US2013158024A1PendingUtilityA1
Tricyclic necrostatin compounds
Est. expiryDec 20, 2025(expired)· nominal 20-yr term from priority
A61P 43/00A61P 9/00A61P 35/00A61P 25/28A61P 25/00C07D 491/052C07D 495/04A61P 1/16C07D 231/54A61K 31/4178C07D 403/06A61P 13/12Y02A50/30
46
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Claims
Abstract
The present invention features compounds, pharmaceutical compositions, and methods for treating trauma, ischemia, stroke, degenerative diseases associated with cellular necrosis, and other conditions. Screening assays for identifying compounds useful for treating these conditions are also described.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A Nec-3 compound of formula (VI):
or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
Z is CH 2 ;
the bond indicated by (a) can be a single or double bond;
R 1 is hydrogen, alkanoyl of one to six carbon atoms; alkoxy of one to six carbon atoms; alkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; alkylsulfinyl of one to six carbon atoms; alkylsulfinylalkyl, wherein the alkyl and alkylene groups are independently of from one to six carbon atoms; alkylsulfonyl of one to six carbon atoms; alkylsulfonylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; C 7-16 aralkyl; amino; aminoalkyl of one to six carbon atoms; C 6 or C 10 aryl; C 7 or C 11 aryloyl; azido; azidoalkyl of one to six carbon atoms; carboxaldehyde; (carboxaldehyde)alkyl, wherein the alkylene group is of one to six carbon atoms; cycloalkyl of three to eight carbon atoms; cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms and the alkylene group is of one to ten carbon atoms; halo; haloalkyl of one to six carbon atoms; C 2-9 heterocyclyl; C 2-9 (heterocyclyl)oxy; C 3-10 (heterocyclyl)oyl; hydroxyl; hydroxyalkyl of one to six carbon atoms; nitro; nitroalkyl of one to six carbon atoms; N-protected amino; N-protected aminoalkyl, wherein the alkylene group is of one to six carbon atoms; thioalkoxy of one to six carbon atoms; thioalkoxyalkyl, wherein the alkyl and alkylene groups are independently of from one to six carbon atoms; —(CH 2 ) q CO 2 R A , wherein q is zero to four and R A is selected from the group consisting of (a) C 1-6 alkyl, (b) C 6 or C 10 aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH 2 ) q CONR B R C , wherein R B and R C are independently selected from the group consisting of (a) hydrogen, (b) C 1-6 alkyl, (c) C 6 or C 10 aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH 2 ) q SO 2 R D , wherein R D is selected from the group consisting of (a) C 1-6 alkyl, (b) C 6 or C 10 aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH 2 ) q SO 2 NR E R F , wherein R E and R F are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) C 6 or C 10 aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH 2 ) q NR G R H , wherein R G and R H are independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) C 6 or C 10 aryl; (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; C 1-6 perfluoroalkyl; C 1-6 perfluoroalkoxy; C 6 or C 10 aryloxy; C 3-8 cycloalkoxy; C 9-14 cycloalkylalkoxy; or C 7-16 arylalkoxy;
each of R 2 , R 4 , R 7 , R 8 , R 10 , and R 11 , independently, represents hydrogen, alkanoyl of one to six carbon atoms; alkyl of one to six carbon atoms; alkoxy of one to six carbon atoms; alkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; alkylsulfinyl of one to six carbon atoms; alkylsulfinylalkyl, wherein the alkyl and alkylene groups are independently of from one to six carbon atoms; alkylsulfonyl of one to six carbon atoms; alkylsulfonylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; C 7-16 aralkyl; amino; aminoalkyl of one to six carbon atoms; C 6 or C 10 aryl; C 7 or C 11 aryloyl; azido; azidoalkyl of one to six carbon atoms; carboxaldehyde; (carboxaldehyde)alkyl, wherein the alkylene group is of one to six carbon atoms; cycloalkyl of three to eight carbon atoms; cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms and the alkylene group is of one to ten carbon atoms; halo; haloalkyl of one to six carbon atoms; C 2-9 heterocyclyl; C 2-9 (heterocyclyl)oxy; C 3-10 (heterocyclyl)oyl; hydroxyl; hydroxyalkyl of one to six carbon atoms; nitro; nitroalkyl of one to six carbon atoms; N-protected amino; N-protected aminoalkyl, wherein the alkylene group is of one to six carbon atoms; thioalkoxy of one to six carbon atoms; thioalkoxyalkyl, wherein the alkyl and alkylene groups are independently of from one to six carbon atoms; —(CH 2 ) q CO 2 R A , wherein q is zero to four and R A is selected from the group consisting of (a) C 1-6 alkyl, (b) C 6 or C 10 aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH 2 ) q CONR B R C , wherein R B and R C are independently selected from the group consisting of (a) hydrogen, (b) C 1-6 alkyl, (c) C 6 or C 10 aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH 2 ) q SO 2 R D , wherein R D is selected from the group consisting of (a) C 1-6 alkyl, (b) C 6 or C 10 aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH 2 ) q SO 2 NR E R F , wherein R E and R F are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) C 6 or C 10 aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH 2 ) q NR G R H , wherein R G and R H are independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) C 6 or C 10 aryl; (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; C 1-6 perfluoroalkyl; C 1-6 perfluoroalkoxy; C 6 or C 10 aryloxy; C 3-8 cycloalkoxy; C 9-14 cycloalkylalkoxy; or C 7-16 arylalkoxy;
R 3 is alkyl of one to six carbon atoms; alkoxy of one to six carbon atoms; halo; or amino;
R 9 is alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms;
R 5 is C(O)R 13 , C(S)R 13 , C(O)OR 13 , C(O)NR 13 R 14 , C(S)NR 13 R 14 , C(NH)R 13 , or S(O 2 )R 13 , wherein each of R 13 and R 14 , independently, represents hydrogen, an optionally substituted C 1-12 alkyl, an optionally substituted C 1-7 heteroalkyl, an optionally substituted C 6 or C 10 aryl, an optionally substituted C 2-9 heteroaryl, an optionally substituted C 7-16 aralkyl, or an optionally substituted C 2-15 heteroaralkyl; and
R 6 is hydrogen, C 1-6 alkyl, an optionally substituted C 6 or C 10 aryl, an optionally substituted C 7-16 aralkyl, an optionally substituted C 2-9 heteroaryl, or an optionally substituted C 2-15 heteroaralkyl, wherein when each of R 1 , R 2 , R 4 , and R 6 through R 11 is selected from the group consisting of hydrogen, amino, halide, and hydroxyl and Z is CH 2 , R 3 is not hydroxyl or methoxyl.
2 . The Nec-3 compound of claim 1 , wherein said Nec-3 compound is a substantially pure (3R,3aR)-rel isomer,
or a pharmaceutically acceptable salt thereof.
3 . The Nec-3 compound of claim 2 , wherein R 5 is —C(O)R 13 , and R 13 is substituted C 1-12 alkyl,
or a pharmaceutically acceptable salt thereof.
4 . The Nec-3 compound of claim 2 , wherein said Nec-3 compound is a substantially pure (3R,3aR)-enantiomer,
or a pharmaceutically acceptable salt thereof.
5 . The Nec-3 compound of claim 2 , wherein said Nec-3 compound is a substantially pure (3S,3aS)-enantiomer,
or a pharmaceutically acceptable salt thereof.
6 . The Nec-3 compound of claim 2 , wherein
the bond indicated by (a) is a double bond; Z is CH 2 ; and each of R 1 , R 2 , R 4 , R 6 , R 7 , R 10 , and R 11 , independently, represents hydrogen, or a pharmaceutically acceptable salt thereof.
7 . The Nec-3 compound of claim 6 , wherein
R 8 is H, or a pharmaceutically acceptable salt thereof.
8 . The Nec-3 compound of claim 2 , wherein
R 3 represents methoxyl; R 5 represents C(O)CH 2 OH; and R 9 represents alkoxy of one to six carbon atoms, a pharmaceutically acceptable salt thereof.
9 . A Nec-3 compound of formula (VI):
or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof wherein
said Nec-3 compound is a substantially pure (3R,3aR)-rel isomer;
Z is CH 2 CH 2 ;
the bond indicated by (a) can be a single or double bond;
each of R 1 , R 2 , R 4 , R 7 , R 8 , R 10 , and R 11 , independently, represents hydrogen, alkanoyl of one to six carbon atoms; alkyl of one to six carbon atoms; alkoxy of one to six carbon atoms; alkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; alkylsulfinyl of one to six carbon atoms; alkylsulfinylalkyl, wherein the alkyl and alkylene groups are independently of from one to six carbon atoms; alkylsulfonyl of one to six carbon atoms; alkylsulfonylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; C 7-16 aralkyl; amino; aminoalkyl of one to six carbon atoms; C 6 or C 10 aryl; C 7 or C 11 aryloyl; azido; azidoalkyl of one to six carbon atoms; carboxaldehyde; (carboxaldehyde)alkyl, wherein the alkylene group is of one to six carbon atoms; cycloalkyl of three to eight carbon atoms; cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms and the alkylene group is of one to ten carbon atoms; halo; haloalkyl of one to six carbon atoms; C 2-9 heterocyclyl; C 2-9 (heterocyclyl)oxy; C 3-10 (heterocyclyl)oyl; hydroxyl; hydroxyalkyl of one to six carbon atoms; nitro; nitroalkyl of one to six carbon atoms; N-protected amino; N-protected aminoalkyl, wherein the alkylene group is of one to six carbon atoms; thioalkoxy of one to six carbon atoms; thioalkoxyalkyl, wherein the alkyl and alkylene groups are independently of from one to six carbon atoms; —(CH 2 ) q CO 2 R A , wherein q is zero to four and R A is selected from the group consisting of (a) C 1-6 alkyl, (b) C 6 or C 10 aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH 2 ) q CONR B R C , wherein R B and R C are independently selected from the group consisting of (a) hydrogen, (b) C 1-6 alkyl, (c) C 6 or C 10 aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH 2 ) q SO 2 R D , wherein R D is selected from the group consisting of (a) C 1-6 alkyl, (b) C 6 or C 10 aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH 2 ) q SO 2 NR E R F , wherein R E and R F are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) C 6 or C 10 aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH 2 ) q NR G R H , wherein R G and R H are independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) C 6 or C 10 aryl; (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; C 1-6 perfluoroalkyl; C 1-6 perfluoroalkoxy; C 6 or C 10 aryloxy; C 3-8 cycloalkoxy; C 9-14 cycloalkylalkoxy; or C 7-16 arylalkoxy;
R 3 is alkoxy of one to six carbon atoms; halo; or amino;
R 9 is alkyl of one to six carbon atoms; alkoxy of one to six carbon atoms; or halo;
R 5 is C(O)R 13 , C(S)R 13 , C(O)OR 13 , C(O)NR 13 R 14 , C(S)NR 13 R 14 , C(NH)R 13 , or S(O 2 )R 13 , wherein each of R 13 and R 14 , independently, represents hydrogen, an optionally substituted C 1-12 alkyl, an optionally substituted C 1-7 heteroalkyl, an optionally substituted C 6 or C 10 aryl, an optionally substituted C 2-9 heteroaryl, an optionally substituted C 7-16 aralkyl, or an optionally substituted C 2-15 heteroaralkyl; and
R 6 is hydrogen, C 1-6 alkyl, an optionally substituted C 6 or C 10 aryl, an optionally substituted C 7-16 aralkyl, an optionally substituted C 2-9 heteroaryl, or an optionally substituted C 2-15 heteroaralkyl, wherein when each of R 1 , R 2 , R 4 , and R 6 through R 11 is selected from the group consisting of hydrogen, amino, halide, and hydroxyl and Z is CH 2 , R 3 is not hydroxyl or methoxyl.
10 . The Nec-3 compound of claim 9 , wherein said Nec-3 compound is a substantially pure (3R,3aR)-enantiomer,
or a pharmaceutically acceptable salt thereof.
11 . The Nec-3 compound of claim 9 , wherein said Nec-3 compound is a substantially pure (3S,3aS)-enantiomer,
or a pharmaceutically acceptable salt thereof.
12 . A pharmaceutical composition comprising:
(i) the compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable excipient.
13 . A pharmaceutical composition comprising:
(i) the compound of claim 2 , or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable excipient.
14 . The pharmaceutical composition of claim 13 , wherein
the bond indicated by (a) is a double bond; Z is CH 2 ; and each of R 1 , R 2 , R 4 , R 6 , R 7 , R 10 , and R 11 , independently, represents hydrogen, or a pharmaceutically acceptable salt thereof.
15 . The pharmaceutical composition of claim 14 , wherein
R 8 is H, or a pharmaceutically acceptable salt thereof.
16 . The pharmaceutical composition of claim 13 , wherein
R 3 represents methoxyl; R 5 represents C(O)CH 2 OH; and R 9 represents alkoxy of one to six carbon atoms, a pharmaceutically acceptable salt thereof.
17 . The pharmaceutical composition of claim 13 , wherein said compound is selected from the group consisting of:
(a) a Nec-3 compound wherein R 1 , R 2 , R 4 , R 6 , R 10 , and R 11 are H, R 5 is —C(O)R 13 , the bond indicated by (a) is a double bond, and Z, R 3 , R 7 , R 8 , R 9 , and R 13 are as follows:
Cmpd
C3/
No.
Z
R 3
R 7
R 8
R 9
R 13
C3a*
25
CH 2
OCH 3
H
H
OCH 3
H
cis
26
CH 2
OCH 3
H
H
OCH 3
H
trans
39
CH 2
OCH 3
H
H
OCH 3
CH 2 CH 3
cis
42
CH 2
OCH 3
H
H
OCH 3
CH 2 Cl
cis
46
CH 2
OCH 3
H
H
OCH 3
CH 2 N(CH 3 ) 2
cis
47
CH 2
OCH 3
H
H
OCH 3
CH 2 OAc
cis
71
CH 2
OCH 3
H
H
OCH 3
CF 3
cis
79
CH 2
OCH 3
H
H
OCH 3
CH 2 CH 3
trans
80
CH 2
OCH 3
H
H
OCH 3
CH 2 OAc
trans
85
CH 2
OCH 3
H
H
OCH 3
(CH 2 ) 3 CO 2 CH 3
cis
86
CH 2
OCH 3
H
H
OCH 3
(CH 2 ) 3 CO 2 H
cis
87
CH 2
OCH 3
H
H
OCH 3
(CH 2 ) 3 C(O)-morpholine
cis
88
CH 2
OCH 3
H
H
OCH 3
CH 2 NHCH 3
cis
92
CH 2
OCH 3
H
H
OCH 3
CH 2 OCH 3
cis
93
CH 2
OCH 3
H
H
OCH 3
OH
cis
94
CH 2
OCH 3
H
H
OCH 3
(CH 2 ) 8 C(O)-morpholine
cis
97
CH 2
OCH 3
H
H
OCH 3
CF 3
cis
98
CH 2
OCH 3
H
H
OCH 3
C(O)CH 3
cis
99
CH 2
OCH 3
H
H
OCH 3
(CH 2 ) 3 C(O)—NH(CH 2 ) 3 CO 2 Et
cis
138
CH 2
OCH 3
H
H
OCH 3
(CH 2 ) 3 CO 2 CH 3
trans
(b) a Nec-3 compound selected from the group consisting of
(c) a Nec-3 compound having the following structure,
wherein R 5 is as follows
Cmpd
R
147
HC=O
148
C(=O)Et
150
C(=O)CH 2 OAc
151
C(=O)CH 2 OH
158
C(=O)CH 2 OMe
159
C(=O)CF 3
153
C(=O)NH 2
152
C(=S)NH 2
154
C(=S)NHMe
and
(d) a Nec-3 compound having the following structure,
wherein R 13 and the relative C3/C3a stereochemistry are as follows
C3/C3a
No.
stereochemistry
R 13
214
trans
CH 2 OH
215
cis
CH 2 OH
or a pharmaceutically acceptable salt thereof.
18 . The pharmaceutical composition of claim 17 , wherein said compound is selected from compounds (147), (148), (150), (151), (154), (158), and (159),
or a pharmaceutically acceptable salt thereof.
19 . A pharmaceutical composition comprising:
(i) the compound of claim 9 , or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable excipient.Cited by (0)
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