their metabolic products. The type and amount of exfoliated cells, cervical mucosa, and upper reproductive tract are measured by biochemical methods influenced by hormone levels (Huggins, GR) and Preti, G.), Clin Obstet Gynecol , 1981; 24 : 355-377. Vaginal epidermal tissue consists of vaginal epithelial cells that respond to varying amounts of estrogen and progesterone. Superficial cells, the predominant cell type in women of reproductive age, are dominant when there is estrogen stimulation. Intermediate cells predominate during the luteal phase due to progesterone stimulation. Swelling cells predominate in the absence of either hormone and are symptoms that can be found in postmenopausal women who have not received hormone replacement therapy.
[7] The normal bacterial phase is predominantly aerobic with six different types of bacteria, the most common of which is hydrogen peroxide producing lactobacillus. Microorganisms in the vagina are determined by factors affecting the viability of bacteria. These factors include the availability of glucose for vaginal pH and bacterial metabolism. Premenopausal is acidic, typically less than pH 4.5. This environment is maintained by the presence of estrogen, which stimulates vaginal epithelial cells to produce glycogen, which can then be converted to lactic acid by Lactobacillus. Lack of estrogen stimulation of the vagina reduces the available glycogen, increasing vaginal pH and altering vaginal bacterial phase.
[8] Bacterial vaginosis (BV) was previously referred to as nonspecific vaginitis or Gardnella vaginitis . The alteration of normal vaginal bacterial phase is the loss of hydrogen peroxide-producing Lactobacillus and the overgrowth of predominantly anaerobic bacteria (Eschenbach, DA et al., J. Clin Microbiol, 1989; 27 : 251-256, Spiegel, CA, et al., N Engl J Med, 1980; 303 : 601-608. The most common form of vaginitis in the United States is BV. Anaerobic bacteria can be found in less than 1% of normal female bacteria. However, in women with BV, the concentrations of anaerobic bacteria, Gardnella vaginalis and Mycoplasma hominis are 100-1000 times higher than in normal women. Lactobacillus is not normally present.
[9] Many studies have demonstrated the association between BV and very detrimental sequelae. Women with BV have pelvic inflammatory disease (PID) (Am J Obstet Gynecol, 1988; 158 : 819-828), postoperative cuff infections after hysterectomy (Sof, Soper, DE et al., Am J Obstet Gynecol, 1990; 163 : 1016-1023, and aberrant neck cells (Platz-Christensen JJ et al. Acta Obstet Gynecol Scand, 1994; 73 : 586-588).
[10] Urinary tract infections in women will include acute cystitis, recurrent cystitis and urethritis. Women with acute cystitis have suddenly begun to develop complex severe urinary tract symptoms, including urinary disturbances such as above and below the pubic bone, including urination disorders, anemia and urinary insufficiency. On physical examination, you can observe fragility on the pubic bone. Urinary analysis refers to purulenturia and sometimes hematuria. Infection occurs in about 20% of premenopausal women with the first experience of vaginitis. More than 90% of these relapses are caused by exogenous reinfection. Postmenopausal women can also be frequently reinfected. In combination with antimicrobial prophylaxis, hormone replacement therapy or topical application of estrogen creams have been used to treat these patients. Women with urination disorders caused by urethritis develop mild symptoms gradually, which may be accompanied by abnormal vaginal excretion or bleeding associated with concurrent cervicitis. The patient will also experience lower abdominal pain. A physical exam may reveal the presence of mucous cervicitis.
[11] Vaginal dryness in postmenopausal women is believed to be caused by vaginal atrophy due to reduced estrogen stimulation. When estrogen levels are low or absent, vasculature of the vagina is reduced and vaginal epithelium is thinned. Reduction of vasculature and vaginal epithelium results in less secretion and vaginal moisture.
[12] The genital and urinary tract are anatomically and embryologically linked from their early stages of development. The bladder is located directly above the anterior vaginal wall and the urethra is fused. Both these structures and those of the pelvis are at risk during pregnancy and childbirth. In postmenopausal women, the pelvic floor can change due to changes in hormonal status, resulting in incontinence, prolapse and other diseases.
[13] Each organ, urinary, genital and digestive system in the pelvic floor traverses the pelvis and connects to the outside through its own opening. Therefore, these organs are intricately involved in function and anatomical support (Wall, LL) and Delancy, J. L. Perspect Biol Med. , 1991; 34 : 486-496]. Abnormalities of each of these components can essentially damage the function of the surrounding structure and the functional anatomical structure of the pelvic floor. The rhabdomyomus of the pelvic floor, along with the fascinating part of the fascia, acts over the entire pelvis to prevent pelvic organ migration, to maintain excretory capacity and to regulate contractile activity. Due to their complex correlation, each disorder of pelvic support can cause problems for other organ organs. For example, the case of incontinence failure is mentioned.
[14] Naming of the pelvic muscles is under review. The levator ani muscle (a broad generic name for the pelvic floor muscle) is described as being composed of the diaphragm portion (rose bone) and the more important "endosternal root" portion (Lawson, JO). [Ann R Coll Sur Engl 1974; 54 : 244-252] The rosacea or "diaphragm" part of the big muscle is a thin muscle sheet that begins from the pelvic side wall on either side of the iliac and sciatic poles and into the midline of the rectum. The alveolar root muscle ("the pubis root") of the large muscle consists of thick U-shaped band muscles that begin from the pubic bone and are joined to the posterior wall of the vagina and rectum. Supported by muscle slings pulled toward the pubic bone, the muscle band is often called the pubic or pubic coccyx or the pubic bone. Pulled forward toward the pubic bone and the lumen of these pelvic organs contracts, which maintains the ability to inhibit urinary and fecal excretion and supports the genital organs (vaginal, cervical, uterus) that are located on and supported by the big muscle plate. very important.
[15] The connective tissue consists mainly of elastin and collagen fibers in the polysaccharide base material. The composition of connective tissue is not constant and changes in various parts of the whole body. Connective tissue forms capsules to help maintain structural integrity of organs. If the connective tissue is damaged, muscle support will weaken. The connective organization is not static but instead is a dynamic organization that undergoes constant upset and reconstruction. Hormonal changes have a significant effect on collagen, which in turn is related to aging and postmenopausal conditions (Brincat, M. et al., Obset Gynecol, 1987; 70 : 123-127; Castello-Bran) Castelo-Branco, C. et al. (Maturitas, 1992; 15 : 113-119). Connective tissue abnormalities are important factors causing prolapse and related symptoms such as urine and stool incontinence.
[16] In premenopausal women, 17β-estradiol produced by the ovary is the major active circulating estrogen. Serum estradiol levels are low in prepubertal girls and elevated at menarche. In women, it ranges from about 100 pg / milliliter (367 pmol / liter) of follicles to about 600 pg / milliliter (2200 pmol / liter) at ovulation. This will rise to nearly 20,000 pg / milliliter (70,000 pmol / liter) during pregnancy. After menopause, serum estradiol concentrations drop to similar or lower values than men of comparable age (5-20 pg / milliliter [18-74 pmol / liter]) (Yen, SSC). And Jaffe, RB (Reproductive Endocrinology; Physiology, Pathophysiology and Clinical Management, 3rd Edition. Philadelphia: WB Saunders, (1991)).
[17] The effect of estrogen on the health and condition of the genitourinary system is generally positive, but the specific risk of estrogen's specific non-urinogenital effects, such as breast cancer and thrombus development, offsets its beneficial effects.
[18] Breast cancer is a disease that is typically or frequently hormone dependent. Women who do not have ovarian function and do not have estrogen replacement rarely develop breast cancer. The female-to-male ratio for this disease is about 150 to 1. These findings indicate that hormones play an important role as promoters of the disease. For most epithelial malignancies, the log-log plot of incidence versus age shows a linear increase every year of survival. The same plot for breast cancer shows the same linear increase but decreases in slope as menopause age begins. Three phases that have a major impact on the development of breast cancer in women's lives are menarche age, first full gestational age, and menopause age. Women who have had menarche at age 16 are only 50-60% of the lifetime breast cancer risk of women who have had menarche at age 12. Similarly, if menopause occurs 10 years before middle age (52 years), whether it is natural or surgically induced, the lifetime breast cancer risk is reduced by about 35%. Compared to women who are not pregnant, women who have their first full-term pregnancy at age 18 have a risk of breast cancer of 30 to 40%. Therefore, the period of menstruation, especially before the first full term pregnancy, is a substantial component of the total risk of breast cancer. This factor can cause 70 to 80 percent of breast cancer incidence in many countries.
[19] International incidence has provided certain important clues to hormonal carcinogenesis. A woman who survives to 80 years of age in North America has a chance of 1 out of 9 invading breast cancers. Asian women are 1/5 to 1/10 of the risk of breast cancer in North American or Western European women. Asian women have significantly lower concentrations of estrogen and progesterone. This difference cannot be explained on a genetic basis, because Asian women living in a western environment have the same risk as women in their western counterparts. These women also differ markedly in height and weight from Asian women living in Asia: height and weight are important regulators of menarche age and have a significant impact on plasma concentrations of estrogen (Lipman, M. E. (Lippman, ME), Breast cancer, Chapter 91, in Harrison's Principles of Internal Medicine, 14th edition, 1998.
[20] The present invention provides a method for enhancing or maintaining the health of a comparative genital organ comprising administering a therapeutically effective amount of an estrogen agonist / antagonist to a patient in need thereof.
[21] In a preferred embodiment of this method, the patient is a postmenopausal woman.
[22] In another preferred embodiment of this method, the estrogen agonist / antagonist comprises a compound of formula (1) or an optical or geometric isomer thereof; Or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or precursor thereof:
[23]
[24] In the above formula:
[25] A is selected from CH ₂ and NR;
[26] B, D and E are independently selected from CH and N;
[27] Y is
[28] (a) phenyl optionally substituted with 1-3 substituents independently selected from R ⁴ ;
[29] (b) naphthyl optionally substituted with 1-3 substituents independently selected from R ⁴ ;
[30] (c) C ₃ -C ₈ cycloalkyl optionally substituted with 1-2 substituents independently selected from R ⁴ ;
[31] (d) C ₃ -C ₈ cycloalkenyl optionally substituted with 1-2 substituents independently selected from R ⁴ ;
[32] (e) ⁵ , optionally substituted with 1-3 substituents independently selected from R ⁴ , containing up to 2 heteroatoms selected from the group consisting of -O-, -NR ^2- , and -S (O) _n- Circle heterocycle;
[33] (f) ⁶ , optionally substituted with 1-3 substituents independently selected from R ⁴ , containing up to 2 heteroatoms selected from the group consisting of -O-, -NR ² -and -S (O) _n- Circle heterocycle; or
[34] (g) ⁵ , optionally substituted with 1-3 substituents independently selected from R ⁴ , containing up to 2 heteroatoms selected from the group consisting of -O-, -NR ² -and -S (O) _n- A membered or 6 membered heterocycle ring is a bicyclic structure fused to a phenyl ring;
[35] Z ¹ is
[36] (a)-(CH ₂ ) _p W (CH ₂ ) _q- ;
[37] (b) -O (CH ₂ ) _p CR ⁵ R ^6- ;
[38] (c) -O (CH ₂ ) _p W (CH ₂ ) _q- ;
[39] (d) -OCHR ² CHR ^3- ; or
[40] (e) -SCHR ² CHR ^3- ;
[41] G is
[42] (a) -NR ⁷ R ⁸ ;
[43] (b)
[44] (Wherein n is 0, 1 or 2; m is 1, 2 or 3; Z ² is —NH—, —O—, —S— or —CH ₂ —; on optionally adjacent carbon atoms) Fused with one or two phenyl rings, optionally substituted independently with one to three substituents on carbon, and optionally independently with a chemically appropriate substituent selected from R ⁴ on nitrogen); or
[45] (c) a bicyclic amine having 5 to 12 carbon atoms optionally substituted and linked or fused with 1-3 substituents independently selected from R ⁴ ;
[46] Z ¹ and G are combined Can be;
[47] W is
[48] (a) -CH _2- ;
[49] (b) -CH = CH-;
[50] (c) -O-;
[51] (d) -NR ^2- ;
[52] (e) -S (O) _n- ;
[53] (f) ;
[54] (g) -CR ² (OH)-;
[55] (h) -CONR ^2- ;
[56] (i) -NR ² CO-;
[57] (j) ;or
[58] (k) -C≡C-;
[59] R is hydrogen or C ₁ -C ₆ alkyl;
[60] R ² and R ³ are independently
[61] (a) hydrogen; or
[62] (b) C ₁ -C ₄ alkyl;
[63] R ⁴ is
[64] (a) hydrogen;
[65] (b) halogen;
[66] (c) C ₁ -C ₆ alkyl;
[67] (d) C ₁ -C ₄ alkoxy;
[68] (e) C ₁ -C ₄ acyloxy;
[69] (f) C ₁ -C ₄ alkylthio;
[70] (g) C ₁ -C ₄ alkylsulfinyl;
[71] (h) C ₁ -C ₄ alkylsulfonyl;
[72] (i) hydroxy (C ₁ -C ₄ ) alkyl;
[73] (j) aryl (C ₁ -C ₄ ) alkyl;
[74] (k) -CO ₂ H;
[75] (l) -CN;
[76] (m) -CONHOR;
[77] (n) -SO ₂ NHR;
[78] (o) -NH ₂ ;
[79] (p) C ₁ -C ₄ alkylamino;
[80] (q) C ₁ -C ₄ dialkylamino;
[81] (r) -NHSO ₂ R;
[82] (s) -NO ₂ ;
[83] (t) -aryl; or
[84] (u) -OH;
[85] R ⁵ and R ⁶ are independently C ₁ -C ₈ alkyl or together form a C ₃ -C ₁₀ carbocyclic ring;
[86] R ⁷ and R ⁸ are independently
[87] (a) phenyl;
[88] (b) saturated or unsaturated C ₃ -C ₁₀ carbocyclic ring;
[89] (c) a C ₃ -C ₁₀ heterocyclic ring comprising up to two heteroatoms selected from -O-, -N-, and -S-;
[90] (d) H;
[91] (e) C ₁ -C ₆ alkyl; or
[92] (f) forms a 3-8 membered nitrogen containing ring with R ⁵ or R ⁶ ;
[93] Linear or cyclic R ⁷ and R ⁸ may be optionally substituted with up to three substituents independently selected from C ₁ -C ₆ alkyl, halogen, alkoxy, hydroxy and carboxy;
[94] The ring formed by R ⁷ and R ⁸ may be optionally fused to a phenyl ring;
[95] e is 0, 1 or 2;
[96] m is 1, 2 or 3;
[97] n is 0, 1 or 2;
[98] p is 0, 1, 2, or 3;
[99] q is 0, 1, 2 or 3.
[100] In another preferred embodiment of the invention, the estrogen agonist / antagonist comprises a compound of formula (1a) or an optical or geometric isomer thereof; Or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or precursor thereof.
[101]
[102] In the above formula, G is
[103] ego
[104] R ⁴ is H, OH, F or Cl; B and E are independently selected from CH and N.
[105] In a preferred embodiment of this method, the estrogen agonist / antagonist is (-)-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6 , 7,8-tetrahydro-naphthalen-2-ol or its optical or geometric isomers; Or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or precursor thereof.
[106] In another preferred embodiment of this method, the estrogen agonist / antagonist is (-)-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl]- 5,6,7,8-tetrahydro-naphthalen-2-ol, D-tartrate salt.
[107] In another preferred embodiment of this method, the estrogen agonist / antagonist is tamoxifen, 4-hydroxy tamoxifen, raloxyphene, drroloxyphene, toremifene, centchroma, idoxifen, 6- (4-hydride Oxy-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -naphthalen-2-ol, {4- [2- (2-aza-bicyclo [2.2. 1] hept-2-yl) -ethoxy] -phenyl}-[6-hydroxy-2- (4-hydroxy-phenyl) -benzo [b] thiophen-3-yl] -methanone, GW 5638 , GW 7604, and its optical or geometric isomers; And pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts and precursors thereof; Or a compound of formula (5) or (6) or an optical and geometric isomer thereof; Or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or precursor thereof; Or a compound of formula (5a), TSE-424 or an optical or geometric isomer thereof; Or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or precursor thereof; Or compound EM-652 of the formula (3) or EM-800 or the optical or geometric isomer thereof of the formula (4); Or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or precursor thereof.
[108]
[109]
[110]
[111]
[112]
[113] In the above formula:
[114] R _1B is H, OH, —OC (O) —C ₁ -C ₁₂ alkyl (straight or branched), —OC ₁ -C ₁₂ alkyl (straight or branched or cyclic), or halogen or C ₁ -C ₄ Selected from halogenated ethers;
[115] R _2B , R _3B , R _4B , R _5B and R _6B are independently H, OH, —OC (O) —C ₁ -C ₁₂ alkyl (straight or branched), -OC ₁ -C ₁₂ alkyl (straight or Branched or cyclic), halogen or C ₁ -C ₄ halogenated ether, cyano, C ₁ -C ₆ alkyl (straight or branched), or trifluoromethyl;
[116] X _A is selected from H, C ₁ -C ₆ alkyl, cyano, nitro, trifluoromethyl and halogen;
[117] s is 2 or 3;
[118] Y _A is the part: And wherein
[119] a) R _7B and R _8B are independently H, C ₁ -C ₆ alkyl, or CN, C ₁ -C ₆ alkyl (straight or branched), C ₁ -C ₆ alkoxy (straight or branched), halogen, Or is selected from the group of phenyl optionally substituted by -OH, -CF ₃ or -OCF ₃ ;
[120] b) R _7B and R _8B are linked to contain one nitrogen heteroatom, hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _2- , -NHSO ₂ R _1B , -NHCOR _1B , -NO ₂ , or To form a 5-membered saturated heterocycle optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl optionally substituted with 1-3 (C ₁ -C ₄ ) alkyl;
[121] c) R _7B and R _8B are linked to contain one nitrogen heteroatom, hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _2- , -NHSO ₂ R _1B , -NHCOR _1B , -NO ₂ , or To form a 6 membered saturated heterocycle optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl optionally substituted with 1-3 (C ₁ -C ₄ ) alkyl;
[122] d) R _7B and R _8B are linked to contain one nitrogen heteroatom, hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _2- , -NHSO ₂ R _1B , -NHCOR _1B , -NO ₂ , or To form a 7 membered saturated heterocycle optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl optionally substituted with 1-3 (C ₁ -C ₄ ) alkyl;
[123] e) R _7B and R _8B are linked to contain one nitrogen heteroatom, hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _2- , -NHSO ₂ R _1B , -NHCOR _1B , -NO ₂ , or To form an 8-membered saturated heterocycle optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl optionally substituted with 1-3 (C ₁ -C ₄ ) alkyl; or
[124] f) R _7B and R _8B are linked to contain 6-12 carbon atoms and 1 nitrogen heteroatom, hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ), Alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _2- , -NHSO ₂ R _1B ,- Saturated bicyclic hetero, optionally substituted with 1-3 substituents independently selected from the group consisting of NHCOR _1B , -NO ₂ , or phenyl optionally substituted with 1-3 (C ₁ -C ₄ ) alkyl Form a cycle.
[125] Lowering vaginal pH, further comprising administering to the patient in need thereof a therapeutically effective amount of estrogen agonist / antagonist; Treatment of urinary tract infections; Treatment of vaginal dryness; Treatment of vaginal itching; Treatment of undesirable vaginal spasms; Treatment of vaginitis; Treatment of yeast or bacterial infections of the vagina; Treatment of vulvar atrophy; Treatment of bladder, urethral, rectal or hernia prolapse; Treatment of urine and fecal incontinence; Treatment of undesirable uremia and urinary urgency; Or a method for increasing the frequency or intensity of orgasm.
[126] In a preferred embodiment of this method, the patient is a postmenopausal woman.
[127] In another preferred embodiment of this method, the estrogen agonist / antagonist comprises a compound of formula (1) or an optical or geometric isomer thereof; Or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or precursor thereof:
[128] <Formula 1>
[129]
[130] In the above formula:
[131] A is selected from CH ₂ and NR;
[132] B, D and E are independently selected from CH and N;
[133] Y is
[134] (a) phenyl optionally substituted with 1-3 substituents independently selected from R ⁴ ;
[135] (b) naphthyl optionally substituted with 1-3 substituents independently selected from R ⁴ ;
[136] (c) C ₃ -C ₈ cycloalkyl optionally substituted with 1-2 substituents independently selected from R ⁴ ;
[137] (d) C ₃ -C ₈ cycloalkenyl optionally substituted with 1-2 substituents independently selected from R ⁴ ;
[138] (e) ⁵ , optionally substituted with 1-3 substituents independently selected from R ⁴ , containing up to 2 heteroatoms selected from the group consisting of -O-, -NR ^2- , and -S (O) _n- Circle heterocycle;
[139] (f) ⁶ , optionally substituted with 1-3 substituents independently selected from R ⁴ , containing up to 2 heteroatoms selected from the group consisting of -O-, -NR ² -and -S (O) _n- Circle heterocycle; or
[140] (g) ⁵ , optionally substituted with 1-3 substituents independently selected from R ⁴ , containing up to 2 heteroatoms selected from the group consisting of -O-, -NR ² -and -S (O) _n- A membered or 6 membered heterocycle ring is a bicyclic structure fused to a phenyl ring;
[141] Z ¹ is
[142] (a)-(CH ₂ ) _p W (CH ₂ ) _q- ;
[143] (b) -O (CH ₂ ) _p CR ⁵ R ^6- ;
[144] (c) -O (CH ₂ ) _p W (CH ₂ ) _q- ;
[145] (d) -OCHR ² CHR ^3- ; or
[146] (e) -SCHR ² CHR ^3- ;
[147] G is
[148] (a) -NR ⁷ R ⁸ ;
[149] (b)
[150] (Wherein n is 0, 1 or 2; m is 1, 2 or 3; Z ² is —NH—, —O—, —S— or —CH ₂ —; on optionally adjacent carbon atoms) Fused with one or two phenyl rings, optionally substituted independently with one to three substituents on carbon, and optionally independently with a chemically appropriate substituent selected from R ⁴ on nitrogen); or
[151] (c) a bicyclic amine having 5 to 12 carbon atoms optionally substituted and linked or fused with 1-3 substituents independently selected from R ⁴ ;
[152] Z ¹ and G are combined Can be;
[153] W is
[154] (a) -CH _2- ;
[155] (b) -CH = CH-;
[156] (c) -O-;
[157] (d) -NR ^2- ;
[158] (e) -S (O) _n- ;
[159] (f) ;
[160] (g) -CR ² (OH)-;
[161] (h) -CONR ^2- ;
[162] (i) -NR ² CO-;
[163] (j) ;or
[164] (k) -C≡C-;
[165] R is hydrogen or C ₁ -C ₆ alkyl;
[166] R ² and R ³ are independently
[167] (a) hydrogen; or
[168] (b) C ₁ -C ₄ alkyl;
[169] R ⁴ is
[170] (a) hydrogen;
[171] (b) halogen;
[172] (c) C ₁ -C ₆ alkyl;
[173] (d) C ₁ -C ₄ alkoxy;
[174] (e) C ₁ -C ₄ acyloxy;
[175] (f) C ₁ -C ₄ alkylthio;
[176] (g) C ₁ -C ₄ alkylsulfinyl;
[177] (h) C ₁ -C ₄ alkylsulfonyl;
[178] (i) hydroxy (C ₁ -C ₄ ) alkyl;
[179] (j) aryl (C ₁ -C ₄ ) alkyl;
[180] (k) -CO ₂ H;
[181] (l) -CN;
[182] (m) -CONHOR;
[183] (n) -SO ₂ NHR;
[184] (o) -NH ₂ ;
[185] (p) C ₁ -C ₄ alkylamino;
[186] (q) C ₁ -C ₄ dialkylamino;
[187] (r) -NHSO ₂ R;
[188] (s) -NO ₂ ;
[189] (t) -aryl; or
[190] (u) -OH;
[191] R ⁵ and R ⁶ are independently C ₁ -C ₈ alkyl or together form a C ₃ -C ₁₀ carbocyclic ring;
[192] R ⁷ and R ⁸ are independently
[193] (a) phenyl;
[194] (b) saturated or unsaturated C ₃ -C ₁₀ carbocyclic ring;
[195] (c) a C ₃ -C ₁₀ heterocyclic ring comprising up to two heteroatoms selected from -O-, -N-, and -S-;
[196] (d) H;
[197] (e) C ₁ -C ₆ alkyl; or
[198] (f) forms a 3-8 membered nitrogen containing ring with R ⁵ or R ⁶ ;
[199] Linear or cyclic R ⁷ and R ⁸ may be optionally substituted with up to three substituents independently selected from C ₁ -C ₆ alkyl, halogen, alkoxy, hydroxy and carboxy;
[200] The ring formed by R ⁷ and R ⁸ may be optionally fused to a phenyl ring;
[201] e is 0, 1 or 2;
[202] m is 1, 2 or 3;
[203] n is 0, 1 or 2;
[204] p is 0, 1, 2 or 3;
[205] q is 0, 1, 2, or 3.
[206] In a preferred embodiment of the invention, the estrogen agonist / antagonist comprises a compound of formula (1a) or an optical or geometric isomer thereof; Or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or precursor thereof.
[207] <Formula 1a>
[208]
[209] In the above formula, G is
[210] ego;
[211] R ⁴ is H, OH, F or Cl; B and E are independently selected from CH and N.
[212] In a preferred embodiment of this method, the estrogen agonist / antagonist is (-)-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6 , 7,8-tetrahydro-naphthalen-2-ol or its optical or geometric isomers; Or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or precursor thereof.
[213] In another preferred embodiment of this method, the estrogen agonist / antagonist is (-)-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl]- 5,6,7,8-tetrahydro-naphthalen-2-ol, D-tartrate salt.
[214] In another preferred embodiment of this method, the estrogen agonist / antagonist is tamoxifen, 4-hydroxy tamoxifen, raloxyphene, drroloxyphene, toremifene, centchroma, idoxifen, 6- (4-hydride Oxy-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -naphthalen-2-ol, {4- [2- (2-aza-bicyclo [2.2. 1] hept-2-yl) -ethoxy] -phenyl}-[6-hydroxy-2- (4-hydroxy-phenyl) -benzo [b] thiophen-3-yl] -methanone, GW 5638 , GW 7604, and its optical or geometric isomers; And pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts and precursors thereof; Or a compound of formula (5) or (6) or an optical and geometric isomer thereof; Or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or precursor thereof; Or a compound of formula (5a), TSE-424 or an optical or geometric isomer thereof; Or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or precursor thereof; Or compound EM-652 of the formula (3) or EM-800 or the optical or geometric isomer thereof of the formula (4); Or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or precursor thereof.
[215] <Formula 5>
[216]
[217] <Formula 6>
[218]
[219] In the above formula:
[220] R _1B is H, OH, —OC (O) —C ₁ -C ₁₂ alkyl (straight or branched), —OC ₁ -C ₁₂ alkyl (straight or branched or cyclic), or halogen or C ₁ -C ₄ Selected from halogenated ethers;
[221] R _2B , R _3B , R _4B , R _5B and R _6B are independently H, OH, —OC (O) —C ₁ -C ₁₂ alkyl (straight or branched), -OC ₁ -C ₁₂ alkyl (straight or Branched or cyclic), halogen, or C ₁ -C ₄ halogenated ether, cyano, C ₁ -C ₆ alkyl (linear or branched chain), or trifluoromethyl;
[222] X _A is selected from H, C ₁ -C ₆ alkyl, cyano, nitro, trifluoromethyl and halogen;
[223] s is 2 or 3;
[224] Y _A is the part: ego,
[225] In the above formula:
[226] a) R _7B and R _8B are independently H, C ₁ -C ₆ alkyl, or CN, C ₁ -C ₆ alkyl (straight or branched), C ₁ -C ₆ alkoxy (straight or branched), halogen, Or is selected from the group of phenyl optionally substituted by -OH, -CF ₃ or -OCF ₃ ;
[227] b) R _7B and R _8B are linked to contain one nitrogen heteroatom, hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _2- , -NHSO ₂ R _1B , -NHCOR _1B , -NO ₂ , or To form a 5-membered saturated heterocycle optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl optionally substituted with 1-3 (C ₁ -C ₄ ) alkyl;
[228] c) R _7B and R _8B are linked to contain one nitrogen heteroatom, hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _2- , -NHSO ₂ R _1B , -NHCOR _1B , -NO ₂ , or To form a 6 membered saturated heterocycle optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl optionally substituted with 1-3 (C ₁ -C ₄ ) alkyl;
[229] d) R _7B and R _8B are linked to contain one nitrogen heteroatom, hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _2- , -NHSO ₂ R _1B , -NHCOR _1B , -NO ₂ , or To form a 7 membered saturated heterocycle optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl optionally substituted with 1-3 (C ₁ -C ₄ ) alkyl;
[230] e) R _7B and R _8B are linked to contain one nitrogen heteroatom, hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _2- , -NHSO ₂ R _1B , -NHCOR _1B , -NO ₂ , or To form an 8-membered saturated heterocycle optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl optionally substituted with 1-3 (C ₁ -C ₄ ) alkyl; or
[231] f) R _7B and R _8B are linked to contain 6-12 carbon atoms and 1 nitrogen heteroatom, hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ), Alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _2- , -NHSO ₂ R _1B ,- Saturated bicyclic hetero, optionally substituted with 1-3 substituents independently selected from the group consisting of NHCOR _1B , -NO ₂ , or phenyl optionally substituted with 1-3 (C ₁ -C ₄ ) alkyl To form a cycle;
[232] <Formula 5a>
[233]
[234] <Formula 3>
[235]
[236] <Formula 4>
[237]
[238] The invention also provides a kit comprising the following for use by a consumer to promote or maintain urogenital health:
[239] (a) a pharmaceutical composition comprising an estrogen agonist / antagonist and a pharmaceutically acceptable carrier, excipient or diluent; And
[240] (b) to promote or maintain urogenital health; Lowering of vaginal pH; Treatment of urinary tract infections; Treatment of vaginal dryness; Treatment of vaginal itching; Treatment of undesirable vaginal spasms; Treatment of vaginitis; Treatment of yeast or bacterial infections of the vagina; Treatment of vulvar atrophy; Treatment of bladder, urethral, rectal, hernia prolapse; Treatment of feces and urinary incontinence; Treatment of undesired uremia or urinary perforation; Or instructions describing the use of the pharmaceutical composition for increasing the strength or frequency of orgasm.
[241] In another embodiment of this kit, the method comprises: promoting or maintaining urogenital health; lowering vaginal pH; Treatment of urinary tract infections; Treatment of vaginal dryness; Treatment of vaginal itching; Treatment of undesirable vaginal spasms; Treatment of vaginitis; Treatment of yeast or bacterial infections of the vagina; Treatment of vulvar atrophy; Treatment of bladder, urethral, rectal, hernia prolapse; Treatment of feces and urinary incontinence; Treatment of undesired uremia or urinary perforation; Or further compounds useful in increasing the strength or frequency of orgasm are included in the kit.
[242] Also provided are methods of analyzing vaginal health of a patient, including:
[243] a) performing a gynecological examination;
[244] b) measuring the pH of the vagina;
[245] c) measuring vaginal cell maturity index;
[246] d) measure vaginal escape;
[247] e) give the patient a survey;
[248] f) Plasma hormone levels are measured and the patient's vaginal health is analyzed taking into account the data from steps a) -f) above.
[249] In a preferred embodiment of this method, the gynecological examination comprises an internal evaluation of the vagina describing the characteristics of the vaginal state by successively representing the vaginal state using the following I and III as the lowest and highest points and the following II as the midpoint. do:
[250] I. No wrinkles, no elasticity, very mucous membranes, soft and bleeding to the touch, no depth of vagina, very dry;
[251] II. Less wrinkles, some water loss, weak elastic discomfort when inspecting, pale colors, shortened depth of vagina; or
[252] III. Estrogenization vagina, wrinkles of normal, good elasticity, strong mucous membrane of pink, good vaginal moisture and good vaginal health.
[253] In another preferred embodiment of this method, the gynecological examination includes the analysis of pubic and vulva thickness.
[254] In another preferred embodiment of this method, the plasma hormone levels measured include estradiol, progesterone, follicle-stimulating hormone, testosterone and androstenedione.
[255] In another preferred embodiment of this method, vaginal escape is measured by grading escape using the following scale:
[256] Class 0: Normal position inside the vaginal central axis for anterior posterior wall prolapse and above the sciatic pole for a cervical or vaginal cuff. By definition, the peak is -3 cm above the hymen;
[257] Class 1: the escape past each starting point to the mid-point to the hymen;
[258] Class 2: down to hymen;
[259] Class 3: down 2 cm past hymen;
[260] Grade 4: Lowered to the maximum extent possible for each site. Complete valgus about 5 cm past hymen.
[261] In another preferred embodiment of this method, the questionnaire includes questions relating to:
[262] 1) the number of vaginal infections;
[263] 2) the number of urinary infections;
[264] 3) the amount of urine leakage;
[265] 4) the degree of vaginal dryness;
[266] 5) degree of vaginal itching; And
[267] 6) Subjective assessment of overall quality health by the patient.
[268] Also provided are methods for analyzing vaginal health of a patient, including:
[269] a) Gynecologic, including internal evaluation of the vagina describing the characteristics of the vaginal state and analysis of pubic and vulva thicknesses by successively representing vaginal state using the following I and III as the lowest and highest points and the following II as the midpoint. Perform the check:
[270] I. No wrinkles, no elasticity, very mucous membranes, soft and bleeding to the touch, no depth of vagina, very dry;
[271] II. Less wrinkles, some water loss, weak elastic discomfort when inspecting, pale colors, shortened depth of vagina; or
[272] III. Normal estrogenation vagina, wrinkles, good elasticity, pink strong mucous membranes, good vaginal moisture and good vaginal health;
[273] b) measuring the pH of the vagina;
[274] c) determining the vaginal cell maturation index;
[275] d) Measure vaginal escape using the following scales:
[276] Class 0: Normal position inside the vaginal central axis for anterior posterior wall prolapse and above the sciatic pole for a neck or vaginal cuff. By definition, the highest point is -3 cm above the hymen;
[277] Class 1: the escape past each starting point to the mid-point to the hymen;
[278] Class 2: down to hymen;
[279] Class 3: 2cm past hymen:
[280] Grade 4: Lowered to the maximum extent possible for each site. Complete valgus about 5 cm past hymen;
[281] e) Give the patient a questionnaire including questions relating to:
[282] 1) the number of vaginal infections during a particular period of time;
[283] 2) the number of urinary infections during a particular time period;
[284] 3) the amount of urine leakage over a certain period of time;
[285] 4) the degree of vaginal dryness during a certain period of time;
[286] 5) degree of vaginal itching; And
[287] 6) subjective assessment of overall quality health by the patient;
[288] f) Plasma levels of estradiol, progesterone, follicle-stimulating hormone, testosterone and androstenedione are measured, and the patient's vaginal health is analyzed in light of the data from steps a-f.
[289] The present invention relates to a method for promoting or maintaining the health of the genitourinary system. In particular, the present invention relates to a decrease in vaginal pH, treatment of urinary tract infections, treatment of vaginal dryness, treatment of vaginal itching, treatment of undesirable vaginal spasms, treatment of vaginitis, treatment of vaginal yeast or bacterial infections, treatment of vulvar atrophy; Treatment of bladder, urethral, rectal or hernia prolapse, treatment of urine or stool incontinence; The present invention relates to a method for the treatment of undesired uremia or urinary insufficiency, or for increasing the frequency and intensity of orgasm. The present invention also relates to a method of vaginal health analysis, which is useful for demonstrating the efficacy and stability of novel pharmaceutical substances and compositions affecting the vagina and for making diagnostic decisions.
[290] As used herein, the terms “treat”, “treatment” and “treating” include prophylactic and palliative treatment of a disease or condition, or ameliorating symptoms of a disease or condition.
[291] The phrase “maintaining or promoting the health of the genitourinary system” refers to the prevention of the symptoms of a pathological urogenital state or condition, or to the slowing down of a process or the reversal of the condition or the reversal of the condition that results in the development of the condition or condition's symptoms. Means. Enhancement of urogenital health includes the reduction of urogenital infections, including vaginal and urinary infections; Reduction of vaginal dryness, itching and irritation; And / or a reduction in incontinence. Promoting urogenital health will also include maintaining or improving pelvic floor integrity including prolapse.
[292] The term "incontinence" includes urine and stool incontinence. If incontinence is in fact urine, this is defined as the loss of unconscious urine, which can be a social or hygiene problem. Urinary incontinence may be stress incontinence, acute incontinence, or mixed incontinence in which both stress and acute incontinence occur simultaneously, or may be involuntary incontinence that occurs without awareness of leakage without urinary insufficiency. Reduced flow in the urine stem can lead to poor performance, difficulty urinating, and thinner stems. Intermittent stems can be observed as urination in a "stop and start" pattern. Or after urination, which is a loss of urine that is issued immediately after the bladder is incompletely emptied or normal urination is complete.
[293] "Fecal incontinence" is an involuntary loss of stool or gas that may be caused by a rectal escape. Normally, the rectum is firmly bound to the large muscle complex through prolonged intermingling of myofibrils. This combination is very important because of the complex changes in the location of the rectum during normal bowel movements. Without this linkage, the rectum will slide through the big muscle tear during defecation. On exiting the workplace, this happens.
[294] "Excession" is the movement of one of the pelvic organs downward or forward from its normal position. Traditionally, prolapse refers to movement of the bladder, uterus or rectum. Escape may also be related to the movement of the vagina. These shifts have been typically rated 0-4; The higher this level, the more severe the escape. A number of terms defined in the literature are used to describe female genital exit, and these terms include:
[295] "Burst flow" is the downward movement of the bladder.
[296] A "bladder urethra" is a bladder that includes the urethra as part of an organ complex that escapes.
[297] "Uterine prolapse" is the uterus and cervix descending down the vaginal canal toward the vaginal opening.
[298] "Rectal dislocation" is the protrusion of the rectum into the posterior vaginal cavity.
[299] "Hernia" is the escape of the small intestine into the vaginal cavity.
[300] The term "chondritis" means inflammation of the vagina.
[301] The phrase “undesired uremia and urinary insufficiency” means that a patient urinates more often than the average of a similar patient group. Typically, an increase in the frequency of urination makes the patient mentally uneasy and shy. In addition, the patient may experience a feeling of wanting to urinate compared to a similar group. A stronger feeling of wanting to urinate can also cause mental discomfort and shame.
[302] The term “increasing the frequency or intensity of orgasm” means that a patient experiences more orgasm or experiences or senses enhanced orgasm as compared to untreated after being treated with the present compounds. A method of measuring a patient's detection of increased frequency and / or increased intensity orgasm is to ask the patient. For example, you can use a questionnaire.
[303] Certain aspects of vaginal health status can be measured by analyzing vaginal secretions. Normal vaginal discharge is fluffy, white in color, and is usually located in the vaginal appendage (back posterior). Vaginal secretions can be analyzed by wet inclusion formulations. Samples of vaginal secretions are suspended in 0.4 mL of normal saline in glass test tubes, transferred to slides, covered with slips and analyzed microscopically. Some clinicians prefer to make slides by suspending secretions directly in saline solution on the slides. Secretions should not be placed directly on the slides without saline, because the vaginal secretions can dry out to form a well-suspended formulation. Normal microscopic examination of vaginal secretions reveals a number of superficial epithelial cells, a few leukocyte cells (up to one per epithelial cell), and a small number of clue cells, if present. Clu cells destroy the crisp cell boundaries and are usually visible under a microscope. It is a superficial vaginal epithelial cell with engraftment bacteria, G. vaginalis . 10% potassium hydroxide (KOH) may be added to the slides or a separate formulation may be prepared to examine the secretion for fungal components. For women of normal vaginal microbes, the result should be negative. In Gram staining, normal superficial epithelial cells are typical and Gram positive rods (Lactobacillus) will appear to be dominant.
[304] The phrase “side effects associated with estrogen” includes chest sensitivity, edema, headache, increased blood clotting in women and menstrual bleeding and breast cancer. Estrogen treatment increases the risk of endometrioma. Women who have been on estrogen for a long time will have an increased risk that is not reversed even by the simultaneous administration of progestin (N, Engl J Med 1995; 332 : 1589).
[305] The term "postmenopausal woman" refers to not only women who have undergone menopause with age, but also those who have undergone hysterectomy or who have certain suppression of estrogen production for some other reason, such as genital malformations, without Cushing's syndrome, who have received long-term administration of corticosteroids. Or women who have received radiation therapy.
[306] "Breast cancer" is defined as the proliferation of malignancies of epithelial cells in the ducts or lobules of the breast.
[307] The term "patient" means an animal, in particular a mammal. Preferred patients are humans and postmenopausal human females are the most preferred patients.
[308] An "estrogen agonist / antagonist" is a compound that, like estrogens, affects several of the same receptors, but not all, and in certain cases, antagonizes or blocks estrogens. It is also known as "selective estrogen receptor activator" (SERM). Estrogen agonists / antagonists may also be referred to as antiestrogens although they have some degree of estrogen activity in certain target tissues. Hence, estrogen agonists / antagonists are not commonly referred to as “pure antiestrogens”. Antiestrogens that can act as effector muscles are referred to as type 1 antiestrogens. Type 1 antiestrogens activate estrogen receptors, allowing them to bind firmly in the nucleus for long periods of time, but continue to increase damaged receptors (Clark et al. (Steroids, 1973; 22 ; 707), Capony et al. Mol Cell Endocrinol, 1975; 3 : 233.
[309] When menopause occurs, the genitourinary system may change. These changes include elevated vaginal pH; An increase in vaginal yeast and bacterial infections that can be caused by an increase in vaginal pH; Increased vaginal dryness and itching; Undesirable vaginal spasms; vaginitis; Vulvar atrophy; Various types of escape as mentioned herein; And urinary or stool incontinence that may occur due to escape. According to the present invention these symptoms can be treated by administering the estrogen agonist / antagonist. By treating these symptoms, the overall vaginal health of the patient can be maintained or promoted.
[310] The estrogen agonist / antagonist of the present invention may be administered systemically or locally. For systemic use, the estrogen agonist / antagonist is a conventional method for parenteral (eg, intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal or transdermal) or enteral (eg oral or rectal) delivery. Can be formulated accordingly. Intravenous administration may be by a series of injections or by prolonged continuous infusion. Administration by spaced administration by injection or other route may be performed at intervals ranging from one to three or more times a few months, weeks to a day.
[311] Another method of administering a compound of the present invention includes use in a topical dosage form. For example, the active agent may be administered to the patient in the form of a cream or ointment applied to the skin, particularly the skin of the vagina. Alternatively, the active agent can be delivered using a patch applied to the skin. The use of topical dosage forms is particularly useful for treating vaginal dryness, urinary and / or vaginal bacterial or yeast infections, and sexual dysfunction.
[312] Preferred estrogen agonists / antagonists that can be used in the methods and kits of the invention include the compounds described in US Pat. No. 5,552,412. These compounds include compounds of the formula designated as general formula (1) and optical and geometric isomers thereof; And non-toxic pharmacologically acceptable acid addition salts, N-oxides, esters, quaternary ammonium salts and precursors thereof:
[313] <Formula 1>
[314]
[315] In the above formula:
[316] A is selected from CH ₂ and NR;
[317] B, D and E are independently selected from CH and N;
[318] Y is
[319] (a) phenyl optionally substituted with 1-3 substituents independently selected from R ⁴ ;
[320] (b) naphthyl optionally substituted with 1-3 substituents independently selected from R ⁴ ;
[321] (c) C ₃ -C ₈ cycloalkyl optionally substituted with 1-2 substituents independently selected from R ⁴ ;
[322] (d) C ₃ -C ₈ cycloalkenyl optionally substituted with 1-2 substituents independently selected from R ⁴ ;
[323] (e) ⁵ , optionally substituted with 1-3 substituents independently selected from R ⁴ , containing up to 2 heteroatoms selected from the group consisting of -O-, -NR ^2- , and -S (O) _n- Circle heterocycle;
[324] (f) ⁶ , optionally substituted with 1-3 substituents independently selected from R ⁴ , containing up to 2 heteroatoms selected from the group consisting of -O-, -NR ² -and -S (O) _n- Circle heterocycle; or
[325] (g) ⁵ , optionally substituted with 1-3 substituents independently selected from R ⁴ , containing up to 2 heteroatoms selected from the group consisting of -O-, -NR ² -and -S (O) _n- A membered or 6 membered heterocycle ring is a bicyclic structure fused to a phenyl ring;
[326] Z ¹ is
[327] (a)-(CH ₂ ) _p W (CH ₂ ) _q- ;
[328] (b) -O (CH ₂ ) _p CR ⁵ R ^6- ;
[329] (c) -O (CH ₂ ) _p W (CH ₂ ) _q- ;
[330] (d) -OCHR ² CHR ^3- ; or
[331] (e) -SCHR ² CHR ^3- ;
[332] G is
[333] (a) -NR ⁷ R ⁸ ;
[334] (b)
[335] (Wherein n is 0, 1 or 2; m is 1, 2 or 3; Z ² is —NH—, —O—, —S— or —CH ₂ —; on optionally adjacent carbon atoms) Fused with one or two phenyl rings, optionally substituted independently with one to three substituents on carbon, and optionally independently with a chemically appropriate substituent selected from R ⁴ on nitrogen); or
[336] (c) a bicyclic amine having 5 to 12 carbon atoms optionally substituted and linked or fused with 1-3 substituents independently selected from R ⁴ ;
[337] Z ¹ and G are combined Can be;
[338] W is
[339] (a) -CH _2- ;
[340] (b) -CH = CH-;
[341] (c) -O-;
[342] (d) -NR ^2- ;
[343] (e) -S (O) _n- ;
[344] (f) ;
[345] (g) -CR ² (OH)-;
[346] (h) -CONR ^2- ;
[347] (i) -NR ² CO-;
[348] (j) ;or
[349] (k) -C≡C-;
[350] R is hydrogen or C ₁ -C ₆ alkyl;
[351] R ² and R ³ are independently
[352] (a) hydrogen; or
[353] (b) C ₁ -C ₄ alkyl;
[354] R ⁴ is
[355] (a) hydrogen;
[356] (b) halogen;
[357] (c) C ₁ -C ₆ alkyl;
[358] (d) C ₁ -C ₄ alkoxy;
[359] (e) C ₁ -C ₄ acyloxy;
[360] (f) C ₁ -C ₄ alkylthio;
[361] (g) C ₁ -C ₄ alkylsulfinyl;
[362] (h) C ₁ -C ₄ alkylsulfonyl;
[363] (i) hydroxy (C ₁ -C ₄ ) alkyl;
[364] (j) aryl (C ₁ -C ₄ ) alkyl;
[365] (k) -CO ₂ H;
[366] (l) -CN;
[367] (m) -CONHOR;
[368] (n) -SO ₂ NHR;
[369] (o) -NH ₂ ;
[370] (p) C ₁ -C ₄ alkylamino;
[371] (q) C ₁ -C ₄ dialkylamino;
[372] (r) -NHSO ₂ R;
[373] (s) -NO ₂ ;
[374] (t) -aryl; or
[375] (u) -OH;
[376] R ⁵ and R ⁶ are independently C ₁ -C ₈ alkyl or together form a C ₃ -C ₁₀ carbocyclic ring;
[377] R ⁷ and R ⁸ are independently
[378] (a) phenyl;
[379] (b) saturated or unsaturated C ₃ -C ₁₀ carbocyclic ring;
[380] (c) a C ₃ -C ₁₀ heterocyclic ring comprising up to two heteroatoms selected from -O-, -N-, and -S-;
[381] (d) H;
[382] (e) C ₁ -C ₆ alkyl; or
[383] (f) forms a 3-8 membered nitrogen containing ring with R ⁵ or R ⁶ ;
[384] Linear or cyclic R ⁷ and R ⁸ may be optionally substituted with up to three substituents independently selected from C ₁ -C ₆ alkyl, halogen, alkoxy, hydroxy and carboxy;
[385] The ring formed by R ⁷ and R ⁸ may be optionally fused to a phenyl ring;
[386] e is 0, 1 or 2;
[387] m is 1, 2 or 3;
[388] n is 0, 1 or 2;
[389] p is 0, 1, 2 or 3;
[390] q is 0, 1, 2, or 3.
[391] Further preferred compounds of the invention, also taught in US Pat. No. 552,412, are represented by compounds of the formula and pharmaceutically acceptable salts thereof designated as Formula (1a) herein:
[392] <Formula 1a>
[393]
[394] In the above formula, G is
[395] ego
[396] R ⁴ is H, OH, F or Cl; B and E are independently selected from CH and N.
[397] Particularly preferred compounds for the process of the invention are:
[398] Cis-6- (4-fluoro-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalene-2 -Ol;
[399] (-)-Cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalen-2-ol;
[400] Cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl-5,6,7,8-tetrahydro-naphthalen-2-ol;
[401] Cis-1- [6'-pyrrolidinoethoxy-3'-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;
[402] 1- (4'-pyrrolidinoethoxyphenyl) -2- (4 "-fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
[403] Cis-6- (4-hydroxyphenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalene-2- Come;
[404] 1- (4'-pyrrolidinoethoxyphenyl) -2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline; And pharmaceutically acceptable salts thereof. Of (-)-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalen-2-ol Particularly preferred salts are the D-tartrate salts.
[405] Synthesis of this compound of formula (I) is described in US Pat. No. 5,552,412.
[406] Other preferred estrogen agonists / antagonists are described in US Pat. No. 5,047,431. The structures of these compounds include compounds of the formula and their optical and geometric isomers designated as formula (2) below; And pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and precursors thereof:
[407]
[408] In the above formula, R ^1A and R ^2A may be the same or different and are H, methyl, ethyl or benzyl group. Particularly preferred compounds are droloxyphene. The synthesis of compounds of formula (2) is described in US Pat. No. 5,047,431.
[409] Further preferred estrogen agonists / antagonists are tamoxifen taught in US Pat. No. 4,536,516: (ethanamine, 2-[-4- (1,2-diphenyl-1-butenyl) phenoxy] -N, N -Dimethyl, (Z) -2, 2-hydroxy-1,2,3-propanetricarboxylate (1: 1)) and other compounds; 4-hydroxy tamoxifen (ie, tamoxifen, wherein the 2-phenyl moiety has a hydroxy group at the 4 position) and other compounds taught in US Pat. No. 4,623,660; U.S. Patent 4,418,068; 5,393,763; 5,393,763; 5,457,117; 5,457,117; No. 5,478,847; And raloxyphene taught in US Pat. No. 5,641,790: (methanone, [6-hydroxy-2- (4-hydroxyphenyl) benzo [b] thien-3-yl] [4- [2- (1- Piperidinyl) ethoxy] phenyl]-, hydrochloride) and other compounds; Torremyfen as taught in US Pat. Nos. 4,696,949 and 4,996,225: (ethanamine, 2- [4- (4-chloro-1,2-diphenyl-1-butenyl) phenoxy] -N, N- Dimethyl, (Z)-, 2-hydroxy-1,2,3-propanetricaloxylate (1: 1) and other compounds; the centromman described in US Pat. No. 3,822,287: 1- [2- [[4-(-methoxy-2,2, dimethyl-3-phenyl-chroman-4-yl) -phenoxy] -ethyl] -pyrrolidine and other compounds; taught in US Pat. No. 4,839,155 Idoxifen: pyrrolidine, 1-[-[4-[[1- (4-iodophenyl) -2-phenyl-1-butenyl] phenoxy] ethyl] and other compounds; US Pat. No. 5,484,795 6- (4-hydroxy-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -naphthalen-2-ol and other compounds taught therein; and published {4- [2- (2-Aza-bicyclo [2.2.1] hept-2-yl) -ethoxy] -phenyl}-[6-hydroxy as taught in WO 95/10513 -2- (4-hydroxy-phenyl) -benzo [b] thiophen-3-yl]- A heptanone, and other compounds.
[410] Still other preferred estrogen agonists / antagonists include EM-652 (expressed as formula (3)) and EM-800 (expressed as formula (4)). Synthesis of EM-652 and EM-800 and synthesis of various enantiomers are described by Gauthier et al. Med. Chem., 1997; 40 : 2117-2122.
[411] <Formula 3>
[412]
[413] <Formula 4>
[414]
[415] Still other preferred estrogen agonists / antagonists include compounds represented by the formulas represented by the following formulas (5) and (6) and their optical and geometric isomers; And US Pat. Nos. 5,998,402, 5,985,910, 5,780,497, 5,880,137 and US Patent Application No. EP 0802183, including pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and precursors thereof. TSE 424 and other compounds taught in A1 include:
[416] <Formula 5>
[417]
[418] <Formula 6>
[419]
[420] In the above formula:
[421] R _1B is H, OH, or a C ₁ -C ₁₂ ester (straight or branched) or a C ₁ -C ₁₂ (straight or branched or cyclic) alkylether, or halogen; Or C ₁ -C ₄ halogenated ether, including trifluoromethyl ether and trichloromethyl ether,
[422] R _2B , R _3B , R _4B , R _5B and R _6B are independently H, OH, or C ₁ -C ₁₂ ester (linear or branched chain) or C ₁ -C ₁₂ alkylether (linear or branched or cyclic) thereof ), Halogen, or C ₁ -C ₄ halogenated ether, including cyano, C ₁ -C ₆ alkyl (straight or branched), or trifluoromethyl, including trifluoromethyl ether and trifluoromethyl ether Become;
[423] X _A is selected from H, C ₁ -C ₆ alkyl, cyano, nitro, trifluoromethyl and halogen;
[424] s is 2 or 3;
[425] Y _A is
[426] a) part:
[427] (In the formula:
[428] R _7B and R _8B are independently H, C ₁ -C ₆ alkyl, or CN, C ₁ -C ₆ alkyl (straight or branched), C ₁ -C ₆ alkoxy (straight or branched), halogen, —OH , Phenyl optionally substituted by -CF ₃ or -OCF ₃ );
[429] b) a group consisting of -O-, -NH-, -N (C ₁ -C ₄ alkyl)-, -N =, and -S (O) _u- , where u is an integer from 0-2 Containing up to 2 heteroatoms selected from hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy , C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , C ₁ -C ₄ alkylamino, -di (C ₁ -C ₄ ) alkylamino-, -NHSO ₂ R _1B , -NHCOR _1B ; A 5-membered saturated, unsaturated or partially unsaturated heterocycle optionally substituted with 1-3 substituents independently selected from the group consisting of —NO ₂ , and phenyl optionally substituted with 1-3 (C ₁ -C ₄ ) alkyl;
[430] c) a group consisting of -O-, -NH-, -N (C ₁ -C ₄ alkyl)-, -N =, and -S (O) _u- , where u is an integer from 0-2 Containing up to 2 heteroatoms selected from hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy , C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -C ₁ -C ₄ alkylamino, -di (C ₁ -C ₄ ) alkylamino-, -NHSO ₂ R _1B , -NHCOR _1B , -NO ₂ , and 1-3 (C ₁ -C ₄ ) 6-membered saturated, unsaturated or partially unsaturated heterocycle optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl optionally substituted with alkyl;
[431] d) a group consisting of -O-, -NH-, -N (C ₁ -C ₄ alkyl)-, -N =, and -S (O) _u- (where u is an integer from 0-2) Containing up to 2 heteroatoms selected from hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy , C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -C ₁ -C ₄ alkylamino, -di (C ₁ -C ₄ ) alkylamino-, -NHSO ₂ R _1B , -NHCOR _1B , -NO ₂ , and 1-3 (C ₁ -C ₄ ) 7 membered saturated, unsaturated or partially unsaturated heterocycle optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl optionally substituted with alkyl; or
[432] e) a group consisting of -O-, -NH-, -N (C ₁ -C ₄ alkyl)-, -N =, and -S (O) _u- (where u is an integer from 0-2) Containing up to 2 heteroatoms selected from hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy , C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -C ₁ -C ₄ alkylamino, -di (C ₁ -C ₄ ) alkylamino-, -NHSO ₂ R _1B , -NHCOR _1B , -NO ₂ , and 1-3 (C ₁ -C ₄ ) optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl optionally substituted with alkyl, and selected from a bicyclic heterocycle having 6 to 12 carbon atoms linked or fused.
[433] Among the compounds having the structure of Formula (5) or (6), more preferred compounds of the present invention are:
[434] R _1B is selected from H, OH, or a C ₁ -C ₁₂ ester or alkyl ether and halogen thereof;
[435] R _2B , R _3B , R _4B , R _5B and R _6B are independently H, OH or C ₁ -C ₁₂ ester or alkyl ethers thereof, halogen, cyano, C ₁ -C ₆ alkyl, or trihalomethyl, Preferably from trifluoromethyl;
[436] X _A is selected from H, C ₁ -C ₆ alkyl, cyano, nitro, trifluoromethyl and halogen;
[437] Y _A is the part: ego,
[438] In the above formula:
[439] R _7B and R _8B are independently selected from H, C ₁ -C ₆ alkyl, or combined by — (CH ₂ ) _w −, where w is an integer from 2 to 6, to form hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, Hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONH (C ₁ -C ₄ ), -NH ₂ , C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino- , A compound which forms a ring optionally substituted with up to three substituents selected from the group of -NHSO ₂ (C ₁ -C ₄ ), -NHCO (C ₁ -C ₄ ) and -NO ₂ , and its optical and geometric isomers ; And pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and precursors thereof.
[440] As mentioned above, the ring formed by linked R _7B and R _8B can include, but is not limited to, aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneamine or heptamethyleneamine rings. .
[441] Most preferred of the compounds of formulas (5) and (6) are those in which R _1B is OH; R _2B -R _6B are as defined above; X _A is selected from the group of Cl, NO ₂ , CN, CF ₃ or CH ₃ ; Y _A is part ego,
[442] _Wherein R _7B and R _8B are joined together as — (CH ₂ ) _t −, where t is an integer from 4 to 6 and is hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl , C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONH (C ₁ -C ₄ ) alkyl, -NH ₂ , C ₁ -C ₄ alkylamino, di (C ₁ -C ₄ ) alkylamino, -NHSO ₂ (C ₁ -C ₄ ) a compound which forms a ring optionally substituted with up to 3 substituents selected from the group of alkyl, -NHCO (C ₁ -C ₄ ) alkyl and -NO ₂ ; Its optical and geometric isomers; And pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts and precursors thereof.
[443] In a preferred embodiment, the compound is TSE-424, which is a compound represented by the formula represented by formula (5a):
[444] <Formula 5a>
[445]
[446] The synthesis of compounds of formulas (5), (5a) and (6) is described in US Pat. No. 5,998,402. Pharmaceutically acceptable salts of the estrogen agonist / antagonist of the present invention may be formed from the compound itself, or esters thereof, and include pharmaceutically acceptable salts often used in the pharmaceutical chemistry. For example, salts may be inorganic or organic acids, such as sulfonic acids including hydrochloric acid, hydrobromic acid, hydroiodic acid, naphthalenesulfone, methanesulfone and toluenesulfonic acid, sulfuric acid, nitric acid, phosphoric acid, tartaric acid, pyrosulfuric acid, metaphosphoric acid, succinic acid, formic acid, It may be formed with phthalic acid, lactic acid, and the like, most preferably with hydrochloric acid, citric acid, benzoic acid, maleic acid, acetic acid or propionic acid.
[447] Estrogen agonist / antagonist as described above of the present invention may be administered in the form of a pharmaceutically acceptable salt. Salts are formed by reacting a compound of the present invention with a suitable acid as described above, as is common in organic chemistry. Salts are rapidly formed in high yield at appropriate temperatures and are often prepared by only isolating the compound with appropriate acidic washing, which is often the final step in the synthesis. The salt forming acid is dissolved in a suitable organic solvent or an aqueous organic solvent such as alkanol, ketone or ester. On the other hand, if the present invention prefers that the compound is in free base form, it is separated into a final basic wash step according to conventional procedures. A preferred technique for preparing hydrochloride is to dissolve the free base in a suitable solvent, thereby drying the solution completely on the molecular sieve before bubbling hydrogen chloride gas. Of (-)-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalen-2-ol Preferred salts are the D-(-)-tartrate salts. It will also be appreciated that the amorphous form of estrogen agonist / antagonist can be administered.
[448] The term "pharmaceutically acceptable salts" includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts. The expression “pharmaceutically-acceptable cationic salts” includes, but is not limited to, alkali metal salts (eg sodium and potassium), and alkaline earth metal salts (eg calcium and magnesium), aluminum Salts, ammonium salts, and organic amines such as benzartine (N, N'-dibenzylethylenediamine), choline, diethanolamine, ethyleneamine, meglumine (N-methylglucamine), benetamine (N-benzyl Phenethylamine), diethylamine, piperazine, trometamine (2-amino-hydroxymethyl-1,3-propanediol) and salts with procaine. The term "pharmaceutically acceptable acid addition salt" includes, but is not limited to, hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, succinate, sheet Latex, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts.
[449] Those of ordinary skill in the art will appreciate that certain estrogen agonists / antagonists of the present invention contain one or more atoms that may be present in a particular stereochemistry, tautomer, or geometric arrangement, such as stereoisomers, tautomers and structures. It will be appreciated that isomers may be produced. All such tautomers and isomers and mixtures thereof are included in the present invention. Hydrates and solvates of the compounds of the invention are also included.
[450] The invention also encompasses isotopically labeled estrogen agonists / antagonists, which are structurally the same as above, but wherein one or more atoms are replaced by atoms having an atomic mass or mass number that is different from the atomic mass or mass number typically found in nature. will be. Examples of isotopes that may be incorporated into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. Compounds of the invention, precursors thereof, and pharmaceutically acceptable salts of the compounds and the precursors, including the isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the invention, such as those incorporating radioisotopes, such as ³ H and ¹⁴ C, are useful for analyzing compounds and / or substrate tissue distribution. Tritiated, ie ³ H and carbon-14, ie ¹⁴ C isotopes are particularly preferred because of their ease of preparation and detection. In addition, substitutions with heavier isotopes, such as deuterium, i.e. ² H, may increase metabolic stability, for example, to provide certain therapeutic advantages, such as increased in vivo half-life or lower dosage requirements, in certain situations. It may be desirable. The isotopically labeled compounds of the present invention and their precursors can be prepared by carrying out generally known or cited methods and by using readily available isotopically labeled reagents in place of non-isotopically labeled reagents.
[451] When the compound of this invention contains ester, a specific ester group is preferable. Estrogen agonists / antagonists comprising compounds of formula (1), (1a), (2), (3), (5), (5a), or (6) may contain ester groups at various positions as defined above. These groups may be selected from -COOR ⁹ (R ⁹ is C ₁ -C ₁₄ alkyl, C ₁ -C ₃ chloroalkyl, C ₁ -C ₃ fluoroalkyl, C ₅ -C ₇ cycloalkyl, phenyl, or C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, nitro, chloro, fluoro or phenyl substituted or 1 or 2 with tri (chloro or fluoro) methyl.
[452] As used herein, the term “effective amount” means the amount of a combination of estrogen agonist / antagonist or estrogen agonist / antagonist that can treat the pathological condition. The particular dosage of the compound or combination of compounds administered according to the invention will of course be determined by the particular situation, including, for example, the compound or combination administered, the route of administration, and the degree of pathological condition to be treated.
[453] The dosage of the compound of the invention administered to the patient will vary widely and will be at the discretion of the attending physician. It should be noted that when the compound is administered in salt form, such as laurate, where the salt forming moiety has a significant molecular weight, it is necessary to adjust the dosage of the compound.
[454] The following dosages and other dosages set forth herein and in the appended claims are for an average human patient having a body weight of about 65 kg to about 70 kg. The skilled person will readily be able to determine the dosage required when the patient's weight is outside the range of 65 kg to 70 kg. All doses described herein and in the appended claims are daily doses in the free base form of the estrogen agonist / antagonist. Dosages for other forms in the free base form, such as salts or hydrates, can be readily calculated by simply applying a simple ratio to the molecular weight of the elements involved.
[455] The general range of effective dose ratios of estrogen agonist / antagonist is from about 0.001 mg / day to about 200 mg / day. Preferred ratio ranges are from about 0.010 mg / day to 100 mg / day. Of course, it may often be practical to administer a daily dose of a compound in portions at various times of the day. In any case, however, the amount of the compound of the invention administered will depend on factors such as the potency of the particular estrogen agonist / antagonist, the solubility of the compound, the agent used and the route of administration. (-)-Cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol, L For tartrate salts, the preferred dosage range for humans is from about 0.025 mg to about 1 mg per day. A more preferred dosage range is about 0.25 to about 0.5 mg per day.
[456] Formulation methods are known in the art and are taught, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19th Edition (1995). Pharmaceutical compositions that can be used within the scope of the present invention may be sterile, non-pyrogenic liquid solutions or suspensions, coated capsules, suppositories, lyophilized powders, transdermal patches or other forms known in the art.
[457] Capsules can be made by mixing the compound with an appropriate diluent and filling the capsule with the appropriate amount of the mixture. Conventional diluents include inert powder materials such as various types of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain powder and similar edible powders.
[458] Tablets are prepared by direct compression, wet granulation, or dry granulation. Its formulations typically include the compound and diluents, binders, lubricants and disintegrants. Typical diluents include, for example, various forms of starch, lactose, mannitol, kaolin, calcium phosphate or sulfates, inorganic salts such as sodium chloride and powdered sugars. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic rubbers are also convenient, including acacia, alginate, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
[459] Lubricants may be necessary in the tablet formulation to prevent tablets and punches from sticking to the template. Lubricants are selected from slippery solids such as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
[460] Tablet disintegrants are substances that, when the tablet is wet, disintegrate the tablet to facilitate release of the compound. These include starch, clay, cellulose, algin and rubber, more particularly corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponges, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose. And, for example, sodium lauryl sulfate can also be used together.
[461] Tablets are often coated with sugars as flavors and sealants, or film forming protective agents that modify the solubility of the tablets. The compounds may also be formulated as chewable tablets, as known in the art, by using a large amount of taste-flavoring material such as mannitol in the formulation.
[462] When it is desired to administer the compound as a suppository, a typical base may be used. Cocoa butter is a traditional suppository base, and wax can be added to slightly increase its melting point. In particular, water-miscible suppository bases comprising polyethylene glycols of various molecular weights are widely used.
[463] The effect of the compound may be delayed or prolonged by appropriate formulation. For example, small pills of slowly soluble compounds can be prepared and incorporated into tablets or capsules. This technique can be improved by making several small tablets of different dissolution rates and filling the capsules with a mixture of small pills. Tablets or capsules may be coated with a film that prevents dissolution for a predetermined time. Topical formulations may also be designed to delay and / or prolong the compound for transdermal absorption. Even parenteral preparations can be prepared to maintain long-term activity by dissolving or suspending the compound in an oily or emulsifying excipient that allows the compound to be dispersed only in serum.
[464] The term "precursor" means a compound that is converted in vivo to produce the compound of the present invention. Transformation can occur by a variety of mechanisms, such as by hydrolysis in blood. A description of the use of precursors is available. T. Higuchi and W. W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
[465] For example, if the compound of the present invention contains a carboxylic acid functional group, the precursor may contain a hydrogen atom of the acid group (C ₁ -C ₈ ) alkyl, (C ₂ -C ₁₂ ) alkanoyloxymethyl, 4 carbon atoms 1- (alkanoyloxy) ethyl of 9 to 9, 1-methyl-1- (alkanoyloxy) -ethyl of 5 to 10 carbon atoms, alkoxycarbonyloxymethyl of 3 to 6 carbon atoms, 4 carbon atoms 1- (alkoxycarbonyloxy) ethyl of 7 to 7, 1-methyl-1- (alkoxycarbonyloxy) ethyl of 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl of 3 to 9 carbon atoms , 1- (N- (alkoxycarbonyl) amino) ethyl, having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactone-4-yl, di-N, N -(C ₁ -C ₂ ) alkylamino (C ₂ -C ₃ ) alkyl (eg β-dimethylaminoethyl), carbamoyl- (C ₁ -C ₂ ) alkyl, N, N-di (C ₁ -C ₂₎ alkyl, carbamoyl - (C ₁ -C ₂₎ alkyl and piperidino-, pyrrolidino-or know Paul No (C ₂ -C ₃₎ may comprise an ester formed by a substituted group such as alkyl.
[466] Similarly, if a compound of the present invention comprises an alcoholic functional group, the precursor is selected from the hydrogen atoms of the alcohol group (C ₁ -C ₆ ) alkanoyloxymethyl, 1-((C ₁ -C ₆ ) alkanoyloxy) ethyl , 1-methyl-1-((C ₁ -C ₆ ) alkanoyloxy) ethyl, (C ₁ -C ₆ ) alkoxycarbonyloxymethyl, N- (C ₁ -C ₆ ) alkoxycarbonylaminomethyl, succinct Noyl, (C ₁ -C ₆ ) alkanoyl, α-amino (C ₁ -C ₄ ) alkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl Wherein each α-aminoacyl group is a natural L-amino acid, P (O) (OH ₂ ), -P (O) (O (C ₁ -C ₆ ) alkyl) ₂ or glycosyl (hemi of carbohydrates). Radicals formed by removing the hydroxyl group of the acetal type).
[467] If the compound of the present invention comprises an amine functional group, the precursor is selected from the group consisting of R ^x -carbonyl, R ^X O-carbonyl, NR ^X R ^{X '} -carbonyl, wherein R ^X and R ^{X Are} each independently (C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, benzyl or R ^X -carbonyl is a natural α-aminoacyl or a natural α-aminoacyl-natural α-aminoacyl , -C (OH) C (O) OY ^X (wherein Y ^X is H, (C ₁ -C ₆ ) alkyl or benzyl), -C (OY ^X0 ) Y ^X1 (wherein Y ^X0 is ( C ₁ -C ₄ ) alkyl, Y ^X1 is (C ₁ -C ₆ ) alkyl, carboxy (C ₁ -C ₆ ) alkyl, amino (C ₁ -C ₄ ) alkyl or mono-N- or di-N, N- (C ₁ -C ₆ ) alkylaminoalkyl), -C (Y ^X2 ) Y ^X3 , wherein Y ^X2 is H or methyl and Y ^X3 is mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl)).
[468] The invention also advantageously provides a kit for promoting or maintaining urogenital health for use by a consumer. The kit comprises a) a pharmaceutical composition comprising an estrogen agonist / antagonist and a pharmaceutically acceptable carrier, excipient or diluent; And b) instructions describing the use of the pharmaceutical composition for the promotion or maintenance of urogenital health. The instructions may also explain that the kit enhances or maintains the health of the genitourinary tract while significantly reducing the accompanying incidence of side effects associated with estrogen administration.
[469] Kits for use in the present invention include a container for containing the pharmaceutical composition, and may also include a divided container, such as a divided bottle or a divided foil bag. This container may be in any conventional form or type as known in the art made of pharmaceutically acceptable materials, such as paper or cardboard boxes, glass or plastic bottles or jars, resealable bags (e.g. For example, a "refill" of tablets for transfer into another container), or a blister pack that can squeeze the pack out of the individual dosages according to the treatment schedule. The container used depends on the exact dosage form to be preserved, for example a conventional cardboard box cannot generally be used to preserve a liquid suspension. It is also possible to sell a single dosage form using more than one container together in a single package. For example, you can include tablets in a bottle and put them back in a box.
[470] One example of such a kit is a so-called blister pack. Blister packs are known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). The blister pack generally consists of a sheet of relatively hard material, preferably covered with a transparent plastic material. During the packaging process, recesses are formed in the plastic foil. Such recesses will have the size and shape of individual tablets or capsules to be packaged or will have a size and shape that can accommodate a plurality of tablets and / or capsules to be packaged. The tablets or capsules are then placed in the recesses and the plastic sheet is sealed on the side of the foil opposite to the direction in which the recesses are formed with sheets of relatively hard material. As a result, the tablets or capsules are sealed individually or collectively in the recesses between the plastic foil and the sheet as necessary. The strength of the sheet is preferably such that, by hand pressing the recessed portion, a hole is formed in the sheet at the position of the recessed portion so that the tablet or capsule can be removed. Tablets or capsules may be removed through the holes.
[471] It may be desirable to provide memory aids, wherein the memory aids described may be in the form of information and / or instructions for the physician, pharmacist or patient, for example the date on which the specified tablet or capsule should be taken. And a number corresponding to the capsule or tablet in the form of a number or in the form of a card containing the same type of information. Another example of the memory assisting means is a calendar printed on a card such as "first week, monday, tuesday", ..., etc., "second week, monday, tuesday, ..." . Other variations of the memory assistance means will be readily appreciated. A "daily dose" can be a single tablet or capsule or several tablets or capsules that must be taken on a given day.
[472] Another preferred embodiment of the kit is a dispenser designed to dispense the daily dose at one time. Preferably, this dispenser is equipped with memory-assisting means so that it can be more easily adapted to the prescription. One example of such memory-assisting means is a mechanical counter indicating the number of daily doses dispensed. Another example of said memory-assisting means is a liquid crystal indicator, or a battery equipped with an audible reminder signal, for example reading the date when the last daily dose was taken and / or reminding the date when the next dose should be taken. Power micro-chip memory.
[473] It should be noted that the estrogen agonist / antagonist may be used in combination with other estrogen agonist / antagonist to maintain or promote urogenital health. In addition, estrogen agonists / antagonists can be used in combination with estrogens. Estrogen agonists / antagonists can also be used in combination with one or more additional compounds that are therapeutically effective for promoting or maintaining the health of the genitourinary system. For example, estrogen agonists / antagonists can be used in combination with compounds used to treat pelvic floor integrity, including urinary incontinence, stool incontinence, vaginal infections, urinary infections, vaginal dryness, vaginal itching, or vaginal prolapse. . Examples of additional compounds that can be used in combination with estrogen agonists / antagonists include Detrol® and anti-fungal and anti-fungal products.
[474] In addition, estrogen agonists / antagonists can be used in combination with drugs that can be used to acidify the urinary tract and / or vagina (ie, lower the pH). Examples of such drugs include potassium acid phosphate and sodium acid phosphate.
[475] Estrogen agonists / antagonists can be used in combination with cGMP synergists to treat the symptoms taught herein.
[476] cGMP synergists are preferably cGMP phosphodiesterase (PDE) inhibitors. Particular preference is given to cGMP PDE inhibitors which are selective for cGMP PDE and selective inhibitors of cGMP PDE _v isoenzyme than cyclic adenosine 3 ', 5'-monophosphate phosphodiesterase (cAMP PDE). Such particularly preferred cGMP PDE inhibitors are disclosed in U.S. Patent Nos. 5,250,534; 5,346,901; 5,346,901; 5,272,147; 5,272,147; And International Patent Application WO 94/28902.
[477] Preferred cGMP PDE _v inhibitors are compounds of the formula (7); And pharmaceutically acceptable salts thereof:
[478]
[479] In the above formula:
[480] R ^1C is H; C ₁ -C ₃ alkyl; C ₁ -C ₃ perfluoroalkyl; Or C ₃ -C ₅ cycloalkyl;
[481] R ^2C is H; C ₃ -C ₆ cycloalkyl optionally substituted C ₁ -C ₆ alkyl with alkyl; C ₁ -C ₃ perfluoroalkyl; Or C ₃ -C ₆ cycloalkyl;
[482] R ^3C is C ₃ -C ₆ cycloalkyl optionally substituted C ₁ -C ₆ alkyl with alkyl; C ₁ -C ₆ perfluoroalkyl; C ₃ -C ₅ cycloalkyl; C ₃ -C ₆ alkenyl; Or C ₃ -C ₆ alkynyl;
[483] R ^4C is C ₁ -C ₄ alkyl optionally substituted with OH, NR ^5C R ^6C , CN, CONR ^5C R ^6C or CO ₂ R ^7C ; C ₂ -C ₄ alkenyl optionally substituted with CN, CONR ^5C R ^6C or CO ₂ R ^7C ; C ₂ -C ₄ alkanoyl optionally substituted with NR ^5C R ^6C ; (Hydroxy) C ₂ -C ₄ alkyl optionally substituted with NR ^5C R ^6C ; (C ₂ -C ₃ alkoxy) C ₁ -C ₂ alkyl optionally substituted with OH or NR ^5C R ^6C ; CONR ^5C R ^6C ; CO ₂ R ^7C ; Halo; NR ^5C R ^6C ; NHSO ₂ NR ^5C R ^6C; NHSO ₂ R ^8C ; Phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl optionally substituted with SO ₂ NR ^9C R ^10C or methyl;
[484] R ^5C and R ^6C are each independently H or C ₁ -C ₄ alkyl or pyrrolidinyl, piperidino, morpholino, 4-N (R ^11C ) -piperazinyl or together with the nitrogen atom to which they are attached; An imidazolyl group, wherein the group is optionally substituted with methyl or OH;
[485] R ^7C is H or C ₁ -C ₄ alkyl;
[486] R ^8C is C ₁ -C ₃ alkyl optionally substituted with NR ^5C R ^6C ;
[487] R ^9C and R ^10C together with the nitrogen atom to which they are attached are pyrrolidinyl, piperidino, morpholy optionally substituted by C ₁ -C ₄ alkyl, C ₁ -C ₃ alkoxy, NR ^13C R ^14C or CONR ^13C R ^14C Forming a furnace or 4-N (R ^12C ) -piperazinyl group;
[488] R ^11C is H; C ₁ -C ₃ alkyl optionally substituted with phenyl; (Hydroxy) C ₂ -C ₃ alkyl; Or C ₁ -C ₄ alkanoyl;
[489] R ^12C is H; C ₁ -C ₆ alkyl; (C ₁ -C ₃ alkoxy) C ₂ -C ₆ alkyl; (Hydroxy) C ₂ -C ₆ alkyl; (R ^{13 C} R ^{14 C} N) C ₂ -C ₆ alkyl; (R ^{13 C} R ^{14 C} NOC) C ₁ -C ₆ alkyl; CONR ^13C R ^14C ; CSNR ^13C R ^14C ; Or C (NH) NR ^{13 C} R ^{14 C} ;
[490] R ^13C and R ^14C are each independently H; C ₁ -C ₄ alkyl; (C ₁ -C ₃ alkoxy) C ₂ -C ₄ alkyl; Or (hydroxy) C ₂ -C ₄ alkyl.
[491] Preferred cGMP PDE _v inhibitors are 1-[[3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo [4,3-] having the structure of formula (8) d] -pyrimidin-5-yl) -4-ethoxy-phenyl] sulfonyl] -4-methylpiperazin (sildenafil) and pharmaceutically acceptable salts thereof; And a compound of formula (9) and a pharmaceutically acceptable salt thereof; And 3-ethyl-5- {5-[(4-ethylpiperazino) sulfonyl] -2- (2-methoxyethoxy) pyrid-3-yl} -2- (2-pyridylmethyl) -6,7-dihydro-2H-pyrazolo [4,3-d] pyrimidin-7-one:
[492]
[493]
[494]
[495] Compounds of formula (9) are taught, for example, in US Pat. Nos. 5,272,147 and 5,426,107.
[496] Preferred pharmaceutically acceptable salts for sildenafil for use in the present invention are citrate salts, with a preferred dosage range of about 1 mg to about 100 mg.
[497] As cGMP PDE _v inhibitors are also preferably compounds of the formula (11) and salts and solvates thereof as taught in WO 95/19978:
[498]
[499] In the above formula:
[500] R ^0D represents hydrogen, halogen or C ₁ -C ₆ alkyl;
[501] R ^1D is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, haloC ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cyclo Alkyl C ₁ -C ₃ alkyl, arylC ₁ -C ₃ alkyl or heteroarylC ₁ -C ₃ alkyl;
[502] R ^2D is an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyrimidine, or ring A bonded and fused to the remaining molecule via one of the benzene ring carbon atoms is saturated or partially or completely unsaturated An optionally substituted bicyclic ring which may be a 5- or 6-membered ring containing one or two heteroatoms selected from carbon atoms and oxygen, sulfur and nitrogen ego;
[503] R ^3D represents hydrogen or C ₁ -C ₃ alkyl, or R ^1D and R ^3D together represent a 3- or 4-membered alkyl or alkenyl ring.
[504] Preferred groups of this compound having formula 11a include compounds of formula 11a and salts and solvates thereof:
[505]
[506] In the above formula:
[507] R ^0D represents hydrogen, halogen or C ₁ -C ₆ alkyl;
[508] R ^1D is hydrogen, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkyl-C ₁ -C ₃ alkyl, arylC ₁ -C ₃ alkyl Or heteroarylC ₁ -C ₃ alkyl;
[509] R ^2D is an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyrimidine, or ring A bonded and fused to the remaining molecule via one of the benzene ring carbon atoms is saturated or partially or completely unsaturated An optionally substituted bicyclic ring which may be a 5- or 6-membered ring containing one or two heteroatoms selected from carbon atoms and oxygen, sulfur and nitrogen to be.
[510] CGMP synergists of the present invention include precursors, geometric isomers, stereoisomers, hydrates, tautomers and salts of the compounds.
[511] Suitable cGMP PDE inhibitors also include those taught in the following US patents:
[512] 5-substituted pyrazolo [4,3-d] pyrimidin-7-ones taught in US Pat. No. 4,666,908;
[513] Griceol acid derivatives taught in US Pat. Nos. 4,634,706, 4,783,532, 5,498,819, 5,532,369, 5,556,975, and 5,516,600;
[514] 2-phenylpurinone derivatives taught in US Pat. No. 4,885,301;
[515] Phenylpyridone derivatives taught in US Pat. No. 5,254,571;
[516] Fused pyrimidine derivatives taught in US Pat. No. 5,047,404;
[517] Condensed pyrimidine derivatives taught in US Pat. No. 5,075,310;
[518] Pyrimidopyrimidine derivatives taught in US Pat. No. 5,162,316;
[519] Purine compounds taught in US Pat. No. 5,073,559;
[520] Quinazoline derivatives taught in US Pat. No. 5,147,875;
[521] Phenylpyrimidone derivatives taught in US Pat. No. 5,118,686;
[522] Imidazoquinoxylinone derivatives or aza analogs thereof taught in US Pat. Nos. 5,055,465 and 5,166,344;
[523] Phenylpyrimidone derivatives taught in US Pat. No. 5,290,933;
[524] 4-aminoquinazoline derivatives taught in US Pat. No. 5,436,233 or 5,439,895;
[525] 4,5-dihydro-4-oxo-pyrrolo [1,2-a] quinoxanoline derivatives taught in US Pat. No. 5,405,847;
[526] Polycyclic guanine derivatives taught in US Pat. No. 5,393,755;
[527] Nitrogen heterocycle compounds taught in US Pat. No. 5,576,322;
[528] Quinazoline derivatives taught in US Pat. No. 4,060,615;
[529] 6-heterocyclyl pyrazolo [3,4-d] pyrimidin-4-one taught in US Pat. No. 5,294,612; And
[530] 4-aminoquinazoline derivatives taught in US Pat. No. 5,436,233;
[531] Other cGMP PDE inhibitors include:
[532] European Patent Application (EPA) Publication No. 0428268;
[533] European Patent No. 0442204;
[534] International Patent Application Publication No. WO 94/19351;
[535] Japanese Patent Application No. 5-222000;
[536] European Journal of Pharmacology, 251 , (1994), 1;
[537] International Patent Application Publication No. WO 94/22855;
[538] Pyrazolopyrimidine derivatives taught in European Patent Application No. 0636626;
[539] 4-aminopyrimidine derivatives taught in European Patent Application No. 0640599;
[540] Imidazolquinazoline derivatives taught in International Patent Application WO95 / 06648;
[541] Anthranilic acid derivatives taught in International Patent Application WO95 / 18097;
[542] Tetracycle derivatives taught in International Patent Application WO95 / 19978;
[543] Amidazoquinazoline derivatives taught in European Patent Application No. 0668280;
[544] Quinazolin compounds taught in European Patent Application No. 0669324.
[545] CGMP PDE inhibition of a compound can be measured using standard assays known in the art, for example taught in US Pat. No. 5,250,534. Compounds that are selective inhibitors of cGMP PDEs over cAMP PDEs are preferred and the determination of such compounds is also taught in US Pat. No. 5,250,534. Particularly preferably the compounds taught in WO 94/28902, which selectively inhibit PDE _v isoenzyme.
[546] In addition, estrogen agonists / antagonists can be used in combination with antibiotics such as azithromycin and / or antifungal agents such as fluconazole and borconazole. The combination is particularly useful for treating bacterial or yeast infections of the vagina or urine.
[547] Additional compounds that may be administered with the estrogen agonist / antagonist may be administered in the same dosage form or in different dosage forms. Similarly, additional compounds may be administered concurrently or at different times with the estrogen agonist / antagonist. All combinations of dosage forms and times are contemplated.
[548] It should also be noted that the estrogen agonist / antagonist may be administered in a topical dosage form such as a patch placed on the skin or an ointment applied to the skin. The dosage form can also be used to administer other compounds that can be used in combination with estrogen agonists / antagonists. In one embodiment, the estrogen agonist / antagonist is administered in combination with one or more additional compounds. In another embodiment, the additional compound is administered using a topical dosage form and the estrogen agonist / antagonist is administered using a different dosage form such as a tablet.
[549] Methods of measuring vaginal health include assessment of vaginal health symptoms and physical examinations that measure physiological indicators of vaginal health. The method will also include measuring the frequency of vaginal and / or urinary tract infections and / or the frequency of urinary incontinence. Assessment of pathological vaginal symptoms and subjective vaginal health status is self-assessed by the subject.
[550] Measurements made during gynecological examination include vaginal pH measurements and vaginal maturation indicators. Vaginal pH measurements are performed first, always before vaginal maturity index or PAP smear specimens at the time of testing. If at the beginning of the test a significant amount of lubricant is needed to insert the mirror, the pH will be measured before the insertion of the mirror.
[551] Vaginal pH measurements can be performed using a single-use pH probe, such as a pHem-Alert ™ pH probe (Imagyn Media Technologies, Inc., Costa Mesa, CA.) Remove the package, insert it into the outer 1/3 of the vagina, and fix it to the posterior wall for about 2 seconds to wet the paper Contact of the pH probe with blood or the cervical mucosa should be avoided, since the pH of these materials is generally neutral The pH is determined by removing the probe and immediately comparing it to the pH color chart enclosed with the pH probe.
[552] Vaginal maturation indicators indicate the extent of proliferation and maturation of vaginal cells. Results are reported as percentage of swelling, intermediate and epithelial cells as measured by techniques known in the art. A quality maturity index smear should be taken before the PAP smear sample. Commercially available kits for cell sample collection (PAP Pak ™, Medical Packaging Corp. (Camarillo, CA)) can be used to obtain maturity index samples. Generally, using the ends of a round thin spatula, the middle lateral area of the third quarter of the vagina is gently scraped off and applied to the microscope slide. Samples should not be taken from the cervix or any other area of the vagina. Samples should also be collected from healthy areas free of inflammation, infections, ulcers, debris or other contaminants. These formulations are immediately fixed by dripping standard cell fixative onto the entire slide. This fixative may be a standard fixative for cell specimens such as that included in the PAP Pak ™ Specimen Collection Kit. Once the fixative is dried, the specimen is evaluated under a microscope and the maturity index is measured.
[553] Subject self-assessment of quality health is performed by a subjective quality health questionnaire. Typically, questionnaires are written personally and the results are kept confidential. The questionnaire may include a specially-encrypted envelope for later confirmation of the treatment received by the subject. Examples of questions and grades for the questions are shown in Table 1. Additional questions may be added to future questionnaires after assignment of the base question, which will ask: "What positive or negative changes have you made after taking the study drug " This question ranges from "very positive change" to "moderately positive change" to "slightly positive change" to "no change" to "slightly negative change" to "moderately negative change" to "very negative change". It can be linked to the multi-point grading scale of.
[554] Subjective Quality Health Questionnaire QuestionsQuestionChoose a response or record a number OneHow many children do you have By natural delivery By caesarean section 2How many vaginal infections have you had in the last six months 3How many urinary tract infections have you had in the last 6 months 4How severe was any urinary incontinence experienced a) Was there a leak (does not use a protector) b) Was there a weak leak (doesn't need to use the protector) c) Was there a normal leak (has the guard intermittently worn) d ) How severe were the leaks (always put on guards) E) Was there a heavy leak (should you change the guards more than once a day) 5When have you experienced any amount of incontinence a) Was it when you laughed, coughed, strained or exercised b) Was it impossible to control the leak and was urinating or urinating the next time c) Was it leaking for no particular reason 6What is the best indicator of your vaginal dryness Scales 1 to 7 indicating no vaginal dryness and 7 indicating extreme vaginal dryness. 7What number best represents your vaginal itching or irritation Scales 1 to 1 indicating no vaginal itching or irritation and 7 indicating extreme vaginal itching or irritation 8Are you using any product to help with vaginal dryness, irritation or itching
[555] Subjective Quality Health Questionnaire QuestionsQuestionChoose response 9What about your overall quality health No problem.Some problems.Moderate problems.Severe problems.Severe problems. 10What is the frequency and frequency of any form of sex a) none b) rare (less than once a month) c) occasionally (1-3 times a month) d) moderate (1-3 times a week) e) frequent (more than 3 times a week) 11Is there orgasm (by any means) during sex a) none b) rare (less than once a month) c) occasionally (1-3 times a month) d) moderate (1-3 times a week) e) frequent (more than 3 times a week) 12What has happened in your privacy that reduces your interest in sex (For example, changes in health status or relationships)
[556] When this assessment method of vaginal health is used to evaluate the efficacy of a drug or other treatment, a vaginal health assessment is performed at the beginning of treatment. Further assessments are performed at least once during or at the end of treatment, such as every six months during the study.
[557] An important aspect of the present invention is the standardized analysis of pelvic organ prolapse and pelvic floor dysfunction. The method is described in Baden, W. and Walter, T. Surgical Repair of Vaginal Defects, Philadelphia, JB Linnincott, 1992 and Bump, RC. The standardization of terminology of female pelvic organ prolapse and pelvic floor dysfuntion, Am. J. Obstet. Gynecol. 175: 10-17, 1996, a standardization system of terms and grades can be used.
[558] Test parameters are adjusted to allow accurate testing to be performed during the period of observation, which may range from six months to two years or more. Therefore, certain test variables, such as: (i) the location of the subject during the test; (ii) the form of an examination table or chair; (iii) the form of warp or retractor; (iv) the type of tension (balsalva handwriting or coughing); (v) the degree of filling of the bladder (urination before testing); And (vi) it is important that the rectal dose (if there is a bowel movement at the time of rectal examination) is fixed constantly.
[559] Vaginal escape is graded on a scale of 0 to 4 for the following types of escape: anterior wall urethral; Anterior wall rectum; Upper wall uterine prolapse, posterior wall hernia; And rear wall rectal. All escapes are rated as determined in Table 2.
[560] Symptoms that correspond to an escape rating RatingCriteria for rating Grade 0Normal position inside the vaginal central axis for anterior posterior wall prolapse and above the sciatic pole for cervical or vaginal cuffs. By definition, the peak is -3 cm above the hymen. Grade 1The escape goes past each starting point and down to the mid-point to the hymen. Grade 2Down to the hymen. Grade 32 cm down past the hymen. Grade 4Down as much as possible for each part. Complete valgus about 5 cm past hymen.
[561] The following conditions apply for the quantification of pelvic organ location and prolapse: (i) Prolapse should be assessed for a fixed location for control; (ii) the sciatic pole is a control for neck or vaginal cuff prolapse; (iii) the central axis of the vagina is the criterion for anterior and posterior wall escape; (iv) The hymen is the criterion for any escape that extends beyond the sciatic pole or vaginal centerline axis. Here's how to visualize the escape:
[562] (1) If a hernia is foreseen but the grade is uncertain, the examination is performed with the subject standing.
[563] (2) Insert the posterior lumbar blade or finger to the vaginal apex, compress the perineum, induce tension, and slowly pull out to observe hernia and grading.
[564] (3) If hernias and rectums are not visible in (2) above, move the neck forward to repeat the method to grade hernias and rectums.
[565] Finally, external urogenital measurements are in cm. The propensity of pelvic escape increases as the ratio of genital tears to perineal body increases, and genital tears and perineal body are measured as follows:
[566] Genital tear: The distance from the center of the outer tube to the posterior centerline hymen.
[567] Perineal Body: The distance from the posterior edge of the genital tear to the central opening.
[568] During the examination of pelvic organ prolapse and pelvic floor dysfunction, objective measurements may also be performed to assess the subject's quality health. These measurements may include measuring blood estrogen and testosterone levels, measuring vaginal pH and measuring vaginal maturity index.
[569] Internal vaginal health assessments can be performed on a continuously varying scale used under the following criteria: providing the examiner with printed lines of 3-20 cm long, preferably 6-15 cm long, and most preferably 10 cm long. . This line is marked with an axis mark corresponding to the degree of internal quality health. For example, on a 10 cm long horizontal line, one end of the line is represented by the number I, the center of the line is represented by the number II, and the other end of the line is represented by the number III. Numbers I-III correspond to the following symptoms:
[570] I. No wrinkles, no elasticity, soft and bleeding to the touch, very pale mucosa, very dry, narrowed, narrow in quality;
[571] II. Less wrinkles, less elasticity, pale mucosa (pink), some loss of moisture, slightly constricted, slightly narrow vaginal; or
[572] III. Wrinkles are present, normal elasticity of good elasticity, strong pink mucous membranes, good vaginal moisture and good depth.
[573] The inspector is instructed to give an indication that best describes the internal assessment on the line representing the continuous quality status of figures I-III.
[574] In addition to internal evaluation, for example, the appearance of the pubic hair (ie very poor, lacking, moderate, normal, excessive) and the state of the vulva (ie full thickness, slight vulva degeneration, normal vulva degeneration (atrophic labia) External evaluations explaining labial fusion can also be obtained.
[575] The vaginal examination and the data obtained from the test are used as a whole to analyze the patient's vaginal health. This method can be used to determine whether a compound administered to a patient affects vaginal health, or this method can be used to help clinicians analyze vaginal health for the purpose of making a diagnosis. The method can also be used to analyze changes over time in quality health.
[576] Interestingly, using the self-assessment questionnaire, estrogen agonist / antagonist (-)-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5, Postmenopausal women who ingest 6,7,8-tetrahydro-naphthalene-2-ol, D-tartrate salt have increased frequency and / or increased number of orgasms and / or increased intensity orgasms Was reported.
[577] All references, and patents, cited herein are incorporated by reference.
[578] The following examples are intended to describe certain embodiments of the invention, and do not in any way limit the scope of the specification, including the claims.
[579] Example
[580] Example 1: Enhancement or Maintenance of Urogenital Health.
[581] The effect of estrogen agonists / antagonists on promoting or maintaining urogenital health was analyzed in a group of patients of postmenopausal women who did not receive hormone replacement therapy. The effect of estrogen agonists / antagonists on promoting or maintaining urogenital health was measured randomly in a double-blind, placebo controlled clinical trial.
[582] Patients were randomly divided into treatment or placebo groups. Subjects were first given a subjective vaginal health questionnaire prior to administering placebo or estrogen agonist / antagonist. Placebo administration or treatment was started and continued for 6 months. The questionnaire was given to all patients at 3 and 6 months.
[583] Patient self-analysis of vaginal health was performed as a subjective vaginal health questionnaire. The questionnaire was written and kept private. The questionnaire was specifically encoded to later confirm the treatment the patient received. Examples of questions are shown in Table 1 below. Add additional questions to the continuation questionnaire following the baseline questionnaire and ask: "What positive or negative changes have you made after taking the study drug ". This question ranges from "very positive change" to "moderately positive change" to "slightly positive change" to "no change" to "slightly negative change" to "moderately negative change" to "very negative change". Is linked to the multipoint rating scale of.
[584] TABLE 1
[585] Subjective Quality Health Questionnaire QuestionsQuestionChoose a response or record a number OneHow many children do you have By natural childbirth By Caesarean section 2How many vaginal infections have you had in the last six months 3How many urinary tract infections have you had in the last 6 months 4How severe was the random incontinence experienced a) Was there a leak (does not use a protector) b) Was there a weak leak (doesn't need to use the protector) c) Was there a normal leak (has the guard intermittently worn) d ) How severe were the leaks (always put on guards) E) Was there a heavy leak (should you change the guards more than once a day) 5When have you experienced any amount of incontinence a) Did you laugh, cough, tense, or exercise b) Was it impossible to control the leak and you needed to urinate or urinate the next time c) Was it leaked for no particular reason 6What is the best indicator of your vaginal dryness Scales 1 to 7 indicating no vaginal dryness and 7 representing extreme vaginal dryness 7What number best represents your vaginal itching or irritation Scales 1 to 1 indicating no vaginal itching or irritation and 7 indicating extreme vaginal itching or irritation 8Are you using any product to help with vaginal dryness, irritation or itching
[586] TABLE 1a
[587] Subjective Quality Health Questionnaire QuestionsQuestionChoose response 9What about your overall quality health No problem.Slightly problematic.Normal problem.Severe problem.Severe problem. 10What is the frequency and frequency of any form of sex a) none b) rare (less than once a month) c) occasionally (1-3 times a month) d) moderate (1-3 times a week) e) frequent (more than 3 times a week) 11Is there orgasm (by any means) during sex a) none b) rare (less than once a month) c) occasionally (1-3 times a month) d) moderate (1-3 times a week) e) frequent (more than 3 times a week) 12What has happened in your privacy that reduces your interest in sex (For example, changes in health status or relationships)
[588] According to the method described above, the patient received 0.25-0.5 mg / kg of placebo or lasofoxifene. After starting placebo administration or treatment and continuing for 12 months, the effect on vaginal pH was confirmed. Patients in the treatment group with lasopoxifen (N = 98) reported improved vaginal health by 57.1 ^* % and patients in the placebo group (N = 46) with placebo reported 34.8 ^* % improvement ( ^* p <0.0001 vs. Placebo).
[589] In addition, after the placebo administration or treatment was started and lasted for 6 months and 12 months, the effect on the number of orgasms was confirmed. Patients in the treatment group with lasopoxifen (N = 74) increased 29.7 ^** % for 6 months or 31.9 ^** % for 12 months, and 6 in the placebo group (N = 46) with placebo. Months were reported to increase by 12.2 ^** % and 12 months by 12.8 ^** % ( ^** p <0.05 vs placebo).
[590] The method of the present invention uses estrogen agonists / antagonists to promote or maintain the health of the genitourinary system. Urinary and vaginal infections in postmenopausal women; incontinence; And symptoms such as vaginal dryness can be treated using the methods of the invention.

权利要求:
Claims (14)
[1" claim-type="Currently amended] Enhancing or maintaining urogenital health, comprising administering to a patient in need thereof a therapeutically effective amount of estrogen agonist / antagonist; Lowering of vaginal pH; Treatment of urinary tract infections; Treatment of vaginal dryness; Treatment of vaginal itching; Treatment of undesirable vaginal spasms; Treatment of vaginitis; Treatment of yeast or bacterial infections of the vagina; Treatment of vulvar atrophy; Treatment of urethral, bladder, rectal, hernia prolapse; Treatment of urine or stool incontinence; Treatment of undesired uremia or urinary insufficiency; Or a method for increasing the frequency or intensity of orgasm in a female patient.
[2" claim-type="Currently amended] The method of claim 1, wherein the patient is a postmenopausal woman.
[3" claim-type="Currently amended] According to claim 1, wherein the estrogen agonist / antagonist is a compound of formula (1) or an optical or geometric isomer thereof; Or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or precursor thereof.
<Formula 1>

In the above formula:
A is selected from CH ₂ and NR;
B, D and E are independently selected from CH and N;
Y is
(a) phenyl optionally substituted with 1-3 substituents independently selected from R ⁴ ;
(b) naphthyl optionally substituted with 1-3 substituents independently selected from R ⁴ ;
(c) C ₃ -C ₈ cycloalkyl optionally substituted with 1-2 substituents independently selected from R ⁴ ;
(d) C ₃ -C ₈ cycloalkenyl optionally substituted with 1-2 substituents independently selected from R ⁴ ;
(e) ⁵ , optionally substituted with 1-3 substituents independently selected from R ⁴ , containing up to 2 heteroatoms selected from the group consisting of -O-, -NR ^2- , and -S (O) _n- Circle heterocycle;
(f) ⁶ , optionally substituted with 1-3 substituents independently selected from R ⁴ , containing up to 2 heteroatoms selected from the group consisting of -O-, -NR ² -and -S (O) _n- Circle heterocycle; or
(g) ⁵ , optionally substituted with 1-3 substituents independently selected from R ⁴ , containing up to 2 heteroatoms selected from the group consisting of -O-, -NR ² -and -S (O) _n- A membered or 6 membered heterocycle ring is a bicyclic structure fused to a phenyl ring;
Z ¹ is
(a)-(CH ₂ ) _p W (CH ₂ ) _q- ;
(b) -O (CH ₂ ) _p CR ⁵ R ^6- ;
(c) -O (CH ₂ ) _p W (CH ₂ ) _q- ;
(d) -OCHR ² CHR ^3- ; or
(e) -SCHR ² CHR ^3- ;
G is
(a) -NR ⁷ R ⁸ ;
(b)
(Wherein n is 0, 1 or 2; m is 1, 2 or 3; Z ² is —NH—, —O—, —S— or —CH ₂ —; on optionally adjacent carbon atoms) Fused with one or two phenyl rings, optionally substituted independently with one to three substituents on carbon, and optionally independently with a chemically appropriate substituent selected from R ⁴ on nitrogen); or
(c) a bicyclic amine having 5 to 12 carbon atoms optionally substituted and linked or fused with 1-3 substituents independently selected from R ⁴ ;
Z ¹ and G are combined Can be;
W is
(a) -CH _2- ;
(b) -CH = CH-;
(c) -O-;
(d) -NR ^2- ;
(e) -S (O) _n- ;
(f) ;
(g) -CR ² (OH)-;
(h) -CONR ^2- ;
(i) -NR ² CO-;
(j) ;or
(k) -C≡C-;
R is hydrogen or C ₁ -C ₆ alkyl;
R ² and R ³ are independently
(a) hydrogen; or
(b) C ₁ -C ₄ alkyl;
R ⁴ is
(a) hydrogen;
(b) halogen;
(c) C ₁ -C ₆ alkyl;
(d) C ₁ -C ₄ alkoxy;
(e) C ₁ -C ₄ acyloxy;
(f) C ₁ -C ₄ alkylthio;
(g) C ₁ -C ₄ alkylsulfinyl;
(h) C ₁ -C ₄ alkylsulfonyl;
(i) hydroxy (C ₁ -C ₄ ) alkyl;
(j) aryl (C ₁ -C ₄ ) alkyl;
(k) -CO ₂ H;
(l) -CN;
(m) -CONHOR;
(n) -SO ₂ NHR;
(o) -NH ₂ ;
(p) C ₁ -C ₄ alkylamino;
(q) C ₁ -C ₄ dialkylamino;
(r) -NHSO ₂ R;
(s) -NO ₂ ;
(t) -aryl; or
(u) -OH;
R ⁵ and R ⁶ are independently C ₁ -C ₈ alkyl or together form a C ₃ -C ₁₀ carbocyclic ring;
R ⁷ and R ⁸ are independently
(a) phenyl;
(b) saturated or unsaturated C ₃ -C ₁₀ carbocyclic ring;
(c) a C ₃ -C ₁₀ heterocyclic ring comprising up to two heteroatoms selected from -O-, -N-, and -S-;
(d) H;
(e) C ₁ -C ₆ alkyl; or
(f) forms a 3-8 membered nitrogen containing ring with R ⁵ or R ⁶ ;
Linear or cyclic R ⁷ and R ⁸ may be optionally substituted with up to three substituents independently selected from C ₁ -C ₆ alkyl, halogen, alkoxy, hydroxy and carboxy;
The ring formed by R ⁷ and R ⁸ may be optionally fused to a phenyl ring;
e is 0, 1 or 2;
m is 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1, 2 or 3;
q is 0, 1, 2, or 3.
[4" claim-type="Currently amended] According to claim 1, wherein the estrogen agonist / antagonist is a compound of formula (1a) or an optical or geometric isomer thereof; Or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or precursor thereof.
<Formula 1a>

In the above formula, G is
ego;
R ⁴ is H, OH, F or Cl; B and E are independently selected from CH and N.
[5" claim-type="Currently amended] The method of claim 1, wherein the estrogen agonist / antagonist is (-)-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6, 7,8-tetrahydro-naphthalen-2-ol or its optical or geometric isomers; Or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or precursor thereof.
[6" claim-type="Currently amended] 6. The method of claim 5, wherein said estrogen agonist / antagonist is in the form of a D-tartrate salt.
[7" claim-type="Currently amended] The method of claim 1, wherein the estrogen agonist / antagonist is tamoxifen, 4-hydroxy tamoxifen, raloxyphene, droloxyphene, toremifene, centromman, idoxifen, 6- (4-hydroxy-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -naphthalen-2-ol, {4- [2- (2-aza-bicyclo [2.2.1] hept- 2-yl) -ethoxy] -phenyl}-[6-hydroxy-2- (4-hydroxy-phenyl) -benzo [b] thiophen-3-yl] -methanone, GW 5638, GW 7604, And optical or geometric isomers thereof; And pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts and precursors thereof; Or a compound of formula (5) or (6) or an optical and geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or precursor thereof; Or a compound of formula (5a), TSE-424 or an optical or geometric isomer thereof; Or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or precursor thereof; Or compound EM-652 of formula (3) or compound EM-800 of formula (4) or an optical or geometric isomer thereof; Or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or precursor thereof.
<Formula 3>

<Formula 4>

<Formula 5>

<Formula 5a>

<Formula 6>

In the above formula:
R _1B is H, OH, —OC (O) —C ₁ -C ₁₂ alkyl (straight or branched), —OC ₁ -C ₁₂ alkyl (straight or branched or cyclic), or halogen or C ₁ -C ₄ Selected from halogenated ethers,
R _2B , R _3B , R _4B , R _5B and R _6B are independently H, OH, —OC (O) —C ₁ -C ₁₂ alkyl (straight or branched), -OC ₁ -C ₁₂ alkyl (straight or Branched or cyclic), halogen, or C ₁ -C ₄ halogenated ether, cyano, C ₁ -C ₆ alkyl (linear or branched chain), or trifluoromethyl;
X _A is selected from H, C ₁ -C ₆ alkyl, cyano, nitro, trifluoromethyl and halogen;
s is 2 or 3;
Y _A is the part: ego,
In the above formula:
a) R _7B and R _8B are independently H, C ₁ -C ₆ alkyl, or CN, C ₁ -C ₆ alkyl (straight or branched), C ₁ -C ₆ alkoxy (straight or branched), halogen, Or is selected from the group of phenyl optionally substituted by -OH, -CF ₃ or -OCF ₃ ;
b) R _7B and R _8B are linked to contain one nitrogen heteroatom, hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _2- , -NHSO ₂ R _1B , -NHCOR _1B , -NO ₂ , or To form a 5-membered saturated heterocycle optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl optionally substituted with 1-3 (C ₁ -C ₄ ) alkyl;
c) R _7B and R _8B are linked to contain one nitrogen heteroatom, hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _2- , -NHSO ₂ R _1B , -NHCOR _1B , -NO ₂ , or To form a 6 membered saturated heterocycle optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl optionally substituted with 1-3 (C ₁ -C ₄ ) alkyl;
d) R _7B and R _8B are linked to contain one nitrogen heteroatom, hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _2- , -NHSO ₂ R _1B , -NHCOR _1B , -NO ₂ , or To form a 7 membered saturated heterocycle optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl optionally substituted with 1-3 (C ₁ -C ₄ ) alkyl;
e) R _7B and R _8B are linked to contain one nitrogen heteroatom, hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _2- , -NHSO ₂ R _1B , -NHCOR _1B , -NO ₂ , or To form an 8-membered saturated heterocycle optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl optionally substituted with 1-3 (C ₁ -C ₄ ) alkyl; or
f) R _7B and R _8B are linked to contain 6-12 carbon atoms and 1 nitrogen heteroatom, hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ), Alkyl, -CO ₂ H, -CN, -CONHR _1B , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _2- , -NHSO ₂ R _1B ,- Saturated bicyclic hetero, optionally substituted with 1-3 substituents independently selected from the group consisting of NHCOR _1B , -NO ₂ , or phenyl optionally substituted with 1-3 (C ₁ -C ₄ ) alkyl Form a cycle.
[8" claim-type="Currently amended] a) performing a gynecological examination;
b) measuring the pH of the vagina;
c) measuring vaginal cell maturity index;
d) measure vaginal escape;
e) give the patient a questionnaire;
f) Analyzing the quality of a patient's vaginal health comprising measuring plasma hormone levels and integrating the data from steps a-f into consideration.
[9" claim-type="Currently amended] 10. The method of claim 8, wherein the gynecological examination comprises an internal evaluation of the query describing the nature of the vaginal condition by successively representing the query state using the following I and III as the lowest and highest points and the following II as the midpoint. Way.
I. No wrinkles, no elasticity, the mucous membrane is very pale, soft and bleeding to the touch, no depth of vagina and very dry;
II. Less wrinkles, some water loss, weak elastic discomfort when inspecting, pale colors, shortened depth of vagina; or
III. Estrogenization vagina, wrinkles of normal, good elasticity, strong mucous membrane of pink, good vaginal moisture and good vaginal health.
[10" claim-type="Currently amended] 10. The method of claim 9, wherein the gynecological examination further comprises analyzing the amount of pubic hair and the thickness of the vulva.
[11" claim-type="Currently amended] The method of claim 8, wherein the plasma hormone levels measured comprise estradiol, luteinizing hormone, follicle-stimulating hormone, testosterone and androstenedione.
[12" claim-type="Currently amended] The method of claim 8, wherein evaluating the vaginal escape by ranking the escape using the following measures.
Class 0: Normal position inside the vaginal central axis for anterior posterior wall escape and above the sciatic pole for the cervical or vaginal cuff. By definition, the peak is -3 cm above the hymen.
Class 1: Escapes past each starting point and down to the mid-point to the hymen.
Grade 2: down to hymen.
Class 3: 2cm past hymen.
Grade 4: Lowered to the maximum extent possible for each site. Complete valgus about 5 cm past hymen.
[13" claim-type="Currently amended] The method of claim 8, wherein the questionnaire is:
1) the number of vaginal infections;
2) the number of urinary infections;
3) the amount of urine leakage;
4) the degree of vaginal dryness;
5) degree of vaginal itching; And
6) A method comprising questions relating to the subjective analysis of overall vaginal health by the patient.
[14" claim-type="Currently amended] a) Gynecology, including internal evaluation of the vagina describing the characteristics of the vaginal state and analysis of pubic and vulva thicknesses by successively representing vaginal state using the following I and III as the lowest and highest points and the following II as the midpoint. Do the enemy checks:
I. No wrinkles, no elasticity, the mucous membrane is very pale, soft and bleeding to the touch, no depth of vagina and very dry;
II. Less wrinkles, some water loss, weak elastic discomfort when inspecting, pale colors, shortened depth of vagina; or
III. Normal estrogenation vagina, wrinkles, good elasticity, pink strong mucous membranes, good vaginal moisture and good vaginal health;
b) measuring the pH of the vagina;
c) determining the vaginal cell maturation index;
d) Measure vaginal escape using the following scales:
Class 0: Normal position inside the vaginal central axis for anterior posterior wall prolapse and above the sciatic pole for a neck or vaginal cuff. By definition, the peak is -3 cm above the hymen;
Class 1: the escape past each starting point to the mid-point to the hymen;
Class 2: down to hymen;
Class 3: down 2 cm past hymen;
Grade 4: Lowered to the maximum extent possible for each site. Complete valgus about 5 cm past hymen;
e) Give the patient a questionnaire including questions relating to:
1) the number of vaginal infections during a particular period of time;
2) the number of urinary infections during a particular time period;
3) the amount of urine leakage over a certain period of time;
4) the degree of vaginal dryness during a certain period of time;
5) degree of vaginal itching; And
6) subjective assessment of overall quality health by the patient;
f) Vaginal health of the patient, including measuring plasma levels of estradiol, progesterone, follicle-stimulating hormone, testosterone and androstenedione, and analyzing the patient's vaginal health, taking into account the data from step af as a whole Analytical Method.

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同族专利:

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AU7941201A|2002-04-18|

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US20050215592A1|2005-09-29|

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JP2002179593A|2002-06-26|

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CA2358938A1|2002-04-16|

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IL145838D0|2002-07-25|

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HU0104300A3|2003-05-28|

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TWI282736B|2007-06-21|

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PT1199069E|2007-01-31|

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DE60123546D1|2006-11-16|

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EP1199069A3|2003-11-19|

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KR100463964B1|2005-01-03|

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AU783821B2|2005-12-08|

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US20030125319A1|2003-07-03|

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DK1199069T3|2007-01-15|

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HU0104300A2|2002-08-28|

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ZA200108443B|2003-04-15|

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EP1199069A2|2002-04-24|

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CA2358938C|2006-08-08|

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NZ514821A|2004-01-30|

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EP1199069B1|2006-10-04|

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HU0104300D0|2001-12-28|

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ES2272424T3|2007-05-01|

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US20100204294A1|2010-08-12|

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DE60123546T2|2007-02-08|

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AT341313T|2006-10-15|

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IL145838A|2008-11-03|

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US20020128276A1|2002-09-12|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2000-10-16|Priority to US24078900P

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2000-10-16|Priority to US60/240,789

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2001-10-16|Application filed by 데이비드 존 우드, 화이자 프로덕츠 인크.

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2002-04-22|Publication of KR20020030035A

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2005-01-03|Application granted

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2005-01-03|Publication of KR100463964B1

优先权:

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申请号 | 申请日 | 专利标题

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US24078900P| true| 2000-10-16|2000-10-16|

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US60/240,789|2000-10-16|