Methods of Treating Heavy Menstrual Bleeding

Abstract

The present invention relates to the method of treating heavy menstrual bleeding in a subject with or without uterine fibroids and in need of treatment by administering an effective amount of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid or a pharmaceutically acceptable salt thereof, in combination with estrogens and progestogens.

What is claimed is: 
     
         1 . A method of treating endometriosis associated pain wherein the method further reduces fatigue in a patient with moderate to severe endometriosis, or wherein the method further reduces use of pain medications in patients with moderate to severe endometriosis, the method comprising administering to 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid (Compound A) or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein Compound A or its pharmaceutically acceptable salt is administered in combination with estrogens and progestogens wherein the estrogen is selected from the group consisting of estradiol, ethinyl estradiol, and conjugated estrogens, and the progestogen is selected from the group consisting of progesterone, norethindrone acetate, norgestimate, drospirenone, and medroxyprogesterone. 
     
     
         3 . The method of  claim 2 , wherein the estrogen is estradiol and the progestogen is norethindrone acetate. 
     
     
         4 . The method of  claim 3 , wherein the estradiol is administered in an amount of about 0.5 mg and the norethindrone acetate is administered in an amount of about 0.1 mg per day. 
     
     
         5 . The method of  claim 4 , wherein the estradiol and norethindrone acetate are administered once per day. 
     
     
         6 . The method of  claim 3 , wherein the estradiol is administered in an amount of about 1.0 mg and the norethindrone acetate is administered in an amount of about 0.5 mg per day. 
     
     
         7 . The method of  claim 6 , wherein the estradiol and norethindrone acetate are administered once per day. 
     
     
         8 . The method of  claim 4  or  6 , wherein the estradiol is administered continuously and norethindrone acetate are administered once per day during the last 12-14 days of a menstrual cycle. 
     
     
         9 . The method of any of  claims 1 - 8 , wherein Compound A is dosed 150 mg once-a-day, 200 mg twice-a-day, 300 mg twice-a-day or 600 mg once-a-day. 
     
     
         10 . The method of any of  claims 1 - 8 , wherein 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid or a pharmaceutically acceptable salt thereof is administered in an amount of about 300 mg per day. 
     
     
         11 . The method of  claim 10 , wherein 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid or a pharmaceutically acceptable salt thereof is administered twice per day. 
     
     
         12 . The method of any of  claims 1 - 8 , wherein 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid or a pharmaceutically acceptable salt thereof is administered in an amount of about 400 mg per day. 
     
     
         13 . The method of  claim 12 , wherein 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid or a pharmaceutically acceptable salt thereof is administered twice per day. 
     
     
         14 . The method of any of  claims 1 - 8 , wherein 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid or a pharmaceutically acceptable salt thereof is administered in an amount of about 600 mg per day. 
     
     
         15 . The method of  claim 14 , wherein 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid or a pharmaceutically acceptable salt thereof is administered twice per day. 
     
     
         16 . The method of any of  claims 2 - 15 , wherein 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid, estrogens, and progestogens are administered daily for at least 28 days. 
     
     
         17 . The method of  claim 16 , wherein 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid, estrogens, and progestogens are administered daily for at least 56 days. 
     
     
         18 . The method of  claim 17 , wherein 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid, estrogens, and progestogens are administered daily for at least 84 days. 
     
     
         19 . The method of  claim 18 , wherein 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid, estrogens, and progestogens are administered daily for at least 168 days. 
     
     
         20 . The method of  claim 19 , wherein 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid, estrogens, and progestogens are administered daily for about 168 days to about 1 year. 
     
     
         21 . The method of  claim 2 , wherein the estrogen is estradiol and the progestogen is progesterone. 
     
     
         22 . The method of  claim 21 , wherein the estradiol is administered continuously and the progesterone is administered once per day during the last 12-14 days of a menstrual cycle. 
     
     
         23 . A method of reducing fatigue or pain medications in a patient wherein the patient is diagnosed with a condition selected from a group consisting of Uterine Fibroids, Endometriosis, Adenomyosis or Polycystic Ovary Syndrome, the method comprising administering to 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid (Compound A) or a pharmaceutically acceptable salt thereof, wherein fatigue is reduced in said patient or wherein pain medications is reduced to said patient. 
     
     
         24 . The method of  claim 23 , wherein the patient is diagnosed with Uterine Fibroids. 
     
     
         25 . The method of  claim 23 , wherein the patient is diagnosed with Endometriosis. 
     
     
         26 . The method of  claim 23 , wherein the patient is diagnosed with Adenomyosis. 
     
     
         27 . The method of  claim 23 , wherein the patient is diagnosed with Polycystic Ovary Syndrome. 
     
     
         28 . A method of treating endometriosis, the method comprising administering to a patient in need thereof 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid (Compound A) or a pharmaceutically acceptable salt thereof, wherein said patient experiences bone mineral density loss, wherein the bone mineral density loss is substantially reversed upon discontinuation of Compound A, or pharmaceutically acceptable salt thereof. 
     
     
         29 . A method of treating a patient in need thereof 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid (Compound A) or a pharmaceutically acceptable salt thereof, wherein said patient experiences bone mineral density loss, wherein the bone mineral density loss is substantially reversed upon discontinuation of Compound A, or pharmaceutically acceptable salt thereof.