COMPOSITIONS AND METHODS FOR THE TREATMENT OF ADENOMYOSIS AND RECTOVAGINAL ENDOMETRIOSIS
20220117969 · 2022-04-21
Inventors
Cpc classification
A61K47/541
HUMAN NECESSITIES
A61K31/513
HUMAN NECESSITIES
A61K31/519
HUMAN NECESSITIES
A61K45/06
HUMAN NECESSITIES
A61K31/4184
HUMAN NECESSITIES
A61K31/565
HUMAN NECESSITIES
A61K31/4439
HUMAN NECESSITIES
A61K31/57
HUMAN NECESSITIES
A61K31/567
HUMAN NECESSITIES
A61K31/573
HUMAN NECESSITIES
A61K31/585
HUMAN NECESSITIES
A61P15/00
HUMAN NECESSITIES
International classification
A61K31/519
HUMAN NECESSITIES
A61K31/4184
HUMAN NECESSITIES
A61K31/4439
HUMAN NECESSITIES
A61K31/513
HUMAN NECESSITIES
A61K31/55
HUMAN NECESSITIES
A61K31/565
HUMAN NECESSITIES
A61K31/567
HUMAN NECESSITIES
A61K31/57
HUMAN NECESSITIES
A61K31/573
HUMAN NECESSITIES
A61K31/585
HUMAN NECESSITIES
Abstract
The present disclosure provides compositions and methods for treating endometrial growth disorders in a patient, such as a human patient, and particularly pre-menopausal female human patients. Exemplary disorders that may be treated using the compounds and therapeutic regimens described herein include adenomyosis and rectovaginal endometriosis. The compounds described herein that may be used to treat such indications include gonadotropin-releasing hormone (GnRH) antagonists. Suitable GnRH antagonists useful in conjunction with the compositions and methods described herein include thieno[3,4d]pyrimidine derivatives, such as 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid and the choline salt thereof, among others.
Claims
1. A method of treating adenomyosis in a human patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a gonadotropin-releasing hormone (GnRH) antagonist.
2. A method of treating adenomyosis in a human patient, the method comprising: a) diagnosing the patient as having adenomyosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
3. A method of reducing uterine volume in a human patient diagnosed as having adenomyosis, the method comprising administering to the patient a therapeutically effective amount of a GnRH antagonist.
4. A method of reducing uterine volume in a human patient, the method comprising: a) diagnosing the patient as having adenomyosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
5. A method of reducing the thickness of the anterior and/or posterior region of the uterine myometrium in a human patient diagnosed as having adenomyosis, the method comprising administering to the patient a therapeutically effective amount of a GnRH antagonist.
6. A method of reducing the thickness of the anterior and/or posterior region of the uterine myometrium in a human patient, the method comprising: a) diagnosing the patient as having adenomyosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
7. A method of reducing pelvic pain in a human patient diagnosed as having adenomyosis, the method comprising administering to the patient a therapeutically effective amount of a GnRH antagonist.
8. A method of reducing pelvic pain in a human patient, the method comprising: a) diagnosing the patient as having adenomyosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
9. A method of reducing dysmenorrhea in a human patient diagnosed as having adenomyosis, the method comprising administering to the patient a therapeutically effective amount of a GnRH antagonist.
10. A method of reducing dysmenorrhea in a human patient, the method comprising: a) diagnosing the patient as having adenomyosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
11. A method of reducing dyspareunia in a human patient diagnosed as having adenomyosis, the method comprising administering to the patient a therapeutically effective amount of a GnRH antagonist.
12. A method of reducing dyspareunia in a human patient, the method comprising: a) diagnosing the patient as having adenomyosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
13. A method of reducing dyschezia in a human patient diagnosed as having adenomyosis, the method comprising administering to the patient a therapeutically effective amount of a GnRH antagonist.
14. A method of reducing dyschezia in a human patient, the method comprising: a) diagnosing the patient as having adenomyosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
15. A method of reducing uterine tenderness in a human patient diagnosed as having adenomyosis, the method comprising administering to the patient a therapeutically effective amount of a GnRH antagonist.
16. A method of reducing uterine tenderness in a human patient, the method comprising: a) diagnosing the patient as having adenomyosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
17. A method of reducing uterine bleeding in a human patient diagnosed as having adenomyosis, the method comprising administering to the patient a therapeutically effective amount of a GnRH antagonist.
18. A method of reducing uterine bleeding in a human patient, the method comprising: a) diagnosing the patient as having adenomyosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
19. A method of inducing amenorrhea in a human patient diagnosed as having adenomyosis, the method comprising administering to the patient a therapeutically effective amount of a GnRH antagonist.
20. A method of inducing amenorrhea in a human patient, the method comprising: a) diagnosing the patient as having adenomyosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
21. The method of any one of claims 1-20, wherein the GnRH antagonist is a compound represented by formula (I) ##STR00619## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof.
22. The method of claim 21, wherein the ring A is a thiophene ring represented by formula (IIa) ##STR00620##
23. The method of claim 21 or 22, wherein m is 1.
24. The method of claim 23, wherein the ring A is an optionally substituted thiophene ring represented by formula (IIb) ##STR00621##
25. The method of any one of claims 21-24, wherein each R.sup.A is independently a halogen atom, an optionally substituted lower alkyl group, COOW.sup.1, or CONW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group.
26. The method of claim 25, wherein each R.sup.A is COOH or pharmaceutically acceptable salt thereof.
27. The method of any one of claims 21-26, wherein ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring.
28. The method of claim 27, wherein ring B is represented by a formula selected from the group consisting of: ##STR00622##
29. The method of any one of claims 21-28, wherein n is 2.
30. The method of claim 29, wherein ring B is represented by a formula selected from the group consisting of: ##STR00623##
31. The method of any one of claims 21-30, wherein each R.sup.B is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.4, wherein each W.sup.4 is independently a hydrogen atom or an optionally substituted lower alkyl group.
32. The method of claim 31, wherein each R.sup.B is independently a fluorine atom, chlorine atom, bromine atom, methyl group, or methoxy group.
33. The method of any one of claims 21-32, wherein U is a single bond.
34. The method of any one of claims 21-33, wherein X is a group represented by —O-L-Y.
35. The method of any one of claims 21-34, wherein L is a methylene group.
36. The method of any one of claims 21-35, wherein Y is an optionally substituted benzene ring represented by formula (V) ##STR00624## wherein each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3.
37. The method of claim 36, wherein Y is a substituted benzene ring represented by formula (Va) ##STR00625##
38. The method of claim 21, wherein the compound is represented by formula (Ia) ##STR00626## wherein each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; q is an integer from 0 to 3; each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3; or a pharmaceutically acceptable salt thereof.
39. The method of claim 38, wherein the compound is represented by formula (Ib) ##STR00627##
40. The method of claim 39, wherein the compound is represented by formula (Ic) ##STR00628## or a pharmaceutically acceptable salt thereof.
41. The method of claim any one of claims 21-40, wherein the compound is represented by formula (VI) ##STR00629## or a pharmaceutically acceptable salt thereof.
42. The method of claim 41, wherein the compound is administered to the patient in the form of the choline salt of (VI), choline 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylate.
43. The method of claim 42, wherein the compound is in a crystalline state.
44. The method of claim 43, wherein the compound exhibits characteristic X-ray powder diffraction (XRPD) peaks at about 7.1° 2θ, about 11.5° 2θ, about 19.4° 2θ, about 21.5° 2θ, about 22.0° 2θ, about 22.6° 2θ, about 23.5° 2θ, and about 26.2° 2θ.
45. The method of claim 43 or 44, wherein the compound exhibits .sup.13C solid-state nuclear magnetic resonance (NMR) peaks centered at about 55.5 ppm, about 57.1 ppm, about 58.7 ppm, about 69.8 ppm, about 98.1 ppm, about 110.3 ppm, about 111.6 ppm, about 113.7 ppm, about 118.0 ppm, about 145.3 ppm, about 149.8 ppm, and about 155.8 ppm.
46. The method of any one of claims 42-45, wherein the compound exhibits .sup.19F solid-state NMR peaks centered at about −151.8 ppm, −145.2 ppm, and −131.6 ppm.
47. The method of any one of claims 21-46, wherein the compound is orally administered to the patient.
48. The method of any one of claims 21-47, wherein the compound is administered to the patient one or more times per day, week, or month.
49. The method of claim 48, wherein the compound is administered to the patient one or more times daily.
50. The method of claim 49, wherein the compound is administered to the patient once daily.
51. The method of any one of claims 48-50, wherein the compound is administered to the patient in an amount of from about 50 mg per day to about 400 mg per day.
52. The method of claim 51, wherein the compound is administered to the patient in an amount of about 100 mg per day.
53. The method of claim 51, wherein the compound is administered to the patient in an amount of about 200 mg per day.
54. The method of any one of claims 48-53, wherein the compound is administered to the patient over a treatment period of at least four weeks.
55. The method of claim 54, wherein the compound is administered to the patient over a treatment period of at least eight weeks.
56. The method of claim 55, wherein the compound is administered to the patient over a treatment period of at least 12 weeks.
57. The method of claim 56, wherein the compound is administered to the patient over a treatment period of at least 24 weeks.
58. The method of any one of claims 48-53, wherein the compound is administered to the patient over a treatment period of from about four weeks to about twelve months.
59. The method of claim 58, wherein the compound is administered to the patient over a treatment period of from about eight weeks to about ten months.
60. The method of claim 59, wherein the compound is administered to the patient over a treatment period of from about 16 weeks to about 48 weeks.
61. The method of claim 60, wherein the compound is administered to the patient over a treatment period of about 24 weeks.
62. The method of any one of claims 48-53, wherein the compound is administered to the patient in an amount of from about 150 mg per day to about 250 mg per day over a first treatment period, and is subsequently administered to the patient in an amount of from about 50 mg per day to about 150 mg per day over a second treatment period.
63. The method of claim 62, wherein the compound is administered to the patient in an amount of from about 175 mg per day to about 225 mg per day over a first treatment period, and is subsequently administered to the patient in an amount of from about 75 mg per day to about 125 mg per day over a second treatment period.
64. The method of claim 63, wherein the compound is administered to the patient in an amount of from about 185 mg per day to about 215 mg per day over a first treatment period, and is subsequently administered to the patient in an amount of from about 85 mg per day to about 115 mg per day over a second treatment period.
65. The method of claim 64, wherein the compound is administered to the patient in an amount of about 200 mg per day over a first treatment period, and is subsequently administered to the patient in an amount of about 100 mg per day over a second treatment period.
66. The method of any one of claims 62-65, wherein the first treatment period has a duration of from about two weeks to about six months.
67. The method of claim 66, wherein the first treatment period has a duration of from about four weeks to about five months.
68. The method of claim 67, wherein the first treatment period has a duration of from about eight weeks to about 24 weeks.
69. The method of claim 68, wherein the first treatment period has a duration of about 12 weeks.
70. The method of any one of claims 62-69, wherein the second treatment period has a duration of from about two weeks to about six months.
71. The method of claim 70, wherein the second treatment period has a duration of from about four weeks to about five months.
72. The method of claim 71, wherein the second treatment period has a duration of from about eight weeks to about 24 weeks.
73. The method of claim 72, wherein the second treatment period has a duration of about 12 weeks.
74. The method of any one of claims 1-20, wherein the GnRH antagonist is elagolix, relugolix, opigolix (ASP1707), BAY-784, or SK-2706.
75. The method of claim 74, wherein the GnRH antagonist is elagolix.
76. The method of claim 75, wherein the GnRH antagonist is orally administered to the patient.
77. The method of claim 75 or 76, wherein the GnRH antagonist is administered to the patient one or more times per day, week, or month.
78. The method of claim 77, wherein the GnRH antagonist is administered to the patient one or more times daily.
79. The method of claim 78, wherein the GnRH antagonist is administered to the patient once daily.
80. The method of any one of claims 75-79, wherein the GnRH antagonist is administered to the patient in an amount of from about 100 mg to about 600 mg per day.
81. The method of claim 80, wherein the GnRH antagonist is administered to the patient in an amount of about 150 mg per day.
82. The method of claim 80, wherein the GnRH antagonist is administered to the patient in an amount of about 300 mg per day.
83. The method of claim 80, wherein the GnRH antagonist is administered to the patient in an amount of about 400 mg per day.
84. The method of claim 80, wherein the GnRH antagonist is administered to the patient in an amount of about 600 mg per day.
85. The method of claim 74, wherein the GnRH antagonist is relugolix.
86. The method of claim 85, wherein the GnRH antagonist is orally administered to the patient.
87. The method of claim 85 or 86, wherein the GnRH antagonist is administered to the patient one or more times per day, week, or month.
88. The method of claim 87, wherein the GnRH antagonist is administered to the patient one or more times daily.
89. The method of claim 88, wherein the GnRH antagonist is administered to the patient once daily.
90. The method of any one of claims 85-89, wherein the GnRH antagonist is administered to the patient in an amount of from about 10 mg to about 60 mg per day.
91. The method of claim 90, wherein the GnRH antagonist is administered to the patient in an amount of from about 20 mg to about 50 mg per day.
92. The method of claim 91, wherein the GnRH antagonist is administered to the patient in an amount of about 40 mg per day.
93. The method of any one of claims 1-92, wherein the patient is a pre-menopausal female of from about 18 to about 48 years of age.
94. The method of any one of claims 1-93, wherein the patient exhibits a serum concentration of follicle-stimulating hormone (FSH) of about 20 IU/L or less prior to administration of the GnRH antagonist to the patient.
95. The method of any one of claims 1-94, wherein the patient exhibits a junctional-zone width of about 12 mm or more prior to administration of the GnRH antagonist to the patient.
96. The method of claim 95, wherein the junctional-zone width is assessed by way of magnetic resonance imaging (MRI).
97. The method of any one of claims 1-96, wherein the patient exhibits a reduction in serum concentration of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and/or β17-estradiol (E2) following administration of the GnRH antagonist to the patient.
98. The method of claim 97, wherein the patient exhibits the reduction in serum concentration of LH, FSH, and/or E2 within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
99. The method of any one of claims 1, 2, and 5-98, wherein the patient exhibits a reduction in uterine volume following administration of the GnRH antagonist to the patient.
100. The method of claim 99, wherein the patient exhibits the reduction in uterine volume within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
101. The method of any one of claims 3, 4, 99, and 100, wherein the reduction in uterine volume is assessed by way of MRI or transvaginal ultrasound (TVUS).
102. The method of any one of claims 1-4 and 7-101, wherein the patient exhibits a reduction in the thickness of the anterior and/or posterior region of the uterine myometrium following administration of the GnRH antagonist to the patient.
103. The method of claim 102, wherein the patient exhibits the reduction in thickness of the anterior and/or posterior region of the uterine myometrium within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
104. The method of any one of claims 1-6 and 9-103, wherein the patient exhibits a reduction in pelvic pain following administration of the GnRH antagonist to the patient.
105. The method of claim 104, wherein the patient exhibits the reduction in pelvic pain within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
106. The method of any one of claims 7, 8, 104, and 105, wherein the reduction in pelvic pain is assessed by way of a modified Biberoglu & Behrman (mB&B) score, Numerical Rating Scale (NRS) score, or Verbal Rating Scale (VRS) score.
107. The method of any one of claims 1-8 and 11-106, wherein the patient exhibits a reduction in dysmenorrhea following administration of the GnRH antagonist to the patient.
108. The method of claim 107, wherein the patient exhibits the reduction in dysmenorrhea within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
109. The method of any one of claims 9, 10, 107, and 108, wherein the reduction in dysmenorrhea is assessed by way of an mB&B score, NRS score, or VRS score.
110. The method of any one of claims 1-10 and 13-109, wherein the patient exhibits a reduction in dyspareunia following administration of the GnRH antagonist to the patient.
111. The method of claim 110, wherein the patient exhibits the reduction in dyspareunia within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
112. The method of any one of claims 11, 12, 110, and 111, wherein the reduction in dyspareunia is assessed by way of an mB&B score, NRS score, or VRS score.
113. The method of any one of claims 1-12 and 15-112, wherein the patient exhibits a reduction in dyschezia following administration of the GnRH antagonist to the patient.
114. The method of claim 110, wherein the patient exhibits the reduction in dyschezia within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
115. The method of any one of claims 13, 14, 113, and 114, wherein the reduction in dyschezia is assessed by way of an mB&B score, NRS score, or VRS score.
116. The method of any one of claims 1-14 and 17-115, wherein the patient exhibits a reduction in uterine tenderness following administration of the GnRH antagonist to the patient.
117. The method of claim 116, wherein the patient exhibits the reduction in uterine tenderness within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
118. The method of any one of claims 1-16 and 19-117, wherein the patient exhibits a reduction in uterine bleeding following administration of the GnRH antagonist to the patient.
119. The method of claim 118, wherein the patient exhibits the reduction in uterine bleeding within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
120. The method of any one of claims 17, 18, 118, and 119, wherein the reduction in uterine bleeding is assessed by way of an alkaline hematin method.
121. The method of any one of claims 1-18 and 21-112, wherein the patient exhibits amenorrhea following administration of the GnRH antagonist to the patient.
122. The method of claim 121, wherein the patient exhibits the amenorrhea within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the amenorrhea within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
123. The method of any one of claims 1-122, wherein the patient exhibits a reduction in the diameter of a junctional zone of adenomyosis following administration of the GnRH antagonist to the patient.
124. The method of claim 123, wherein the patient exhibits the reduction in the diameter of the junctional zone of adenomyosis within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
125. The method of any one of claims 1-124, wherein the patient exhibits an improvement in Endometriosis Health Profile questionnaire (EHP-30) score following administration of the GnRH antagonist to the patient.
126. The method of claim 125, wherein the patient exhibits the improvement in the EHP-30 score within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the improvement within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
127. The method of any one of claims 1-126, wherein the patient exhibits a positive Patient Global Impression of Change (PGIC) score core following administration of the GnRH antagonist to the patient.
128. The method of claim 127, wherein the patient exhibits the positive PGIC score within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the positive PGIC score within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
129. The method of any one of claims 1-128, wherein the patient does not exhibit a reduction in bone mineral density (BMD) of greater than 5% following administration of the GnRH antagonist to the patient.
130. The method of claim 129, wherein the patient does not exhibit a reduction in BMD of greater than 1% following administration of the GnRH antagonist to the patient.
131. The method of claim 129 or 130, wherein the BMD is assessed by dual energy X-ray absorptiometry.
132. The method of claim 131, wherein the BMD is assessed in the spine or femur of the patient.
133. The method of claim 129 or 130, wherein the BMD is assessed by comparing the concentration of BAP in a sample isolated from the patient following the administration to the concentration of BAP in a sample isolated from the patient prior to the administration.
134. The method of claim 129 or 130, wherein the BMD is assessed by comparing the concentration of DPD in a sample isolated from the patient following the administration to the concentration of DPD in a sample isolated from the patient prior to the administration.
135. The method of claim 129 or 130, wherein the BMD is assessed by comparing the concentration of CTX in a sample isolated from the patient following the administration to the concentration of CTX in a sample isolated from the patient prior to the administration.
136. The method of claim 129 or 130, wherein the BMD is assessed by comparing the concentration of P1NP in a sample isolated from the patient following the administration to the concentration of P1NP in a sample isolated from the patient prior to the administration.
137. A kit comprising a GnRH antagonist and a package insert instructing a user of the kit to administer the GnRH antagonist to a patient having adenomyosis in accordance with the method of any one of claims 1-136.
138. The kit of claim 137, wherein the GnRH antagonist is a compound represented by formula (I) ##STR00630## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof.
139. The kit of claim 138, wherein the ring A is a thiophene ring represented by formula (IIa) ##STR00631##
140. The kit of claim 138 or 139, wherein m is 1.
141. The kit of claim 140, wherein the ring A is an optionally substituted thiophene ring represented by formula (IIb) ##STR00632##
142. The kit of any one of claims 138-141, wherein each R.sup.A is independently a halogen atom, an optionally substituted lower alkyl group, COOW.sup.1, or CONW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group.
143. The kit of claim 142, wherein each R.sup.A is COOH or pharmaceutically acceptable salt thereof.
144. The kit of any one of claims 138-143, wherein ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring.
145. The kit of claim 144, wherein ring B is represented by a formula selected from the group consisting of: ##STR00633##
146. The kit of any one of claims 138-145, wherein n is 2.
147. The kit of claim 146, wherein ring B is represented by a formula selected from the group consisting of: ##STR00634##
148. The kit of any one of claims 138-147, wherein each R.sup.B is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.4, wherein each W.sup.4 is independently a hydrogen atom or an optionally substituted lower alkyl group.
149. The kit of claim 148, wherein each R.sup.B is independently a fluorine atom, chlorine atom, bromine atom, methyl group, or methoxy group.
150. The kit of any one of claims 138-149, wherein U is a single bond.
151. The kit of any one of claims 138-150, wherein X is a group represented by —O-L-Y.
152. The kit of any one of claims 138-151, wherein L is a methylene group.
153. The kit of any one of claims 138-152, wherein Y is an optionally substituted benzene ring represented by formula (V) ##STR00635## wherein each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3.
154. The kit of claim 153, wherein Y is a substituted benzene ring represented by formula (Va) ##STR00636##
155. The kit of claim 138, wherein the compound is represented by formula (Ia) ##STR00637## wherein each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; q is an integer from 0 to 3; each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3; or a pharmaceutically acceptable salt thereof.
156. The kit of claim 155, wherein the compound is represented by formula (Ib) ##STR00638##
157. The kit of claim 156, wherein the compound is represented by formula (Ic) ##STR00639## or a pharmaceutically acceptable salt thereof.
158. The kit of any one of claims 138-157, wherein the compound is represented by formula (VI) ##STR00640## or a pharmaceutically acceptable salt thereof.
159. The kit of claim 158, wherein the compound is the choline salt of the compound represented by formula (VI).
160. The kit of claim 138, wherein the GnRH antagonist is elagolix, relugolix, opigolix (ASP1707), BAY-784, or SK-2706.
161. A method of treating rectovaginal endometriosis in a human patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a GnRH antagonist.
162. A method of treating rectovaginal endometriosis in a human patient, the method comprising: a) diagnosing the patient as having rectovaginal endometriosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
163. A method of reducing the volume of one or more rectovaginal endometriosis nodes in a human patient diagnosed as having rectovaginal endometriosis, the method comprising administering to the patient a therapeutically effective amount of a GnRH antagonist.
164. A method of reducing the volume of one or more rectovaginal endometriosis nodes in a human patient, the method comprising: a) diagnosing the patient as having rectovaginal endometriosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
165. A method of reducing pelvic pain in a human patient diagnosed as having rectovaginal endometriosis, the method comprising administering to the patient a therapeutically effective amount of a GnRH antagonist.
166. A method of reducing pelvic pain in a human patient, the method comprising: a) diagnosing the patient as having rectovaginal endometriosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
167. A method of reducing dysmenorrhea in a human patient diagnosed as having rectovaginal endometriosis, the method comprising administering to the patient a therapeutically effective amount of a GnRH antagonist.
168. A method of reducing dysmenorrhea in a human patient, the method comprising: a) diagnosing the patient as having rectovaginal endometriosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
169. A method of reducing dyspareunia in a human patient diagnosed as having rectovaginal endometriosis, the method comprising administering to the patient a therapeutically effective amount of a GnRH antagonist.
170. A method of reducing dyspareunia in a human patient, the method comprising: a) diagnosing the patient as having rectovaginal endometriosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
171. A method of reducing dyschezia in a human patient diagnosed as having rectovaginal endometriosis, the method comprising administering to the patient a therapeutically effective amount of a GnRH antagonist.
172. A method of reducing dyschezia in a human patient, the method comprising: a) diagnosing the patient as having rectovaginal endometriosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
173. A method of reducing uterine bleeding in a human patient diagnosed as having rectovaginal endometriosis, the method comprising administering to the patient a therapeutically effective amount of a GnRH antagonist.
174. A method of reducing uterine bleeding in a human patient, the method comprising: a) diagnosing the patient as having rectovaginal endometriosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
175. A method of inducing amenorrhea in a human patient diagnosed as having rectovaginal endometriosis, the method comprising administering to the patient a therapeutically effective amount of a GnRH antagonist.
176. A method of inducing amenorrhea in a human patient, the method comprising: a) diagnosing the patient as having rectovaginal endometriosis; and b) administering to the patient a therapeutically effective amount of a GnRH antagonist.
177. The method of any one of claims 161-176, wherein the GnRH antagonist is a compound represented by formula (I) ##STR00641## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof.
178. The method of claim 177, wherein the ring A is a thiophene ring represented by formula (IIa) ##STR00642##
179. The method of claim 177 or 178, wherein m is 1.
180. The method of claim 179, wherein the ring A is an optionally substituted thiophene ring represented by formula (IIb) ##STR00643##
181. The method of any one of claims 177-180, wherein each R.sup.A is independently a halogen atom, an optionally substituted lower alkyl group, COOW.sup.1, or CONW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group.
182. The method of claim 181, wherein each R.sup.A is COOH or pharmaceutically acceptable salt thereof.
183. The method of any one of claims 177-182, wherein ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring.
184. The method of claim 183, wherein ring B is represented by a formula selected from the group consisting of: ##STR00644##
185. The method of any one of claims 177-184, wherein n is 2.
186. The method of claim 185, wherein ring B is represented by a formula selected from the group consisting of: ##STR00645##
187. The method of any one of claims 177-186, wherein each R.sup.B is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.4, wherein each W.sup.4 is independently a hydrogen atom or an optionally substituted lower alkyl group.
188. The method of claim 187, wherein each R.sup.B is independently a fluorine atom, chlorine atom, bromine atom, methyl group, or methoxy group.
189. The method of any one of claims 177-188, wherein U is a single bond.
190. The method of any one of claims 177-189, wherein X is a group represented by —O-L-Y.
191. The method of any one of claims 177-190, wherein L is a methylene group.
192. The method of any one of claims 177-191, wherein Y is an optionally substituted benzene ring represented by formula (V) ##STR00646## wherein each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3.
193. The method of claim 192, wherein Y is a substituted benzene ring represented by formula (Va) ##STR00647##
194. The method of claim 177, wherein the compound is represented by formula (Ia) ##STR00648## wherein each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; q is an integer from 0 to 3; each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3; or a pharmaceutically acceptable salt thereof.
195. The method of claim 194, wherein the compound is represented by formula (Ib) ##STR00649##
196. The method of claim 195, wherein the compound is represented by formula (Ic) ##STR00650## or a pharmaceutically acceptable salt thereof.
197. The method of claim any one of claims 177-196, wherein the compound is represented by formula (VI) ##STR00651## or a pharmaceutically acceptable salt thereof.
198. The method of claim 197, wherein the compound is administered to the patient in the form of the choline salt of (VI), choline 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylate.
199. The method of claim 198, wherein the compound is in a crystalline state.
200. The method of claim 199, wherein the compound exhibits characteristic X-ray powder diffraction (XRPD) peaks at about 7.1° 2θ, about 11.5° 2θ, about 19.4° 2θ, about 21.5° 2θ, about 22.0° 2θ, about 22.6° 2θ, about 23.5° 2θ, and about 26.2° 2θ.
201. The method of claim 199 or 200, wherein the compound exhibits .sup.13C solid-state nuclear magnetic resonance (NMR) peaks centered at about 55.5 ppm, about 57.1 ppm, about 58.7 ppm, about 69.8 ppm, about 98.1 ppm, about 110.3 ppm, about 111.6 ppm, about 113.7 ppm, about 118.0 ppm, about 145.3 ppm, about 149.8 ppm, and about 155.8 ppm.
202. The method of any one of claims 199-201, wherein the compound exhibits .sup.19F solid-state NMR peaks centered at about −151.8 ppm, −145.2 ppm, and −131.6 ppm.
203. The method of any one of claims 177-202, wherein the compound is orally administered to the patient.
204. The method of any one of claims 177-203, wherein the compound is administered to the patient one or more times per day, week, or month.
205. The method of claim 204, wherein the compound is administered to the patient one or more times daily.
206. The method of claim 205, wherein the compound is administered to the patient once daily.
207. The method of any one of claims 204-206, wherein the compound is administered to the patient in an amount of from about 50 mg per day to about 400 mg per day.
208. The method of claim 207, wherein the compound is administered to the patient in an amount of about 100 mg per day.
209. The method of claim 207, wherein the compound is administered to the patient in an amount of about 200 mg per day.
210. The method of any one of claims 204-209, wherein the compound is administered to the patient over a treatment period of at least four weeks.
211. The method of claim 210, wherein the compound is administered to the patient over a treatment period of at least eight weeks.
212. The method of claim 211, wherein the compound is administered to the patient over a treatment period of at least 12 weeks.
213. The method of claim 212, wherein the compound is administered to the patient over a treatment period of at least 24 weeks.
214. The method of any one of claims 208-213, wherein the compound is administered to the patient over a treatment period of from about four weeks to about twelve months.
215. The method of claim 58, wherein the compound is administered to the patient over a treatment period of from about eight weeks to about ten months.
216. The method of claim 59, wherein the compound is administered to the patient over a treatment period of from about 16 weeks to about 48 weeks.
217. The method of claim 60, wherein the compound is administered to the patient over a treatment period of about 24 weeks.
218. The method of any one of claims 204-209, wherein the compound is administered to the patient in an amount of from about 150 mg per day to about 250 mg per day over a first treatment period, and is subsequently administered to the patient in an amount of from about 50 mg per day to about 150 mg per day over a second treatment period.
219. The method of claim 218, wherein the compound is administered to the patient in an amount of from about 175 mg per day to about 225 mg per day over a first treatment period, and is subsequently administered to the patient in an amount of from about 75 mg per day to about 125 mg per day over a second treatment period.
220. The method of claim 219, wherein the compound is administered to the patient in an amount of from about 185 mg per day to about 215 mg per day over a first treatment period, and is subsequently administered to the patient in an amount of from about 85 mg per day to about 115 mg per day over a second treatment period.
221. The method of claim 220, wherein the compound is administered to the patient in an amount of about 200 mg per day over a first treatment period, and is subsequently administered to the patient in an amount of about 100 mg per day over a second treatment period.
222. The method of any one of claims 218-221, wherein the first treatment period has a duration of from about two weeks to about six months.
223. The method of claim 222, wherein the first treatment period has a duration of from about four weeks to about five months.
224. The method of claim 223, wherein the first treatment period has a duration of from about eight weeks to about 24 weeks.
225. The method of claim 224, wherein the first treatment period has a duration of about 12 weeks.
226. The method of any one of claims 218-225, wherein the second treatment period has a duration of from about two weeks to about six months.
227. The method of claim 226, wherein the second treatment period has a duration of from about four weeks to about five months.
228. The method of claim 227, wherein the second treatment period has a duration of from about eight weeks to about 24 weeks.
229. The method of claim 228, wherein the second treatment period has a duration of about 12 weeks.
230. The method of any one of claims 161-176, wherein the GnRH antagonist is elagolix, relugolix, opigolix (ASP1707), BAY-784, or SK-2706.
231. The method of claim 230, wherein the GnRH antagonist is elagolix.
232. The method of claim 231, wherein the GnRH antagonist is orally administered to the patient.
233. The method of claim 231 or 232, wherein the GnRH antagonist is administered to the patient one or more times per day, week, or month.
234. The method of claim 233, wherein the GnRH antagonist is administered to the patient one or more times daily.
235. The method of claim 234, wherein the GnRH antagonist is administered to the patient once daily.
236. The method of any one of claims 231-235, wherein the GnRH antagonist is administered to the patient in an amount of from about 100 mg to about 600 mg per day.
237. The method of claim 236, wherein the GnRH antagonist is administered to the patient in an amount of about 150 mg per day.
238. The method of claim 236, wherein the GnRH antagonist is administered to the patient in an amount of about 300 mg per day.
239. The method of claim 236, wherein the GnRH antagonist is administered to the patient in an amount of about 400 mg per day.
240. The method of claim 236, wherein the GnRH antagonist is administered to the patient in an amount of about 600 mg per day.
241. The method of claim 230, wherein the GnRH antagonist is relugolix.
242. The method of claim 241, wherein the GnRH antagonist is orally administered to the patient.
243. The method of claim 241 or 242, wherein the GnRH antagonist is administered to the patient one or more times per day, week, or month.
244. The method of claim 243, wherein the GnRH antagonist is administered to the patient one or more times daily.
245. The method of claim 244, wherein the GnRH antagonist is administered to the patient once daily.
246. The method of any one of claims 241-245, wherein the GnRH antagonist is administered to the patient in an amount of from about 10 mg to about 60 mg per day.
247. The method of claim 246, wherein the GnRH antagonist is administered to the patient in an amount of from about 20 mg to about 50 mg per day.
248. The method of claim 247, wherein the GnRH antagonist is administered to the patient in an amount of about 40 mg per day.
249. The method of any one of claims 161-248, wherein the patient is a pre-menopausal female of from about 18 to about 48 years of age.
250. The method of any one of claims 161-249, wherein the patient exhibits a serum concentration of FSH of about 20 IU/L or less prior to administration of the GnRH antagonist to the patient.
251. The method of any one of claims 161-250, wherein the patient exhibits a rectal (type II) and/or vaginal (type III) endometriosis node of at least 2 cm prior to administration of the GnRH antagonist to the patient.
252. The method of claim 251, wherein the length of the type II and/or type III endometriosis node is assessed by way of MRI.
253. The method of any one of claims 161-252, wherein the patient exhibits a reduction in serum concentration of LH, FSH, and/or E2 following administration of the GnRH antagonist to the patient.
254. The method of claim 253, wherein the patient exhibits the reduction in serum concentration of LH, FSH, and/or E2 within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
255. The method of any one of claims 161, 162, and 165-254, wherein the patient exhibits a reduction in the volume of one or more rectovaginal endometriosis nodes following administration of the GnRH antagonist to the patient.
256. The method of claim 255, wherein the patient exhibits the reduction in volume of the one or more rectovaginal endometriosis nodes within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
257. The method of any one of claims 163, 164, 255, and 256, wherein the reduction in volume of the one or more rectovaginal endometriosis nodes is assessed by way of MRI or TVUS.
258. The method of any one of claims 161-257, wherein the patient exhibits a reduction in bowel involvement of one or more type III endometriosis nodes following administration of the GnRH antagonist to the patient.
259. The method of claim 258, wherein the patient exhibits the reduction in bowel involvement of the one or more type III endometriosis nodes within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
260. The method of any one of claims 161-164 and 167-259, wherein the patient exhibits a reduction in pelvic pain following administration of the GnRH antagonist to the patient.
261. The method of claim 260, wherein the patient exhibits the reduction in pelvic pain within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
262. The method of any one of claims 165, 166, 260, and 261, wherein the reduction in pelvic pain is assessed by way of an mB&B score, NRS score, or VRS score.
263. The method of any one of claims 161-166 and 169-262, wherein the patient exhibits a reduction in dysmenorrhea following administration of the GnRH antagonist to the patient.
264. The method of claim 263, wherein the patient exhibits the reduction in dysmenorrhea within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
265. The method of any one of claims 167, 168, 263, and 264, wherein the reduction in dysmenorrhea is assessed by way of an mB&B score, NRS score, or VRS score.
266. The method of any one of claims 161-168 and 171-265, wherein the patient exhibits a reduction in dyspareunia following administration of the GnRH antagonist to the patient.
267. The method of claim 266, wherein the patient exhibits the reduction in dyspareunia within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
268. The method of any one of claims 169, 170, 266, and 267, wherein the reduction in dyspareunia is assessed by way of an mB&B score, NRS score, or VRS score.
269. The method of any one of claims 161-170 and 173-268, wherein the patient exhibits a reduction in dyschezia following administration of the GnRH antagonist to the patient.
270. The method of claim 269, wherein the patient exhibits the reduction in dyschezia within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
271. The method of any one of claims 171, 172, 269, and 270, wherein the reduction in dyschezia is assessed by way of an mB&B score, NRS score, or VRS score.
272. The method of any one of claims 161-172 and 175-271, wherein the patient exhibits a reduction in uterine bleeding following administration of the GnRH antagonist to the patient.
273. The method of claim 272, wherein the patient exhibits the reduction in uterine bleeding within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
274. The method of any one of claims 173, 174, 272, and 273, wherein the reduction in uterine bleeding is assessed by way of an alkaline hematin method.
275. The method of any one of claims 161-174 and 177-274, wherein the patient exhibits amenorrhea following administration of the GnRH antagonist to the patient.
276. The method of claim 275, wherein the patient exhibits the amenorrhea within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the amenorrhea within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
277. The method of any one of claims 161-276, wherein the patient exhibits an improvement in EHP-30 score following administration of the GnRH antagonist to the patient.
278. The method of claim 277, wherein the patient exhibits the improvement in the EHP-30 score within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the improvement within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
279. The method of any one of claims 161-278, wherein the patient exhibits a positive PGIC score core following administration of the GnRH antagonist to the patient.
280. The method of claim 279, wherein the patient exhibits the positive PGIC score within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the positive PGIC score within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
281. The method of any one of claims 161-280, wherein the patient does not exhibit a reduction in BMD of greater than 5% following administration of the GnRH antagonist to the patient.
282. The method of claim 281, wherein the patient does not exhibit a reduction in BMD of greater than 1% following administration of the GnRH antagonist to the patient.
283. The method of claim 280 or 281, wherein the BMD is assessed by dual energy X-ray absorptiometry.
284. The method of claim 283, wherein the BMD is assessed in the spine or femur of the patient.
285. The method of claim 281 or 282, wherein the BMD is assessed by comparing the concentration of BAP in a sample isolated from the patient following the administration to the concentration of BAP in a sample isolated from the patient prior to the administration.
286. The method of claim 281 or 282, wherein the BMD is assessed by comparing the concentration of DPD in a sample isolated from the patient following the administration to the concentration of DPD in a sample isolated from the patient prior to the administration.
287. The method of claim 281 or 282, wherein the BMD is assessed by comparing the concentration of CTX in a sample isolated from the patient following the administration to the concentration of CTX in a sample isolated from the patient prior to the administration.
288. The method of claim 281 or 282, wherein the BMD is assessed by comparing the concentration of P1NP in a sample isolated from the patient following the administration to the concentration of P1NP in a sample isolated from the patient prior to the administration.
289. A kit comprising a GnRH antagonist and a package insert instructing a user of the kit to administer the GnRH antagonist to a patient having rectovaginal endometriosis in accordance with the method of any one of claims 161-288.
290. The kit of claim 289, wherein the GnRH antagonist is a compound represented by formula (I) ##STR00652## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof.
291. The kit of claim 290, wherein the ring A is a thiophene ring represented by formula (IIa) ##STR00653##
292. The kit of claim 290 or 291, wherein m is 1.
293. The kit of claim 292, wherein the ring A is an optionally substituted thiophene ring represented by formula (IIb) ##STR00654##
294. The kit of any one of claims 290-293, wherein each R.sup.A is independently a halogen atom, an optionally substituted lower alkyl group, COOW.sup.1, or CONW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group.
295. The kit of claim 294, wherein each R.sup.A is COOH or pharmaceutically acceptable salt thereof.
296. The kit of any one of claims 290-295, wherein ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring.
297. The kit of claim 296, wherein ring B is represented by a formula selected from the group consisting of: ##STR00655##
298. The kit of any one of claims 290-297, wherein n is 2.
299. The kit of claim 298, wherein ring B is represented by a formula selected from the group consisting of: ##STR00656##
300. The kit of any one of claims 290-299, wherein each R.sup.B is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.4, wherein each W.sup.4 is independently a hydrogen atom or an optionally substituted lower alkyl group.
301. The kit of claim 300, wherein each R.sup.B is independently a fluorine atom, chlorine atom, bromine atom, methyl group, or methoxy group.
302. The kit of any one of claims 290-301, wherein U is a single bond.
303. The kit of any one of claims 290-302, wherein X is a group represented by —O-L-Y.
304. The kit of any one of claims 290-303, wherein L is a methylene group.
305. The kit of any one of claims 290-304, wherein Y is an optionally substituted benzene ring represented by formula (V) ##STR00657## wherein each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3.
306. The kit of claim 305, wherein Y is a substituted benzene ring represented by formula (Va) ##STR00658##
307. The kit of claim 306, wherein the compound is represented by formula (Ia) ##STR00659## wherein each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; q is an integer from 0 to 3; each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3; or a pharmaceutically acceptable salt thereof.
308. The kit of claim 307, wherein the compound is represented by formula (Ib) ##STR00660##
309. The kit of claim 308, wherein the compound is represented by formula (Ic) ##STR00661## or a pharmaceutically acceptable salt thereof.
310. The kit of any one of claims 290-309, wherein the compound is represented by formula (VI) ##STR00662## or a pharmaceutically acceptable salt thereof.
311. The kit of claim 310, wherein the compound is the choline salt of the compound represented by formula (VI).
312. The kit of claim 289, wherein the GnRH antagonist is elagolix, relugolix, opigolix (ASP1707), BAY-784, or SK-2706
313. The method of any one of claims 1-136 and 161-288, wherein add-back therapy is administered to the patient.
314. The method of claim 313, wherein the add-back therapy is periodically administered to the patient.
315. The method of claim 313 or 314, wherein the add-back therapy is administered to the patient one or more times daily.
316. The method of claim 315, wherein the add-back therapy is administered to the patient once daily, concurrently with the GnRH antagonist.
317. The method of claim 315, wherein the add-back therapy is administered to the patient once daily, prior to administration of the GnRH antagonist.
318. The method of claim 315, wherein the add-back therapy is administered to the patient once daily, following administration of the GnRH antagonist.
319. The method of claim 318, wherein the add-back therapy is administered to the patient in the form of a pharmaceutical composition comprising the GnRH antagonist.
320. The method of any one of claims 313-319, wherein the add-back therapy comprises an estrogen.
321. The method of claim 320, wherein the estrogen is selected from the group consisting of β17-estradiol, ethinyl estradiol, and conjugated estrogens.
322. The method of claim 321, wherein the estrogen is β17-estradiol.
323. The method of claim 322, wherein the β17-estradiol is administered to the patient in an amount of about 1.0 mg/day.
324. The method of claim 322, wherein the β17-estradiol is administered to the patient in an amount of about 0.5 mg/day.
325. The method of claim 321, wherein the estrogen is ethinyl estradiol.
326. The method of claim 325, wherein the ethinyl estradiol is administered to the patient in an amount of about 5.0 μg/day.
327. The method of claim 325, wherein the ethinyl estradiol is administered to the patient in an amount of about 2.5 μg/day.
328. The method of claim 321, wherein the estrogen is a conjugated estrogen.
329. The method of claim 328, wherein the conjugated estrogen is administered to the patient in an amount of about 0.625 mg/day.
330. The method of claim 328, wherein the conjugated estrogen is administered to the patient in an amount of about 0.45 mg/day.
331. The method of claim 328, wherein the conjugated estrogen is administered to the patient in an amount of about 0.3 mg/day.
332. The method of any one of claims 313-331, wherein the add-back therapy comprises a progestin.
333. The method of claim 332, wherein the progestin is selected from the group consisting of norethindrone or an ester thereof, progesterone, norgestimate, medroxyprogesterone, and drospirenone.
334. The method of claim 333, wherein the progestin is norethindrone or norethindrone acetate.
335. The method of claim 334, wherein the norethindrone or norethindrone acetate is administered to the patient in an amount of about 1.0 mg/day.
336. The method of claim 334, wherein the norethindrone or norethindrone acetate is administered to the patient in an amount of about 0.5 mg/day.
337. The method of claim 334, wherein the norethindrone or norethindrone acetate is administered to the patient in an amount of about 0.1 mg/day.
338. The method of claim 333, wherein the progestin is progesterone.
339. The method of claim 338, wherein the progesterone is administered to the patient in an amount of about 200 mg/day.
340. The method of claim 338, wherein the progesterone is administered to the patient in an amount of about 100 mg/day.
341. The method of claim 333, wherein the progestin is norgestimate.
342. The method of claim 341, wherein the norgestimate is administered to the patient in an amount of about 0.09 mg/day.
343. The method of claim 333, wherein the progestin is medroxyprogesterone.
344. The method of claim 343, wherein the medroxyprogesterone is administered to the patient in an amount of about 5 mg/day.
345. The method of claim 343, wherein the medroxyprogesterone is administered to the patient in an amount of about 2.5 mg/day.
346. The method of claim 343, wherein the medroxyprogesterone is administered to the patient in an amount of about 1.5 mg/day.
347. The method of claim 333, wherein the progestin is drospirenone.
348. The method of claim 347, wherein the drospirenone is administered to the patient in an amount of about 0.5 mg/day.
349. The method of claim 347, wherein the drospirenone is administered to the patient in an amount of about 0.25 mg/day.
350. The method of any one of claims 313-349, wherein the add-back therapy comprises about 1.0 mg of β17-estradiol and about 0.5 mg of norethindrone acetate.
351. The method of any one of claims 313-349, wherein the add-back therapy comprises about 0.5 mg of β17-estradiol and about 0.1 mg of norethindrone acetate.
Description
DETAILED DESCRIPTION
[0629] The present disclosure features compositions and methods for treating adenomyosis and/or rectovaginal endometriosis in a patient, such as a pre-menopausal female human patient. For example, the patient may be presenting with or diagnosed as having adenomyosis, as assessed on the basis of the patient having a junctional-zone width of about 12 mm or more, such as a junctional zone width of from about 12 mm to about 20 mm, as assessed by magnetic resonance imaging (MRI) and/or transvaginal ultrasound (TVUS). In an exemplary case of a patient suffering from rectovaginal endometriosis, the patient may be diagnosed as having this disorder based on a finding that the patient exhibits a rectal (type II) and/or vaginal (type III) endometriosis node of at least 2 cm, such as a rectal (type II) and/or vaginal (type III) endometriosis node of from about 2 cm to about 10 cm, or more. Exemplary qualitative and quantitative scores that can be used to evaluate a patient and determine whether or not the patient is responding to treatment include, without limitation, the patient's Endometriosis Health Profile questionnaire (EHP-30) score, Patient Global Impression of Change (PGIC) score, modified Biberoglu & Behrman (mB&B) score, Numerical Rating Scale (NRS) score, and Verbal Rating Scale (VRS) score.
[0630] The compounds described herein as useful for the treatment of adenomyosis and rectovaginal endometriosis include gonadotropin-releasing hormone (GnRH) antagonists. GnRH antagonists that may be used in conjunction with the compositions and methods described herein include thieno[3,4d]pyrimidine derivatives, such as 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid or a pharmaceutically acceptable salt thereof. Particularly, the GnRH antagonist may be the choline salt thereof. Additional examples of GnRH antagonists that may be used in conjunction with the compositions and methods described herein include optionally substituted 3-aminoalkyl pyrimidine-2,4(1H,3H)-dione derivatives, such as sodium 4-({(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoate, also referred to as elagolix, or the carboxylic acid conjugate thereof, and related compounds described in U.S. Pat. No. 7,056,927, the disclosure of which is incorporated herein by reference in its entirety. Further examples of GnRH antagonists that may be used in conjunction with the compositions and methods described herein include optionally substituted thieno[2,3d]pyrimidine derivatives, such as N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, also referred to as relugolix, or a pharmaceutically acceptable salt thereof, and related compounds described in U.S. Pat. No. 7,300,935, the disclosure of which is incorporated herein by reference in its entirety. Additional examples of GnRH antagonists that may be used in conjunction with the compositions and methods described herein include optionally substituted propane-1,3-dione derivatives, such as (2R)—N-{5-[3-(2,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorobenzene-1-sulfonyl}-2-hydroxypropanimidamide, also referred to as opigolix or ASP-1707, and related compounds described in U.S. Pat. No. 6,960,591, the disclosure of which is incorporated herein by reference in its entirety.
[0631] The GnRH antagonists described herein can provide a variety of therapeutic benefits, including a suppression of endogenous levels of β-17 estradiol (E2), follicle-stimulating hormone (FSH), and/or luteinizing hormone (LH) in a patient exhibiting an elevated serum concentration of one or more of these hormones, as well as a reduction in myometrial invasion by endometrial tissue in patients suffering from adenomyosis and a reduction in endometrial lesion size in patients having rectovaginal endometriosis.
[0632] In addition to treating the underlying causes of adenomyosis and rectovaginal endometriosis, the GnRH antagonists described herein also provide the advantageous therapeutic property of being able to rapidly alleviate the symptoms of these disorders. Adenomyosis and rectovaginal endometriosis are particularly severe endometrial growth pathologies. Adenomyosis, for instance, is a disease in which endometrial glands and stroma invade the uterine myometrium. This penetration of endometrial tissue into the patient's myometrium can cause substantial pain, including global pelvic pain, dysmenorrhea, dyspareunia, and dyschezia. Unlike traditional endometriosis, adenomyosis patients may also exhibit significant uterine blood loss. Rectovaginal endometriosis is another particularly severe endometrial growth disorder in which endometrial tissue extends outside of the uterus and infiltrates rectal and/or vaginal tissue. Patients having rectovaginal endometriosis may experience, for example, endometriosis tissue that penetrates the cervix, as is the case in Type II rectovaginal endometriosis, or may have endometriosis tissue that infiltrates the wall of the rectum or sigmoid, which is diagnostic of Type III rectovaginal endometriosis. The invasion of endometrial tissue into the rectal and vaginal zones causes significant pain, including global pelvic pain, dysmenorrhea, dyspareunia, and dyschezia, and may further result in abnormal uterine bleeding. The GnRH antagonists described herein provide the beneficial feature of being able to suppress these symptoms and enhance the patient's overall quality of life.
[0633] The sections that follow provide a description of the GnRH antagonists that may be used in conjunction with the compositions and methods described herein, as well as a description of diseases that may be treated using these agents.
GnRH Antagonists
Thieno[3,4d]pyrimidines
[0634] GnRH antagonists for use with the compositions and methods described herein include thieno[3,4d]pyrimidine derivatives and variants, such as those described in U.S. Pat. No. 9,040,693, the disclosure of which is incorporated herein by reference in its entirety. Exemplary GnRH antagonists include those represented by formula (I)
##STR00077##
[0635] wherein ring A is a thiophene ring;
[0636] each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group;
[0637] m is an integer from 0 to 3;
[0638] ring B is an aryl group or a monocyclic heteroaryl group;
[0639] each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group;
[0640] n is an integer from 0 to 2;
[0641] U is a single bond;
[0642] X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group;
[0643] Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group;
[0644] Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group;
[0645] or a pharmaceutically acceptable salt thereof.
[0646] In some embodiments, the ring A is a thiophene ring represented by formula (IIa)
##STR00078##
[0647] In some embodiments, m is 1 or 2. In some embodiments, m is 1. For instance, the ring A may be an optionally substituted thiophene ring represented by formula (IIb)
##STR00079##
[0648] Each R.sup.A may independently be, for example, a halogen atom (e.g., fluorine, chlorine, bromine, or iodine), an optionally substituted lower alkyl group, COOW.sup.1, or CONW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group. In some embodiments, each R.sup.A is COOH or pharmaceutically acceptable salt thereof.
[0649] In some embodiments, ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring. For instance, ring B may be represented by a formula selected from the group consisting of:
##STR00080##
[0650] In some embodiments, n is 1 or 2. For instance, in some embodiments, n is 1. Ring B may be, for example, represented by a formula selected from the group consisting of:
##STR00081##
[0651] In some embodiments, each R.sup.B is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.4, wherein each W.sup.4 is independently a hydrogen atom or an optionally substituted lower alkyl group. For instance, each R.sup.B may be independently a fluorine atom, chlorine atom, bromine atom, methyl group, or methoxy group.
[0652] In some embodiments, U is a single bond. X may be, for example, a group represented by —O-L-Y. L may be, for example, a methylene group. In some embodiments, Y is an optionally substituted benzene ring represented by formula (V)
##STR00082##
wherein each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and
[0653] p is an integer from 0 to 3.
[0654] In some embodiments, Y is a substituted benzene ring represented by formula (Va)
##STR00083##
[0655] For example, GnRH antagonists that may be used for the treatment of the endometrial growth disorders described herein include those thieno[3,4d]pyrimidine compounds described in Table 1, below. The synthesis and characterization of these compounds is reported, for instance, in U.S. Pat. No. 9,040,693, incorporated herein by reference.
TABLE-US-00001 TABLE 1 Exemplary Thieno[3,4d]pyrimidine GnRH Antagonists Useful for the Treatment of Adenomyosis and Rectovaginal Endometriosis No. Compound Reported .sup.1H NMR spectral properties 1
[0656] For example, the GnRH antagonist may be 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid, or a pharmaceutically acceptable salt thereof. The salt may be, for instance, the choline salt thereof, represented by formula (Via), below.
##STR00512##
[0657] Compound (VI) and pharmaceutically acceptable salts thereof, such as the choline salt thereof (compound (Via)), can be synthesized, for example, using the methodology described in WO 2014/042176, the disclosure of which is incorporated herein by reference in its entirety. An exemplary synthetic scheme that may be used for the preparation of compound (VI) and the choline salt thereof is shown in Scheme 1, below.
##STR00513##
[0658] wherein R.sub.1 and R.sub.2 are each independently C.sub.1-6 alkoxy groups; LG is a nucleofugal leaving group, such as chlorine or bromine, among others; R.sub.3 represents an optional substituent, such as halogen, acyl group, C.sub.1-6 alkyl group, or a nitro substituent; DMAP denotes N-dimethylaminopyridine; and TEA denotes trimethylamine.
[0659] Crystalline compound (Via) has been characterized spectroscopically, for instance, in U.S. Pat. No. 9,169,266, the disclosure of which is incorporated herein by reference in its entirety. The foregoing crystalline form has been shown to exhibit characteristic X-ray powder diffraction peaks at about 7.1° 2θ, about 11.5° 2θ, about 19.4° 2θ, about 21.5° 2θ, about 22.0° 2θ, about 22.6° 2θ, about 23.5° 2θ, and about 26.2° 2θ. Additionally, this crystalline form exhibits .sup.13C solid-state nuclear magnetic resonance (NMR) peaks centered at about 55.5 ppm, about 57.1 ppm, about 58.7 ppm, about 69.8 ppm, about 98.1 ppm, about 110.3 ppm, about 111.6 ppm, about 113.7 ppm, about 118.0 ppm, about 145.3 ppm, about 149.8 ppm, and about 155.8 ppm. This crystalline form further exhibits .sup.19F solid-state NMR peaks centered at about −151.8 ppm, −145.2 ppm, and −131.6 ppm.
[0660] Compound (VI), as well as pharmaceutically acceptable salts thereof, such as the choline salt thereof, exhibit a high affinity for human GnRH receptor (27.4 nM). Using the compositions and methods described herein, a patient that is presenting with or has been diagnosed as having, adenomyosis or rectovaginal endometriosis may be administered a compound of formula (VI), or a pharmaceutically acceptable salt thereof, such as the choline salt thereof, to treat the disease or ameliorate one or more symptoms of the disease. Exemplary doses of compound (VI) and pharmaceutically acceptable salts thereof, such as the choline salt thereof, include doses of from 25 mg to 500 mg daily, such as doses of 100 mg per day and 200 mg per day. Additional dosing information is provided below.
3-Aminoalkyl pyrimidine-2,4(1H,3H)-diones
[0661] Additional GnRH antagonists that may be used in conjunction with the compositions and methods described herein include optionally substituted 3-aminoalkyl pyrimidine-2,4(1H,3H)-dione derivatives, such as compounds represented by formula (VII)
##STR00514##
[0662] wherein R.sub.1a, R.sub.1b and R.sub.1c are the same or different and are each independently hydrogen, halogen, C.sub.1-4alkyl, hydroxy or alkoxy, or R.sub.1a and R.sub.1b taken together form —OCH.sub.2O— or —OCH.sub.2CH.sub.2—;
[0663] R.sub.2a and R.sub.2b are the same or different and are each independently hydrogen, halogen, trifluoromethyl, cyano or —SO.sub.2CH.sub.3;
[0664] R.sub.3 is hydrogen or methyl;
[0665] R.sub.4 is phenyl or C.sub.3-7alkyl;
[0666] R.sub.5 is hydrogen or C.sub.1-4alkyl;
[0667] R.sub.6 is —COOH or an acid isostere; and
[0668] X is C.sub.1-6alkanediyl optionally substituted with from 1 to 3 C.sub.1-6alkyl groups;
[0669] or a pharmaceutically acceptable salt thereof.
[0670] For example, the GnRH antagonist may be the conjugate acid of elagolix, which is represented by formula (VIII),
##STR00515##
[0671] or a pharmaceutically acceptable salt thereof. In some embodiments, the GnRH antagonist is the sodium salt of the compound represented by formula (VIII), which is represented by formula (IX), below.
##STR00516##
Compound (IX), also referred to as sodium 4-({(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoate, is known as elagolix. Other GnRH antagonists of this chemical class that may be used for the treatment of adenomyosis and/or rectovaginal endometriosis in accordance with the compositions and methods of the disclosure include compounds described in U.S. Pat. No. 7,056,927, the contents of which are incorporated herein by reference. Exemplary GnRH antagonists of this chemical class that may be used for the treatment of adenomyosis and/or rectovaginal endometriosis in accordance with the present disclosure include the compounds set forth in Table 2, below.
TABLE-US-00002 TABLE 2 Exemplary 3-Aminoalkyl pyrimidine-2,4(1H,3H)-dione GnRH Antagonists Useful for the Treatment of Adenomyosis and Rectovaginal Endometriosis No. Compound Reported spectral properties 1
Thieno[2,3d]pyrimidines
[0672] Additional GnRH antagonists that may be used in conjunction with the compositions and methods described herein include optionally substituted thieno[2,3d]pyrimidine derivatives, such as compounds represented by formula (X)
##STR00528##
[0673] wherein R.sup.a is a hydrogen atom, an optionally substituted aryl group (such as an aryl group that may have 1 to 5 substituents selected from halogen, nitro, cyano, amino, a carboxyl group that may be esterified or amidated, an alkylenedioxy, alkyl, alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl), an optionally substituted cycloalkyl group, or an optionally substituted heterocyclic group;
[0674] R.sup.b is an optionally substituted nitrogen-containing heterocyclic group;
[0675] R.sup.c is an optionally substituted amino group;
[0676] R.sup.d is an optionally substituted aryl group;
[0677] p is an integer from 0 to 3; and
[0678] q is an integer from 0 to 3;
[0679] or a pharmaceutically acceptable salt thereof.
[0680] In some embodiments, the GnRH antagonist is a thieno[2,3d]pyrimidine compound represented by formula (XI)
##STR00529##
[0681] wherein R.sup.1 is C.sub.1-4alkyl;
[0682] R.sup.2 is (1) a C.sub.1-6alkyl which may have a substituent selected from the group consisting of (1′) a hydroxy group, (2′) a C.sub.1-4alkoxy, (3′) a C.sub.1-4alkoxy-carbonyl, (4′) a di-C.sub.1-4alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containing heterocyclic group, (6′) a C.sub.1-4alkyl-carbonyl and (7′) a halogen, (2) a C.sub.3-8 cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C.sub.1-4alkyl-carbonylamino, (3) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C.sub.1-4alkyl and (4′) a C.sub.1-4alkoxy, (4) a phenyl which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a C.sub.1-4alkoxy-C.sub.1-4alkyl, (3′) a mono-C.sub.1-4alkyl-carbamoyl-C.sub.1-4alkyl, (4′) a C.sub.1-4alkoxy and (5′) a mono-C.sub.1-4alkylcarbamoyl-C.sub.1-4alkoxy, or (5) a C.sub.1-4alkoxy;
[0683] R.sup.3 is C.sub.1-4alkyl;
[0684] R.sup.4 is (1) hydrogen, (2) C.sub.1-4alkoxy, (3) C.sub.6-10aryl, (4) N—C.sub.1-4alkyl-N—C.sub.1-4alkylsulfonylamino, (5) hydroxyl, or (6) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) oxo, (2′) a C.sub.1-4alkyl, (3′) a hydroxy-C.sub.1-4alkyl, (4′) a C.sub.1-4alkoxy-carbonyl, (5′) a mono-C.sub.1-4alkyl-carbamoyl and (6′) a C.sub.1-4alkylsulfonyl; and
[0685] n is an integer from 1 to 4;
optionally provided that when R.sup.2 is a phenyl which may have a substituent, R.sup.4 is a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1) oxo, (2) hydroxy-C.sub.1-4alkyl, (3) C.sub.1-4alkoxy-carbonyl, (4) mono-C.sub.1-4alkyl-carbamoyl and (5) C.sub.1-4alkylsulfonyl;
[0686] or a pharmaceutically acceptable salt thereof. For example, the GnRH antagonist may be a compound represented by formula (XII), below.
##STR00530##
Compound (XII), also referred to as N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, is known as relugolix. Other GnRH antagonists of this chemical class that may be used for the treatment of adenomyosis and/or rectovaginal endometriosis in accordance with the compositions and methods of the disclosure include compounds described in U.S. Pat. No. 7,300,935, the contents of which are incorporated herein by reference. Exemplary GnRH antagonists of this chemical class that may be used for the treatment of adenomyosis and/or rectovaginal endometriosis in accordance with the present disclosure include the compounds set forth in Table 3, below.
TABLE-US-00003 TABLE 3 Exemplary Thieno[2,3d]pyrimidine GnRH Antagonists Useful for the Treatment of Adenomyosis and Rectovaginal Endometriosis No. Compound Reported spectral properties 1
Propane-1,3-diones
[0687] Additional GnRH antagonists that may be used in conjunction with the compositions and methods described herein include optionally substituted propane-1,3-dione derivatives, such as (2R)—N-{5-[3-(2,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorobenzene-1-sulfonyl}-2-hydroxypropanimidamide, also referred to as opigolix or ASP-1707. Other GnRH antagonists of this chemical class that may be used for the treatment of adenomyosis and/or rectovaginal endometriosis in accordance with the compositions and methods of the disclosure include compounds described in U.S. Pat. No. 6,960,591, the contents of which are incorporated herein by reference.
Add-Back Therapy
[0688] Among the potential side-effects of GnRH antagonist therapy is a reduction in bone mineral density due to excessive depletion of estrogen (Newhall-Perry et al., American Journal of Obstetrics and Gynecology 173:824-829 (1995)). To combat this potential side effect, a patient undergoing GnRH antagonist therapy using the compositions and methods described herein can be administered add-back therapy. Add-back therapy may contain an estrogen (such as β17-estradiol, ethinyl estradiol, or a conjugated estrogen, such as a conjugated equine estrogen) optionally in combination with a progestin (such as norethindrone or an ester thereof, e.g., norethindrone acetate, or another agent such as progesterone, norgestimate, medroxyprogesterone, or drospirenone).
[0689] Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 μg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Circulating estrogens modulate the pituitary secretion of the gonadotropins, LH and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.
[0690] Progestin compounds, such as norethindrone and esters thereof (e.g., norethindrone acetate), as well as progesterone, norgestimate, medroxyprogesterone, and drospirenone, enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone. Progestins may be included in combination with estrogen in add-back therapy. For instance, according to the methods described herein, one can administer estrogen (e.g., E2) in conjunction with a progestin (e.g., norethindrone or an ester thereof, such as norethindrone acetate) to a patient undergoing GnRH antagonist therapy as to counteract the hypoestrogenemia that may be induced by the antagonist. In this way, add-back therapy can be used to mitigate or prevent potentially deleterious side effects, such as a reduction in bone mineral density.
[0691] Add-back therapy may be formulated for oral administration. For instance, add-back therapy administered in conjunction with the compositions and methods described herein may be formulated as a tablet, capsule, gel cap, powder, liquid solution, or liquid suspension. In some embodiments, the add-back therapy includes both an estrogen, such as β17-estradiol, and a progestin, such as norethindrone or norethindrone acetate. The estrogen and progestin may be administered separately or admixed in a single composition, such as a single tablet, capsule, gel cap, powder, liquid solution, or liquid suspension. For example, add-back therapy may feature a co-formulation containing estrogen (e.g., in the form of E2) and an additional agent such as a progestin (e.g., norethindrone or a compound that is metabolized in vivo to produce norethindrone, such as an ester of norethindrone that is de-esterified in vivo to produce norethindrone, for instance, norethindrone acetate). In some embodiments, add-back therapy is administered to a patient in the form of a single tablet, capsule, gel cap, powder, liquid solution, or liquid suspension that contains both estrogen (e.g., in the form of E2) and a progestin (e.g., norethindrone or a compound that is metabolized in vivo to produce norethindrone, such as an ester of norethindrone that is de-esterified in vivo to produce norethindrone, for instance, norethindrone acetate). In some embodiments, add-back therapy is administered as a fixed dose combination containing a GnRH antagonist, estrogen, and one or more additional agents, such as a progestin, in a single pharmaceutical composition. For instance, add-back therapy may be administered as a fixed dose combination of a GnRH antagonist, estrogen (e.g., in the form of E2) and a progestin (e.g., norethindrone or a compound that is metabolized in vivo to produce norethindrone, such as an ester of norethindrone that is de-esterified in vivo to produce norethindrone, for instance, norethindrone acetate) in the form of a single pharmaceutical composition, such as a single tablet, capsule, gel cap, powder, liquid solution, or liquid suspension.
Methods of Treating Adenomyosis and Rectovaginal Endometriosis
[0692] Adenomyosis and rectovaginal endometriosis are estrogen-dependent pathologies that are triggered when endogenous estrogen levels rise beyond a particular threshold level. Taking each condition in turn, the terms “adenomyosis” and “uterine adenomyosis” are used interchangeably to describes the presence of both endometrial glands and stroma deep within the myometrium. This condition is associated with hypertrophy and hyperplasia of the subjacent muscle cells, which may ultimately result in an altered size and globulous morphology of the uterus, although the clinical signs and symptoms are variable. One of the key symptoms of adenomyosis is strong menstrual and even non menstrual pelvic pain with abnormal uterine bleeding.
[0693] There is presently a lack of precise data regarding adenomyosis prevalence among general gynecologic patients. Women are more commonly diagnosed with adenomyosis during the later stages of reproductive age; however the majority of published reports describing adenomyosis prevalence rely on pathologic analysis of surgical specimens. With modern imaging methods like transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI) with T2-weighted images, more detailed evaluation of the changes in the smooth muscle cells is enabled.
[0694] Endometriosis is an estrogen-dependent gynecological condition, defined as the presence of endometrial-like tissue outside the uterus. It is one of the most common gynecological diseases. The condition is predominantly found in women in their reproductive years and disappears spontaneously after menopause. A chronic, inflammatory reaction, induced by the ectopic endometrial cells, results in a variety of pain symptoms including dysmenorrhea, dyspareunia, chronic pelvic pain, dysuria, and dyschezia. In particular, for deep rectovaginal endometriosis, dyschezia may appear due to rectal involvement, and dyspareunia may occur due to the presence of the endometrial lesion in the cul-de-sac and in the vagina. Localized tenderness along the uterosacral ligaments and cul-de-sac is often related to endometrial lesions in these sites.
[0695] The deep rectovaginal form of endometriosis originates most often from the posterior part of the cervix and may infiltrate the anterior wall of the rectum. Endometriosis can be classified based on, for example, MRI and the degree of involvement of the bowel. The pure rectovaginal node, without involvement of the rectum and cervix (type I) accounts for about 12% of cases. Type II rectovaginal endometriosis describes a rectovaginal endometriosis node which is attached to the cervix, and type III rectovaginal endometriosis describes a node which is infiltrating the wall of the rectum or sigmoid.
[0696] Using the compositions and methods described herein, a patient having adenomyosis and/or rectovaginal endometriosis may be administered a GnRH antagonist, such as a compound of formula (I), described above (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid, or a pharmaceutically acceptable salt thereof, such as the choline salt thereof).
[0697] A variety of methods known in the art and described herein can be used to determine whether a patient is responding favorably to GnRH antagonist treatment. For instance, beneficial clinical results in response to GnRH antagonist therapy include, without limitation, alleviation of symptoms of the endometrial growth disorder. Exemplary indicia of successful treatment of an adenomyosis patient that is administered a gonadotropin-releasing hormone (GnRH) antagonist include, without limitation, (i) a reduction in serum concentration of FSH, LH, and/or E2 following administration of the GnRH antagonist to the patient, (ii) a reduction in uterine volume following administration of the GnRH antagonist to the patient, (iii) a reduction in the thickness of the anterior and/or posterior region of the uterine myometrium following administration of the GnRH antagonist to the patient, (iv) a reduction in pelvic pain following administration of the GnRH antagonist to the patient; (v) a reduction in dysmenorrhea following administration of the GnRH antagonist to the patient; (vi) a reduction in dyspareunia following administration of the GnRH antagonist to the patient; (vii) a reduction in dyschezia following administration of the GnRH antagonist to the patient; (viii) a reduction in uterine tenderness following administration of the GnRH antagonist to the patient; (ix) a reduction in uterine bleeding following administration of the GnRH antagonist to the patient; (x) achievement of amenorrhea following administration of the GnRH antagonist to the patient; (xi) a reduction in the diameter of a junctional zone of adenomyosis following administration of the GnRH antagonist to the patient; and (xii) an improvement in the patient's overall well-being as determined by an improvement in the patients Endometriosis Health Profile questionnaire (EHP-30) score following administration of the GnRH antagonist to the patient and/or by way of a positive Patient Global Impression of Change (PGIC) score following administration of the GnRH antagonist to the patient.
[0698] Similarly, exemplary indicia of successful treatment of a rectovaginal endometriosis patient that is administered a GnRH antagonist include, without limitation, (i) a reduction in serum concentration of FSH, LH, and/or E2 following administration of the GnRH antagonist to the patient, (ii) a reduction in the volume of one or more rectovaginal endometriosis nodes following administration of the GnRH antagonist to the patient, (iii) a reduction in bowel involvement of one or more type III endometriosis nodes following administration of the GnRH antagonist to the patient, (iv) a reduction in pelvic pain following administration of the GnRH antagonist to the patient; (v) a reduction in dysmenorrhea following administration of the GnRH antagonist to the patient; (vi) a reduction in dyspareunia following administration of the GnRH antagonist to the patient; (vii) a reduction in dyschezia following administration of the GnRH antagonist to the patient; (viii) a reduction in uterine bleeding following administration of the GnRH antagonist to the patient; (ix) achievement of amenorrhea following administration of the GnRH antagonist to the patient; and (x) an improvement in the patient's overall well-being as determined by an improvement in the patients EHP-30 score following administration of the GnRH antagonist to the patient and/or by way of a positive PGIC score following administration of the GnRH antagonist to the patient.
Modified Biberoglu and Behrman Symptom Severity Scale
[0699] Exemplary methods for assessing a patient's response to GnRH antagonist therapy for the treatment of adenomyosis and/or rectovaginal endometriosis include administration of a modified Biberoglu and Behrman questionnaire, as described herein. An exemplary mB&B questionnaire for use in conjunction with the compositions and methods described herein is shown in Table 4, below.
Endometriosis Health Profile Questionnaire
[0700] Additional methods for assessing patient respond to GnRH antagonist therapy for the treatment of adenomyosis and/or rectovaginal endometriosis include analyzing the patient's score on an Endometriosis Health Profile questionnaire. An exemplary Endometriosis Health Profile questionnaire for use in conjunction with the compositions and methods described herein is the EHP-30 questionnaire shown in Table 5, below.
Patient Global Impression of Change Score
[0701] Additional methods for assessing patient response to GnRH antagonist therapy for the treatment of adenomyosis and/or rectovaginal endometriosis include analyzing the patient's score on a Patient Global Impression of Change (PGIC) scale. An exemplary PGIC questionnaire for use in conjunction with the compositions and methods described herein is shown in Table 6, below.
Quantitation of Uterine Blood Loss by the Alkaline Hematin Method
[0702] Techniques for quantifying uterine blood loss are known in the art and include, for instance, the alkaline hematin method, as described, for instance, in Hallberg et al., Scand. J. Clin. Lab. Invest. 16:244-248 (1964), the disclosure of which is incorporated herein by reference as it pertains to techniques for assessing the volume of blood lost by a patient. In the alkaline hematin approach, uterine blood soaked into, for example, a sanitary napkin, vaginal tampon, or cotton pad, is reconstituted in a basic aqueous solution, such as a solution of 5% (w/v) sodium hydroxide. This incubation enables (i) extraction of the iron-containing porphyrin of hemoglobin and (ii) oxidation of the ferrous ion to a hydroxy-coordinated ferric ion in each chelate, thus forming hematin. Hematin is a detectable chromophore, absorbing light at between 550 and 546 nm. By comparing the concentration of hematin obtained from incubation of a soaked menstrual blood sample with aqueous sodium hydroxide to the concentration of hematin obtained from incubation of a sample of venous blood with aqueous sodium hydroxide, one can stoichiometrically determine the volume of menstrual blood lost by a patient, such as a patient having adenomyosis and/or rectovaginal endometriosis. Improvements to the original alkaline hematin method are known in the art and are described, for example, in Newton et al., Contraception 16:269-282 (1977), and in van Eijkeren et al., Eur. J. Obstet. Gynecol. Reprod. Biol. 22:345-351 (1986), the disclosures of each of which are incorporated herein by reference as they pertain to methods of determining the volume of blood lost by a patient.
Routes of Administration and Dosing of GnRH Antagonists
[0703] The GnRH antagonists described herein may be administered to a patient in need thereof (e.g., a patient suffering from adenomyosis and/or rectovaginal endometriosis) by a variety of routes of administration. For instance, the GnRH antagonists described herein may be formulated for oral administration, among other routes. Exemplary non-oral routes of administration of the GnRH antagonists described herein include, without limitation, intravenous administration, parenteral administration, subcutaneous administration, intramuscular administration, and intradermal administration, among others.
[0704] In some embodiments, the GnRH antagonist is a compound of any one of formulas (I)-(Via), above, and is administered to the patient in an amount of from about 25 mg to about 500 mg per dose, and may be administered in one or more doses per day, for example, in accordance with a dosing schedule described above. For instance, the GnRH antagonist may a compound of any one of formulas (I)-(Via), above, and may be administered to the patient in an amount of from 25 mg to 500 mg, 30 mg to 495 mg, 35 mg to 490 mg, 40 mg to 485 mg, 45 mg to 480 mg, 50 mg to 475 mg, 55 mg to 470 mg, 60 mg to 465 mg, 65 mg to 460 mg, 70 mg to 455 mg, 75 mg to 450 mg, 80 mg to 445 mg, 85 mg to 440 mg, 90 mg to 435 mg, 95 mg to 430 mg, 100 mg to 425 mg, 105 mg to 420 mg, 110 mg to 415 mg, 115 mg to 410 mg, 120 mg to 405 mg, 125 mg to 400 mg, 130 mg to 395 mg, 135 mg to 390 mg, 140 mg to 385 mg, 145 mg to 380 mg, or 150 mg to 375 mg, per dose, and may be administered in one or more doses per day (e.g., in a single daily dose). In some embodiments, the GnRH antagonist is a compound of any one of formulas (I)-(Via), above, and is administered to the patient once daily in an amount of from 100 mg to 300 mg, per dose, such as from 105 mg to 295 mg, 110 mg to 290 mg, 115 mg to 285 mg, 120 mg to 280 mg, 125 mg to 275 mg, 130 mg to 270 mg, 135 mg to 265 mg, 140 mg to 260 mg, 145 mg to 255 mg, 150 mg to 250 mg, 155 mg to 245 mg, 160 mg to 240 mg, 165 mg to 235 mg, 170 mg to 230 mg, 175 mg to 225 mg, 180 mg to 220 mg, 185 mg to 215 mg, 190 mg to 210 mg, or 195 mg to 205 mg, per dose. In some embodiments, the GnRH antagonist is a compound of any one of formulas (I)-(Via), above, and is administered to the patient once daily in an amount of about 100 mg per dose or 200 mg per dose.
[0705] The GnRH antagonists described herein may be administered to a patient a plurality of times over the course of a treatment period. For instance, the GnRH antagonists described herein may be administered to a patient periodically over a treatment period of at least two weeks (e.g., a treatment period of from about two weeks to about six months, about three weeks to about five months, about four weeks to about four months, or about one month to about three months). The GnRH antagonist may be administered to the patient, for example, over a treatment period of from about four weeks to about six months (e.g., from about 28 days to about 180 days, about 30 days to about 175 days, about 35 days to about 170 days, about 40 days to about 165 days, about 45 days to about 160 days, about 50 days to about 155 days, about 55 days to about 150 days, about 60 days to about 145 days, about 65 days to about 140 days, about 70 days to about 135 days, about 75 days, to about 130 days, about 80 days to about 125 days, about 85 days, to about 120 days, or about 90 days to about 115 days). In some embodiments, the GnRH antagonist is periodically administered to the patient over the course of from about eight weeks to about sixteen weeks (e.g., from about 60 days to about 110 days, about 65 days to about 105 days, about 70 days to about 100 days, about 75 days to about 95 days, or about 80 days, to about 90 days). In some embodiments, the GnRH antagonist is periodically administered to the patient over a treatment period of about 12 weeks. In some embodiments, the GnRH antagonist is periodically administered to the patient over a treatment period of about 24 weeks.
[0706] Additional dosing schedules for the treatment of adenomyosis and rectovaginal endometriosis using other GnRH antagonists disclosed herein are described in detail above.
Pharmaceutical Compositions
[0707] GnRH antagonists suitable for use with the compositions and methods described herein can be formulated into a pharmaceutical composition for administration to a patient, such as a female human patient, in a biologically compatible form suitable for administration in vivo. A pharmaceutical composition containing a GnRH antagonist, such as a compound described herein (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid or a pharmaceutically acceptable salt thereof, such as the choline salt thereof), may additionally contain a suitable diluent, carrier, or excipient. GnRH antagonists can be administered to a patient, for example, orally or by intravenous injection. Under ordinary conditions of storage and use, a pharmaceutical composition may contain a preservative, e.g., to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy (2012, 22.sup.nd ed.) and in The United States Pharmacopeia: The National Formulary (2015, USP 38 NF 33).
[0708] Pharmaceutical compositions may include sterile aqueous solutions, dispersions, or powders, e.g., for the extemporaneous preparation of sterile solutions or dispersions. In all cases the form may be sterilized using techniques known in the art and may be fluidized to the extent that may be easily administered to a patient in need of treatment.
[0709] A pharmaceutical composition may be administered to a patient, e.g., a human patient, alone or in combination with one or more pharmaceutically acceptable carriers, e.g., as described herein, the proportion of which may be determined by the solubility and/or chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.
EXAMPLES
[0710] The following examples are put forth so as to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regards as their invention.
Example 1. Use of a GnRH Antagonist for the Treatment of a Patient Having Adenomyosis
[0711] Using the compositions and methods described herein, a patient may be administered a GnRH antagonist so as to treat, and/or ameliorate the symptoms of, adenomyosis. The GnRH antagonist (e.g., a compound of formula (I), above, such as compound (VI) or the choline salt thereof) may be administered to the patient in an amount sufficient to reduce the serum concentration of luteinizing hormone (LH), follicle-stimulating hormone (FHS), and/or β17-estradiol (E2) in circulation. The GnRH antagonist may be administered, for example, in an amount of from about 25 mg to about 500 mg per dose. Exemplary doses of the GnRH antagonist include, without limitation, an amount of from 25 mg to 500 mg, 30 mg to 495 mg, 35 mg to 490 mg, 40 mg to 485 mg, 45 mg to 480 mg, 50 mg to 475 mg, 55 mg to 470 mg, 60 mg to 465 mg, 65 mg to 460 mg, 70 mg to 455 mg, 75 mg to 450 mg, 80 mg to 445 mg, 85 mg to 440 mg, 90 mg to 435 mg, 95 mg to 430 mg, 100 mg to 425 mg, 105 mg to 420 mg, 110 mg to 415 mg, 115 mg to 410 mg, 120 mg to 405 mg, 125 mg to 400 mg, 130 mg to 395 mg, 135 mg to 390 mg, 140 mg to 385 mg, 145 mg to 380 mg, or 150 mg to 375 mg, per dose. For example, when the GnRH antagonist is compound (VI) or the choline salt thereof, the compound may be administered at a dose of 200 mg.
[0712] The GnRH antagonist may be administered to the patient periodically, for instance, over a treatment period of at least two weeks. To determine the responsiveness of the patient to the GnRH antagonist, a physician may monitor the patient's uterine volume, as well as the level of pain experienced by the patient. For example, the physician may observe one or more of the following responses of the patient as an indicator of successful treatment: (i) a reduction in uterine volume following administration of the GnRH antagonist to the patient, (ii) a reduction in the thickness of the anterior and/or posterior region of the uterine myometrium following administration of the GnRH antagonist to the patient, (iii) a reduction in pelvic pain following administration of the GnRH antagonist to the patient; (iv) a reduction in dysmenorrhea following administration of the GnRH antagonist to the patient; (v) a reduction in dyspareunia following administration of the GnRH antagonist to the patient; (vi) a reduction in dyschezia following administration of the GnRH antagonist to the patient; (vii) a reduction in uterine tenderness following administration of the GnRH antagonist to the patient; (viii) a reduction in uterine bleeding following administration of the GnRH antagonist to the patient; (ix) achievement of amenorrhea following administration of the GnRH antagonist to the patient; (x) a reduction in the diameter of a junctional zone of adenomyosis following administration of the GnRH antagonist to the patient; and (xi) an improvement in the patient's overall well-being as determined by an improvement in the patients Endometriosis Health Profile questionnaire (EHP-30) score following administration of the GnRH antagonist to the patient and/or by way of a positive Patient Global Impression of Change (PGIC) score following administration of the GnRH antagonist to the patient.
Example 2. Use of Compound (VI) for the Treatment of a Patient Having Adenomyosis
[0713] This example describes the results of an open-label, Phase II clinical trial examining the safety and efficacy of the GnRH antagonist, compound (VI) (3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid), for treating human female patients suffering from adenomyosis. The study began with a 4-week patient screening period, followed by two consecutive 12-week treatment periods. During the first 12-week treatment period, patients were administered compound (VI) in a single daily dose of 200 mg. During the second 12-week treatment period, patients were administered compound (VI) in a single daily dose of 100 mg. Patients then entered a post-treatment follow-up period during which the effects of compound (VI) were further assessed.
[0714] The sections that follow describe the experimental design of the clinical trial in further detail and provide results for a representative patient.
Study Design
[0715] The total duration of this study (from the screening visit to the end-of-study visit) was 40 weeks per subject. The study began with a 4-week screening period evaluating the symptoms of uterine adenomyosis and assessing the volume of each patient's adenomyosis-affected uterus by way of MRI. During this period, the patients received no study drug.
[0716] At the start of menstruation, the patients were administered 200 mg of compound (VI), once daily, in the form of the corresponding choline salt. The administration continued over the course of a 12-week treatment period, referred to as the “initiation phase,” so as to maximize the effect of the treatment. After the first 12-week treatment period, the therapeutic effect of the GnRH antagonist was maintained by administering 100 mg of compound (VI), once daily, over the course of a second 12-week treatment period. This second treatment period was referred to as the “maintenance phase.”
[0717] At the end of the maintenance phase (at week 24), the patients entered a 12-week follow-up period without any active treatment.
Study Population
[0718] The target population for this study was composed of pre-menopausal women aged 18-48 years with symptomatic uterine adenomyosis and having specified pain symptoms as assessed on the modified Biberoglu & Behrman (mB&B) scale. Patients were subject to the following eligibility criteria:
[0719] Main Inclusion Criteria:
To be eligible for inclusion into this study, patients fulfilled the following inclusion criteria:
1. Patients provided written informed consent prior to initiation of any study related procedures.
2. Patients were pre-menopausal women, aged between 18 and 48 years inclusive at screening.
3. Patients had a history of regular menstrual cycles every 21-35 days and without intermenstrual bleeding heavier than spotting or staining.
4. Patients had Follicle-Stimulating Hormone (FSH) levels≤20 IU/L at screening.
5. Patients had uterine adenomyosis confirmed by MRI with: [0720] Junctional-Zone width on T2 weighted images≥12 mm, and [0721] Moderate to severe pain according to the mB&B classification for two criteria out of deep dyspareunia, pelvic pain or dysmenorrhea, and [0722] Presence of abnormal uterine bleeding.
6. Patients had a Body Mass Index (BMI)≥18 and ≤35 kg/m.sup.2.
7. If of childbearing potential, patients agreed to use one of the following birth control methods during the entire length of the treatment period of the study: [0723] Sexual abstinence from heterosexual intercourse if routinely and consistently practiced [0724] Partner with vasectomy performed at least 6 months prior to the screening visit and with confirmed azoospermia [0725] Double non-hormonal barrier contraception such as condom or diaphragm each combined with spermicide.
8. If of non-childbearing potential, patients had tubal ligation sterilization at least 2 months before the screening visit.
Efficacy Endpoints
[0726] The primary efficacy endpoint of this study was a change, from baseline to week 24, in volume of the adenomyosis-affected uterus, as measured by MRI. Secondary endpoints under investigation in this study were as follows: [0727] Change from baseline to weeks 12 and 36 in volume of the uterus with adenomyosis measured by MRI [0728] Change from baseline to weeks 12, 24 and 36 in volume of the uterus with adenomyosis measured by TVUS [0729] Change from baseline to weeks 12, 24 and 36 in the largest thickness of the anterior and posterior part of the uterus myometrium (sagittal assessment) [0730] Change from baseline to weeks 12, 24 and 36 in the largest diameter of the junctional zone of the uterine adenomyosis measured by MRI [0731] Presence of blood spots on the MRI images [0732] Change from baseline to weeks 12, 24 and 36 in uterus volume assessed at vaginal examination [0733] Change from baseline to weeks 12, 24 and 36 in uterine tenderness assessed at vaginal examination [0734] Change from baseline to weeks 12, 24 and 36 in dysmenorrhea, pelvic pain and dyspareunia according to the mB&B scale [0735] Change from baseline to weeks 4, 8, 12, 16, 20, 24 and 36 for global pelvic pain assessed over the preceding 4-week period using a Numerical Rating Scale (NRS) with a monthly recall [0736] Change from baseline to weeks 4, 8, 12, 16, 20, 24, 28, 32 and 36 in the mean monthly dyspareunia score defined as the mean of available daily dyspareunia scores over the preceding 4-week period assessed on the Verbal Rating Scale (VRS) dyspareunia scale and on a NRS [0737] Change from baseline to weeks 4, 8, 12, 16, 20 and 24 fin the mean monthly dyschezia score defined as the mean of weekly dyschezia scores over the preceding 4-week period using a NRS [0738] No uterine bleeding (or spotting only), during the 4-week period preceding weeks 4, 8, 12, 16, 20 and 24 using a simplified bleeding scale [0739] Time to amenorrhea [0740] Change from baseline to weeks 12, 24 and 36 in the Endometriosis Health Profile questionnaire (EHP-30) [0741] Patient Global Impression of Change (PGIC) score at weeks 12, 24 and 36
Data Analysis and Statistics
[0742] Hypothesis testing was conducted based on change from baseline assessments, testing the null hypothesis of no change from baseline versus the alternative hypothesis of a change (increase/decrease from baseline). Two sided hypotheses tests were carried out, each at a nominal type I error rate (alpha) of 0.05. Calculated p-values were used primarily as a measure of evidence against the null hypothesis rather than just for a formal statement of statistical significance.
[0743] Descriptive statistics were produced for all measured as well as derived endpoints. For continuous data and for ordered categorical data, if appropriate, the number of non-missing observations, mean, standard deviation, median, minimum and maximum were calculated. For ordered categorical data and nominal data, absolute and relative frequencies (in %) were calculated.
Results
[0744] Table 7, below, provides primary and secondary endpoint results for a representative patient in this study. The patient had an age of 42 years, weight of 61.5 kg, and height of 1.74 m at screening. Table 7 shows the patient's reduction in uterine volume from just prior to initiation of 24 weeks of treatment with compound (VI) (“baseline”) to the end of the initiation phase (week 12) and maintenance phase (week 24) of treatment. Table 7 also shows the patient's reduction in pain, as assessed by way of a mB&B score, numerical rating score, EHP-30 score, and PGIC score.
TABLE-US-00004 TABLE 7 Effects of GnRH Antagonist Treatment on Representative Patient Having Adenomyosis Patient Timepoint Characteristic Baseline Week 12 Week 24 Notes Uterus 198 84 75 Volume volume by calculated by MRI (cm.sup.3) radiologist Change from — −114 −123 baseline in uterine volume by MRI (cm.sup.3) Uterus 128 cm.sup.3 48 cm.sup.3 48 cm.sup.3 Volume = volume by Length: Length: Length: l × h × d × transvaginal 6.7 cm 4.5 cm 4.6 cm 0.523 ultrasound Height: Height: Height: (prolate (TVUS) (cm.sup.3) 5.6 cm 4.1 cm 4.0 cm ellipsoid Depth: Depth: Depth: volume) 6.5 cm 5.0 cm 5.0 cm Change from — −79 −79 baseline in uterine volume by TVUS (cm.sup.3) mB&B score 6.0 (Severe) 2.0 (Mild) 2.0 (Mild) Composite Change from — −4 −4 Score (0-15) baseline in None (0) mB&B score Mild (1-2) Moderate (3-5) Severe (6-10) Very severe (11-15) Global pelvic 7 0 1 Scale 0 to 10 pain by 0 (no pain) numerical 10 (worst rating scale pain (NRS) imaginable) Change from — −7 −6 baseline in global pelvic pain by NRS EHP-30 63.6 0.0 6.8 Scale rated 0 Score: Pain to 100 (Questions Each domain 1-11 of EHP- rated 30) independently Change from — −63.6 −56.8 0 = (best baseline in possible EHP-30 score health status for pain as measured by the questionnaire 100 = (worst possible health status as measured by the questionnaire) EHP-30 70.8 0 0 Scale rated 0 Score: to 100 Control and Each domain Powerlessness rated (Questions independently 12-17 of 0 = (best EHP-30) possible Change from — −70.8 −70.8 health status baseline in as measured EHP-30 score by the for control questionnaire and 100 = (worst powerlessness possible health status as measured by the questionnaire) EHP-30 66.7 0 0 Scale rated 0 Score: to 100 Emotional Each domain Well-being rated (Questions independently 18-23 of 0 = (best EHP-30) possible Change from — −66.7 −66.7 health status baseline in as measured EHP-30 score by the for emotional questionnaire well-being 100 = (worst possible health status as measured by the questionnaire) EHP-30 43.8 0 0 Scale rated 0 Score: Social to 100 Support Each domain (Questions rated 24-27 of independently EHP-30) 0 = (best Change from — −43.8 −43.8 possible baseline in health status EHP-30 score as measured for social by the support questionnaire 100 = (worst possible health status as measured by the questionnaire) EHP-30 50.0 0 0 Scale rated 0 Score: to 100 Self-Image (Questions 28-30 of EHP-30) Change from — −50.0 −50.0 Each domain baseline in rated EHP-30 score independently for self-image 0 = (best possible health status as measured by the questionnaire 100 = (worst possible health status as measured by the questionnaire) Patient Global — 1—Very 1—Very Scale rated 1 Impression of much much to 7 Change since improved improved 1 (Very much Baseline improved) (PGIC) 7 (very much worse)
Conclusion
[0745] As shown in Table 7, the results of this study demonstrate that compound (VI) effectuates a sustained reduction in uterine volume, as well as substantial reduction in adenomyosis-associated pain, as assessed by way of various metrics.
Example 3. Use of a GnRH Antagonist for the Treatment of a Patient Having Rectovaginal Endometriosis
[0746] Using the compositions and methods described herein, a patient may be administered a GnRH antagonist so as to treat, and/or ameliorate the symptoms of, rectovaginal endometriosis. The GnRH antagonist (e.g., a compound of formula (I), above, such as compound (VI) or the choline salt thereof) may be administered to the patient in an amount sufficient to reduce the serum concentration of LH, FHS, and/or E2 in circulation. The GnRH antagonist may be administered, for example, in an amount of from about 25 mg to about 500 mg per dose. Exemplary doses of the GnRH antagonist include, without limitation, an amount of from 25 mg to 500 mg, 30 mg to 495 mg, 35 mg to 490 mg, 40 mg to 485 mg, 45 mg to 480 mg, 50 mg to 475 mg, 55 mg to 470 mg, 60 mg to 465 mg, 65 mg to 460 mg, 70 mg to 455 mg, 75 mg to 450 mg, 80 mg to 445 mg, 85 mg to 440 mg, 90 mg to 435 mg, 95 mg to 430 mg, 100 mg to 425 mg, 105 mg to 420 mg, 110 mg to 415 mg, 115 mg to 410 mg, 120 mg to 405 mg, 125 mg to 400 mg, 130 mg to 395 mg, 135 mg to 390 mg, 140 mg to 385 mg, 145 mg to 380 mg, or 150 mg to 375 mg, per dose. For example, when the GnRH antagonist is compound (VI) or the choline salt thereof, the compound may be administered at a dose of 200 mg.
[0747] The GnRH antagonist may be administered to the patient periodically, for instance, over a treatment period of at least two weeks. To determine the responsiveness of the patient to the GnRH antagonist, a physician may monitor the length of one or more rectovaginal endometriosis lesions in the patient, for example, by way of magnetic resonance imaging (MRI) and/or transvaginal ultrasound (TVUS). For example, the physician may observe one or more of the following responses of the patient as an indicator of successful treatment: (i) a reduction in the volume of one or more rectovaginal endometriosis nodes following administration of the GnRH antagonist to the patient, (ii) a reduction in bowel involvement of one or more type III endometriosis nodes following administration of the GnRH antagonist to the patient, (iii) a reduction in pelvic pain following administration of the GnRH antagonist to the patient; (iv) a reduction in dysmenorrhea following administration of the GnRH antagonist to the patient; (v) a reduction in dyspareunia following administration of the GnRH antagonist to the patient; (vi) a reduction in dyschezia following administration of the GnRH antagonist to the patient; (vii) a reduction in uterine bleeding following administration of the GnRH antagonist to the patient; (viii) achievement of amenorrhea following administration of the GnRH antagonist to the patient; and (xi) an improvement in the patient's overall well-being as determined by an improvement in the patients EHP-30 score following administration of the GnRH antagonist to the patient and/or by way of a positive PGIC score following administration of the GnRH antagonist to the patient.
Other Embodiments
[0748] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.
[0749] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the invention that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.
[0750] Other embodiments are within the claims.