# US 2013/0158024 A1 · Tricyclic necrostatin compounds

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- Number: US 2013/0158024 A1
- Document ID: US20130158024A1
- Status: Published application
- Kind: A1
- Application number: 13/665,263
- Filed: 2012-10-31
- Published: 2013-06-20
- Earliest claimed: 2005-12-20
- Inventors: Junying Yuan; Alexei Degterev; Junichi Hitomi; Gregory D. Cuny; Prakash Jagtap
- Web page: https://patentgrep.com/patent/US20130158024A1

## CPC

- C07D 231/54: condensed with carbocyclic rings or ring systems
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 13/12: of the kidneys
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 491/052: the oxygen-containing ring being six-membered
- C07D 495/04: Ortho-condensed systems
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## 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

### Claim 1

A Nec-3 compound of formula (VI):
or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
Z is CH2;
the bond indicated by (a) can be a single or double bond;
R1 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; C7-16 aralkyl; amino; aminoalkyl of one to six carbon atoms; C6 or C10 aryl; C7 or C11 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; C2-9 heterocyclyl; C2-9 (heterocyclyl)oxy; C3-10 (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; —(CH2)qCO2RA, wherein q is zero to four and RA is selected from the group consisting of (a) C1-6 alkyl, (b) C6 or C10 aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH2)qCONRBRC, wherein RB and RC are independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C6 or C10 aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH2)qSO2RD, wherein RD is selected from the group consisting of (a) C1-6 alkyl, (b) C6 or C10 aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH2)qSO2NRERF, wherein RE and RF are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) C6 or C10 aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH2)qNRGRH, wherein RG and RH 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) C6 or C10 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; C1-6 perfluoroalkyl; C1-6 perfluoroalkoxy; C6 or C10 aryloxy; C3-8 cycloalkoxy; C9-14 cycloalkylalkoxy; or C7-16 arylalkoxy;
each of R2, R4, R7, R8, R10, and R11, 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; C7-16 aralkyl; amino; aminoalkyl of one to six carbon atoms; C6 or C10 aryl; C7 or C11 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; C2-9 heterocyclyl; C2-9 (heterocyclyl)oxy; C3-10 (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; —(CH2)qCO2RA, wherein q is zero to four and RA is selected from the group consisting of (a) C1-6 alkyl, (b) C6 or C10 aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH2)qCONRBRC, wherein RB and RC are independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C6 or C10 aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH2)qSO2RD, wherein RD is selected from the group consisting of (a) C1-6 alkyl, (b) C6 or C10 aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH2)qSO2NRERF, wherein RE and RF are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) C6 or C10 aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH2)qNRGRH, wherein RG and RH 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) C6 or C10 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; C1-6 perfluoroalkyl; C1-6 perfluoroalkoxy; C6 or C10 aryloxy; C3-8 cycloalkoxy; C9-14 cycloalkylalkoxy; or C7-16 arylalkoxy;
R3 is alkyl of one to six carbon atoms; alkoxy of one to six carbon atoms; halo; or amino;
R9 is alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms;
R5 is C(O)R13, C(S)R13, C(O)OR13, C(O)NR13R14, C(S)NR13R14, C(NH)R13, or S(O2)R13, wherein each of R13 and R14, independently, represents hydrogen, an optionally substituted C1-12 alkyl, an optionally substituted C1-7 heteroalkyl, an optionally substituted C6 or C10 aryl, an optionally substituted C2-9 heteroaryl, an optionally substituted C7-16 aralkyl, or an optionally substituted C2-15 heteroaralkyl; and
R6 is hydrogen, C1-6 alkyl, an optionally substituted C6 or C10 aryl, an optionally substituted C7-16 aralkyl, an optionally substituted C2-9 heteroaryl, or an optionally substituted C2-15 heteroaralkyl, wherein when each of R1, R2, R4, and R6 through R11 is selected from the group consisting of hydrogen, amino, halide, and hydroxyl and Z is CH2, R3 is not hydroxyl or methoxyl.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 2)

The Nec-3 compound of claim 2, wherein R5 is —C(O)R13, and R13 is substituted C1-12 alkyl,
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 2)

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.

### Claim 5 (depends on 2)

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.

### Claim 6 (depends on 2)

The Nec-3 compound of claim 2, wherein
the bond indicated by (a) is a double bond; Z is CH2; and
each of R1, R2, R4, R6, R7, R10, and R11, independently, represents hydrogen,
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 6)

The Nec-3 compound of claim 6, wherein
R8 is H,
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 2)

The Nec-3 compound of claim 2, wherein
R3 represents methoxyl; R5 represents C(O)CH2OH; and R9 represents alkoxy of one to six carbon atoms,
a pharmaceutically acceptable salt thereof.

### Claim 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 CH2CH2;
the bond indicated by (a) can be a single or double bond;
each of R1, R2, R4, R7, R8, R10, and R11, 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; C7-16 aralkyl; amino; aminoalkyl of one to six carbon atoms; C6 or C10 aryl; C7 or C11 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; C2-9 heterocyclyl; C2-9 (heterocyclyl)oxy; C3-10 (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; —(CH2)qCO2RA, wherein q is zero to four and RA is selected from the group consisting of (a) C1-6 alkyl, (b) C6 or C10 aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH2)qCONRBRC, wherein RB and RC are independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C6 or C10 aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH2)qSO2RD, wherein RD is selected from the group consisting of (a) C1-6 alkyl, (b) C6 or C10 aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH2)qSO2NRERF, wherein RE and RF are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) C6 or C10 aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; —(CH2)qNRGRH, wherein RG and RH 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) C6 or C10 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; C1-6 perfluoroalkyl; C1-6 perfluoroalkoxy; C6 or C10 aryloxy; C3-8 cycloalkoxy; C9-14 cycloalkylalkoxy; or C7-16 arylalkoxy;
R3 is alkoxy of one to six carbon atoms; halo; or amino;
R9 is alkyl of one to six carbon atoms; alkoxy of one to six carbon atoms; or halo;
R5 is C(O)R13, C(S)R13, C(O)OR13, C(O)NR13R14, C(S)NR13R14, C(NH)R13, or S(O2)R13, wherein each of R13 and R14, independently, represents hydrogen, an optionally substituted C1-12 alkyl, an optionally substituted C1-7 heteroalkyl, an optionally substituted C6 or C10 aryl, an optionally substituted C2-9 heteroaryl, an optionally substituted C7-16 aralkyl, or an optionally substituted C2-15heteroaralkyl; and
R6 is hydrogen, C1-6 alkyl, an optionally substituted C6 or C10 aryl, an optionally substituted C7-16 aralkyl, an optionally substituted C2-9 heteroaryl, or an optionally substituted C2-15heteroaralkyl, wherein when each of R1, R2, R4, and R6 through R11 is selected from the group consisting of hydrogen, amino, halide, and hydroxyl and Z is CH2, R3 is not hydroxyl or methoxyl.

### Claim 10 (depends on 9)

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.

### Claim 11 (depends on 9)

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.

### Claim 12 (depends on 1)

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.

### Claim 13 (depends on 2)

A pharmaceutical composition comprising:
(i) the compound of claim 2, or a pharmaceutically acceptable salt thereof; and
(ii) a pharmaceutically acceptable excipient.

### Claim 14 (depends on 13)

The pharmaceutical composition of claim 13, wherein
the bond indicated by (a) is a double bond; Z is CH2; and
each of R1, R2, R4, R6, R7, R10, and R11, independently, represents hydrogen,
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 14)

The pharmaceutical composition of claim 14, wherein
R8 is H,
or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 13)

The pharmaceutical composition of claim 13, wherein
R3 represents methoxyl; R5 represents C(O)CH2OH; and R9 represents alkoxy of one to six carbon atoms,
a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 13)

The pharmaceutical composition of claim 13, wherein said compound is selected from the group consisting of:
(a) a Nec-3 compound wherein R1, R2, R4, R6, R10, and R11 are H, R5 is —C(O)R13, the bond indicated by (a) is a double bond, and Z, R3, R7, R8, R9, and R13 are as follows:
Cmpd
C3/
No.
Z
R3
R7
R8
R9
R13
C3a*
25
CH2
OCH3
H
H
OCH3
H
cis
26
CH2
OCH3
H
H
OCH3
H
trans
39
CH2
OCH3
H
H
OCH3
CH2CH3
cis
42
CH2
OCH3
H
H
OCH3
CH2Cl
cis
46
CH2
OCH3
H
H
OCH3
CH2N(CH3)2
cis
47
CH2
OCH3
H
H
OCH3
CH2OAc
cis
71
CH2
OCH3
H
H
OCH3
CF3
cis
79
CH2
OCH3
H
H
OCH3
CH2CH3
trans
80
CH2
OCH3
H
H
OCH3
CH2OAc
trans
85
CH2
OCH3
H
H
OCH3
(CH2)3CO2CH3
cis
86
CH2
OCH3
H
H
OCH3
(CH2)3CO2H
cis
87
CH2
OCH3
H
H
OCH3
(CH2)3C(O)-morpholine
cis
88
CH2
OCH3
H
H
OCH3
CH2NHCH3
cis
92
CH2
OCH3
H
H
OCH3
CH2OCH3
cis
93
CH2
OCH3
H
H
OCH3
OH
cis
94
CH2
OCH3
H
H
OCH3
(CH2)8C(O)-morpholine
cis
97
CH2
OCH3
H
H
OCH3
CF3
cis
98
CH2
OCH3
H
H
OCH3
C(O)CH3
cis
99
CH2
OCH3
H
H
OCH3
(CH2)3C(O)—NH(CH2)3CO2Et
cis
138
CH2
OCH3
H
H
OCH3
(CH2)3CO2CH3
trans
(b) a Nec-3 compound selected from the group consisting of
(c) a Nec-3 compound having the following structure,
wherein R5 is as follows
Cmpd
R
147
HC=O
148
C(=O)Et
150
C(=O)CH2OAc
151
C(=O)CH2OH
158
C(=O)CH2OMe
159
C(=O)CF3
153
C(=O)NH2
152
C(=S)NH2
154
C(=S)NHMe
and
(d) a Nec-3 compound having the following structure,
wherein R13 and the relative C3/C3a stereochemistry are as follows
C3/C3a
No.
stereochemistry
R13
214
trans
CH2OH
215
cis
CH2OH
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 17)

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.

### Claim 19 (depends on 9)

A pharmaceutical composition comprising:
(i) the compound of claim 9, or a pharmaceutically acceptable salt thereof; and
(ii) a pharmaceutically acceptable excipient.