US 10,420,768 B2Granted

Pyrrolopyrimidine derivatives as NR2B NMDA receptor antagonists

AssigneeRugen Holdings (Cayman) Limited

InventorGideon Shapiro

Life of this patent

Estimating the term…

Abstract

Disclosed are chemical entities of formula I: wherein X, Y, Z, R1, R3, R4, R5 and R6 are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of formula I, and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of formula I.

Claims10

Dependent claims

A chemical entity selected from the group consisting of:

TABLE 1.C
compound
X
R1
C-1
H
H
C-2
F
H
C-3
Cl
H
C-4
CH3
H
C-5
CF3
H
C-6
CF2H
H
C-7
CH2F
H
C-8
CH2CH3
H
C-9
cyclopropyl
H
C-10
CH3O
H
C-11
CF3O
H
C-12
CHF2O
H
C-13
SCH3
H
C-14
CN
H
C-15
F
F
C-16
Cl
F
C-17
CH3
F
C-18
CF3
F
C-19
CF2H
F
C-20
CH2F
F
C-21
CH2CH3
F
C-22
cyclopropyl
F
C-23
F
Cl
C-24
Cl
Cl
C-25
CH3
Cl
C-26
CF3
Cl
C-27
cyclopropyl
Cl
C-28
F
CH3
C-29
Cl
CH3
C-30
CH3
CH3
C-31
CF3
CH3
C-32
cyclopropyl
CH3
TABLE 2.C
compound
X
R1
R4
R5
C-33
CF3
H
CH3
H
C-34
Cl
H
CH3
H
C-35
CH3
H
CH3
H
C-36
CF3
H
Cl
H
C-37
Cl
H
Cl
H
C-38
CH3
H
Cl
H
C-39
CF3
F
CH3
H
C-40
Cl
F
CH3
H
C-41
CH3
F
CH3
H
C-42
CF3
F
Cl
H
C-43
Cl
F
Cl
H
C-44
CH3
F
Cl
H
C-45
CF3
H
H
CH3
C-46
Cl
H
H
CH3
C-47
CH3
H
H
CH3
TABLE 3.C
compound
X
R2
R3
C-48
F
F
H
C-49
Cl
F
H
C-50
CH3
F
H
C-51
CF3
F
H
C-52
F
CH3
H
C-53
Cl
CH3
H
C-54
CH3
CH3
H
C-55
CF3
CH3
H
C-56
F
Cl
H
C-57
Cl
Cl
H
C-58
CH3
Cl
H
C-59
CF3
Cl
F
C-60
F
H
F
C-61
Cl
H
F
C-62
CH3
H
F
C-63
CF3
H
Cl
C-64
F
H
Cl
C-65
Cl
H
Cl
C-66
CH3
H
Cl
C-67
CF3
H
CH3
C-68
F
H
CH3
C-69
Cl
H
CH3
C-70
CH3
H
CH3
TABLE 4.C
compound
X
R1
R6
C-71
F
H
CH3
C-72
Cl
H
CH3
C-73
CH3
H
CH3
C-74
CF3
H
CH3
C-75
CF2H
H
CH3
C-76
CH2F
H
CH3
C-77
OCF3
H
CH3
C-78
OCF2H
H
CH3
C-79
CH2CH3
H
CH3
C-80
cyclopropyl
H
CH3
C-81
F
H
F
C-82
Cl
H
F
C-83
CH3
H
F
C-84
CF3
H
F
C-85
CF2H
H
F
C-86
CH2F
H
F
C-87
OCF3
H
F
C-88
OCF2H
H
F
C-89
CH2CH3
H
F
C-90
cyclopropyl
H
F
C-91
F
F
CH3
C-92
Cl
F
CH3
C-93
CH3
F
CH3
C-94
CF3
F
CH3
C-95
F
F
F
C-96
Cl
F
F
C-97
CH3
F
F
C-98
CF3
F
F
TABLE 5.C
compound
X
R1
R6
C-99
F
H
CH3
C-100
Cl
H
CH3
C-101
CH3
H
CH3
C-102
CF3
H
CH3
C-103
CF2H
H
CH3
C-104
CH2F
H
CH3
C-105
OCF3
H
CH3
C-106
OCF2H
H
CH3
C-107
CH2CH3
H
CH3
C-108
cyclopropyl
H
CH3
C-109
F
H
F
C-110
Cl
H
F
C-111
CH3
H
F
C-112
CF3
H
F
C-113
CF2H
H
F
C-114
CH2F
H
F
C-115
OCF3
H
F
C-116
OCF2H
H
F
C-117
CH2CH3
H
F
C-118
cyclopropyl
H
F
C-119
F
F
CH3
C-120
Cl
F
CH3
C-121
CH3
F
CH3
C-122
CF3
F
CH3
C-123
F
F
F
C-124
Cl
F
F
C-125
CH3
F
F
C-126
CF3
F
F
TABLE 6.C
compound
X
R1
R2
R3
C-127
CF3
H
H
H
C-128
CH3
H
H
H
C-129
F
H
H
H
C-130
Cl
H
H
H
C-131
OCH3
H
H
H
C-132
OCF3
H
H
H
C-133
SCH3
H
H
H
C-134
CH2CH3
H
H
H
C-135
cyclopropyl
H
H
H
C-136
CF3
F
H
H
C-137
CF3
H
F
H
C-138
CF3
H
H
F
C-139
H
CF3
H
H
C-140
H
H
CF3
H
C-141
H
H
H
CF3
TABLE 7.C
compound
X
R4
R6
C-142
CF3
CH3
H
C-143
CH3
CH3
H
C-144
CF3
H
F
C-145
CH3
H
F
C-146
CH2CH3
H
F
C-147
SCH3
H
F
C-148
cyclopropyl
H
F
C-149
OCF3
H
F
C-150
OCH3
H
F
C-151
CF3
H
CH3
C-152
CH3
H
CH3
C-153
CH2CH3
H
CH3
C-154
SCH3
H
CH3
C-155
cyclopropyl
H
CH3
C-156
OCF3
H
CH3
C-157
OCH3
H
CH3
TABLE 8.C
compound
X
R4
R6
C-158
CF3
Cl
H
C-159
CH3
Cl
H
C-160
CF3
H
F
C-161
CH3
H
F
C-162
CH2CH3
H
F
C-163
SCH3
H
F
C-164
cyclopropyl
H
F
C-165
OCF3
H
F
C-166
OCH3
H
F
C-167
CF3
H
CH3
C-168
CH3
H
CH3
C-169
CH2CH3
H
CH3
C-170
SCH3
H
CH3
C-171
cyclopropyl
H
CH3
C-172
OCF3
H
CH3
C-173
OCH3
H
CH3
TABLE 9.C
compound
X
R1
C-174
H
H
C-175
F
H
C-176
Cl
H
C-177
CH3
H
C-178
CF3
H
C-179
CF2H
H
C-180
CH2F
H
C-181
CH2CH3
H
C-182
cyclopropyl
H
C-183
CH3O
H
C-184
CF3O
H
C-185
CHF2O
H
C-186
SCH3
H
C-187
CN
H
C-188
F
F
C-189
Cl
F
C-190
CH3
F
C-191
CF3
F
C-192
CF2H
F
C-193
CH2F
F
C-194
CH2CH3
F
C-195
cyclopropyl
F
C-196
F
Cl
C-197
Cl
Cl
C-198
CH3
Cl
C-199
CF3
Cl
C-200
cyclopropyl
Cl
C-201
F
CH3
C-202
Cl
CH3
C-203
CH3
CH3
C-204
CF3
CH3
C-205
cyclopropyl
CH3
TABLE 10.C
compound
X
R2
R3
C-206
F
F
H
C-207
Cl
F
H
C-208
CH3
F
H
C-209
CF3
F
H
C-210
F
CH3
H
C-211
Cl
CH3
H
C-212
CH3
CH3
H
C-213
CF3
CH3
H
C-214
F
Cl
H
C-215
Cl
Cl
H
C-216
CH3
Cl
H
C-217
CF3
Cl
F
C-218
F
H
F
C-219
Cl
H
F
C-220
CH3
H
F
C-221
CF3
H
Cl
C-222
F
H
Cl
C-223
Cl
H
Cl
C-224
CH3
H
Cl
C-225
CF3
H
CH3
C-226
F
H
CH3
C-227
Cl
H
CH3
C-228
CH3
H
CH3
TABLE 11.C
compound
X
R4
C-229
CF3
H
C-230
CH3
H
C-231
Cl
H
C-232
F
H
C-233
CF2H
H
C-234
OCF3
H
C-235
OCF2H
H
C-236
CH2CH3
H
C-237
cyclopropyl
H
C-238
isopropyl
H
C-239
CF3
CH3
C-240
CH3
CH3
C-241
CH2CH3
CH3
C-242
cyclopropyl
CH3
C-243
isopropyl
CH3
C-244
OCF3
CH3
or a pharmaceutically acceptable salt thereof.

978 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/961,553Filed 24 Apr 2018 · division
Priority: 15 Sep 2014
Published: US 2018/0303834 A125 Oct 2018
Granted: 24 Sep 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification16 codes

A61K 31/519
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with heterocyclic rings
A61K 9/0053
Galenical forms characterised by the site of application: mouth and digestive tract, i.e. intraoral and peroral administration
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 25/00
Drugs for disorders of the nervous system

Family

Application62/050,692Us provisional application · filed 15 Sep 2014
Application14/855,010Parent of this division · filed 15 Sep 2015
Application15/428,321Parent of this division · filed 9 Feb 2017
US 9,567,341 B2Parent of this division · filed 14 Feb 2017
US 2018/0303834 A1Pre-grant publication · published 25 Oct 2018
US 9,968,610 B2Parent of this division
US 2016/0075713 A1Published application
US 2017/0209449 A1Published application
US 10,420,768 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A chemical entity selected from the group consisting of:

TABLE 1.C
compound
X
R1
C-1
H
H
C-2
F
H
C-3
Cl
H
C-4
CH3
H
C-5
CF3
H
C-6
CF2H
H
C-7
CH2F
H
C-8
CH2CH3
H
C-9
cyclopropyl
H
C-10
CH3O
H
C-11
CF3O
H
C-12
CHF2O
H
C-13
SCH3
H
C-14
CN
H
C-15
F
F
C-16
Cl
F
C-17
CH3
F
C-18
CF3
F
C-19
CF2H
F
C-20
CH2F
F
C-21
CH2CH3
F
C-22
cyclopropyl
F
C-23
F
Cl
C-24
Cl
Cl
C-25
CH3
Cl
C-26
CF3
Cl
C-27
cyclopropyl
Cl
C-28
F
CH3
C-29
Cl
CH3
C-30
CH3
CH3
C-31
CF3
CH3
C-32
cyclopropyl
CH3
TABLE 2.C
compound
X
R1
R4
R5
C-33
CF3
H
CH3
H
C-34
Cl
H
CH3
H
C-35
CH3
H
CH3
H
C-36
CF3
H
Cl
H
C-37
Cl
H
Cl
H
C-38
CH3
H
Cl
H
C-39
CF3
F
CH3
H
C-40
Cl
F
CH3
H
C-41
CH3
F
CH3
H
C-42
CF3
F
Cl
H
C-43
Cl
F
Cl
H
C-44
CH3
F
Cl
H
C-45
CF3
H
H
CH3
C-46
Cl
H
H
CH3
C-47
CH3
H
H
CH3
TABLE 3.C
compound
X
R2
R3
C-48
F
F
H
C-49
Cl
F
H
C-50
CH3
F
H
C-51
CF3
F
H
C-52
F
CH3
H
C-53
Cl
CH3
H
C-54
CH3
CH3
H
C-55
CF3
CH3
H
C-56
F
Cl
H
C-57
Cl
Cl
H
C-58
CH3
Cl
H
C-59
CF3
Cl
F
C-60
F
H
F
C-61
Cl
H
F
C-62
CH3
H
F
C-63
CF3
H
Cl
C-64
F
H
Cl
C-65
Cl
H
Cl
C-66
CH3
H
Cl
C-67
CF3
H
CH3
C-68
F
H
CH3
C-69
Cl
H
CH3
C-70
CH3
H
CH3
TABLE 4.C
compound
X
R1
R6
C-71
F
H
CH3
C-72
Cl
H
CH3
C-73
CH3
H
CH3
C-74
CF3
H
CH3
C-75
CF2H
H
CH3
C-76
CH2F
H
CH3
C-77
OCF3
H
CH3
C-78
OCF2H
H
CH3
C-79
CH2CH3
H
CH3
C-80
cyclopropyl
H
CH3
C-81
F
H
F
C-82
Cl
H
F
C-83
CH3
H
F
C-84
CF3
H
F
C-85
CF2H
H
F
C-86
CH2F
H
F
C-87
OCF3
H
F
C-88
OCF2H
H
F
C-89
CH2CH3
H
F
C-90
cyclopropyl
H
F
C-91
F
F
CH3
C-92
Cl
F
CH3
C-93
CH3
F
CH3
C-94
CF3
F
CH3
C-95
F
F
F
C-96
Cl
F
F
C-97
CH3
F
F
C-98
CF3
F
F
TABLE 5.C
compound
X
R1
R6
C-99
F
H
CH3
C-100
Cl
H
CH3
C-101
CH3
H
CH3
C-102
CF3
H
CH3
C-103
CF2H
H
CH3
C-104
CH2F
H
CH3
C-105
OCF3
H
CH3
C-106
OCF2H
H
CH3
C-107
CH2CH3
H
CH3
C-108
cyclopropyl
H
CH3
C-109
F
H
F
C-110
Cl
H
F
C-111
CH3
H
F
C-112
CF3
H
F
C-113
CF2H
H
F
C-114
CH2F
H
F
C-115
OCF3
H
F
C-116
OCF2H
H
F
C-117
CH2CH3
H
F
C-118
cyclopropyl
H
F
C-119
F
F
CH3
C-120
Cl
F
CH3
C-121
CH3
F
CH3
C-122
CF3
F
CH3
C-123
F
F
F
C-124
Cl
F
F
C-125
CH3
F
F
C-126
CF3
F
F
TABLE 6.C
compound
X
R1
R2
R3
C-127
CF3
H
H
H
C-128
CH3
H
H
H
C-129
F
H
H
H
C-130
Cl
H
H
H
C-131
OCH3
H
H
H
C-132
OCF3
H
H
H
C-133
SCH3
H
H
H
C-134
CH2CH3
H
H
H
C-135
cyclopropyl
H
H
H
C-136
CF3
F
H
H
C-137
CF3
H
F
H
C-138
CF3
H
H
F
C-139
H
CF3
H
H
C-140
H
H
CF3
H
C-141
H
H
H
CF3
TABLE 7.C
compound
X
R4
R6
C-142
CF3
CH3
H
C-143
CH3
CH3
H
C-144
CF3
H
F
C-145
CH3
H
F
C-146
CH2CH3
H
F
C-147
SCH3
H
F
C-148
cyclopropyl
H
F
C-149
OCF3
H
F
C-150
OCH3
H
F
C-151
CF3
H
CH3
C-152
CH3
H
CH3
C-153
CH2CH3
H
CH3
C-154
SCH3
H
CH3
C-155
cyclopropyl
H
CH3
C-156
OCF3
H
CH3
C-157
OCH3
H
CH3
TABLE 8.C
compound
X
R4
R6
C-158
CF3
Cl
H
C-159
CH3
Cl
H
C-160
CF3
H
F
C-161
CH3
H
F
C-162
CH2CH3
H
F
C-163
SCH3
H
F
C-164
cyclopropyl
H
F
C-165
OCF3
H
F
C-166
OCH3
H
F
C-167
CF3
H
CH3
C-168
CH3
H
CH3
C-169
CH2CH3
H
CH3
C-170
SCH3
H
CH3
C-171
cyclopropyl
H
CH3
C-172
OCF3
H
CH3
C-173
OCH3
H
CH3
TABLE 9.C
compound
X
R1
C-174
H
H
C-175
F
H
C-176
Cl
H
C-177
CH3
H
C-178
CF3
H
C-179
CF2H
H
C-180
CH2F
H
C-181
CH2CH3
H
C-182
cyclopropyl
H
C-183
CH3O
H
C-184
CF3O
H
C-185
CHF2O
H
C-186
SCH3
H
C-187
CN
H
C-188
F
F
C-189
Cl
F
C-190
CH3
F
C-191
CF3
F
C-192
CF2H
F
C-193
CH2F
F
C-194
CH2CH3
F
C-195
cyclopropyl
F
C-196
F
Cl
C-197
Cl
Cl
C-198
CH3
Cl
C-199
CF3
Cl
C-200
cyclopropyl
Cl
C-201
F
CH3
C-202
Cl
CH3
C-203
CH3
CH3
C-204
CF3
CH3
C-205
cyclopropyl
CH3
TABLE 10.C
compound
X
R2
R3
C-206
F
F
H
C-207
Cl
F
H
C-208
CH3
F
H
C-209
CF3
F
H
C-210
F
CH3
H
C-211
Cl
CH3
H
C-212
CH3
CH3
H
C-213
CF3
CH3
H
C-214
F
Cl
H
C-215
Cl
Cl
H
C-216
CH3
Cl
H
C-217
CF3
Cl
F
C-218
F
H
F
C-219
Cl
H
F
C-220
CH3
H
F
C-221
CF3
H
Cl
C-222
F
H
Cl
C-223
Cl
H
Cl
C-224
CH3
H
Cl
C-225
CF3
H
CH3
C-226
F
H
CH3
C-227
Cl
H
CH3
C-228
CH3
H
CH3
TABLE 11.C
compound
X
R4
C-229
CF3
H
C-230
CH3
H
C-231
Cl
H
C-232
F
H
C-233
CF2H
H
C-234
OCF3
H
C-235
OCF2H
H
C-236
CH2CH3
H
C-237
cyclopropyl
H
C-238
isopropyl
H
C-239
CF3
CH3
C-240
CH3
CH3
C-241
CH2CH3
CH3
C-242
cyclopropyl
CH3
C-243
isopropyl
CH3
C-244
OCF3
CH3
or a pharmaceutically acceptable salt thereof.

978 more elements

Facts

Application

15/961,553Filed 24 Apr 2018 · division

Priority

15 Sep 2014

Published

US 2018/0303834 A125 Oct 2018

Granted

24 Sep 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification16 codes

A61K 31/519
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with heterocyclic rings
A61K 9/0053
Galenical forms characterised by the site of application: mouth and digestive tract, i.e. intraoral and peroral administration
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 25/00
Drugs for disorders of the nervous system

Family

Application62/050,692Us provisional application · filed 15 Sep 2014

Application14/855,010Parent of this division · filed 15 Sep 2015

Application15/428,321Parent of this division · filed 9 Feb 2017

US 9,567,341 B2Parent of this division · filed 14 Feb 2017

US 2018/0303834 A1Pre-grant publication · published 25 Oct 2018

US 9,968,610 B2Parent of this division

US 2016/0075713 A1Published application

US 2017/0209449 A1Published application

US 10,420,768 B2This patent

From the US filing history. Foreign family members aren’t listed.