US2006199835A1PendingUtilityA1
Neuroprotective and anti-proliferative compounds
Est. expiryAug 11, 2023(expired)· nominal 20-yr term from priority
A61P 43/00A61P 35/00C07D 403/08A61P 25/28C07D 403/04C07D 471/04A61P 25/02A61K 31/47A61K 31/415A61K 31/40C07D 403/14A61K 31/435A61P 29/00C07D 401/14A61K 31/4184A61K 31/4178A61K 31/407A61K 31/4045A61K 31/404
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Claims
Abstract
This invention features compounds of formula (I), (II) and (III), which are useful in the treatment of proliferative disorders characterized by loss of growth or cellular differentiation control including, but not limited to, cancer and inflammation. Formulas (I), (II), (III) have functional groups designated as A 1 , A 2 , B 1 , B 2 , X 1 —X 9 and R 1 —R 8 as defined further.
Claims
exact text as granted — not AI-modified1 - 30 . (canceled)
1 . A compound represented by the following formula:
or a pharmaceutically acceptable salt thereof
wherein:
X 1 —X 3 are independently C or N;
X 4 is CH or N, wherein not more than two of X 1 —X 4 is N;
X 6 —X 8 are independently C or N;
X 9 is CH or N, wherein not more than two of X 6 —X 9 is N;
X 5 is N, R 5 is a lone pair, and X 10 is CH, when the bond between X 5 and X 10 is a double bond; or
X 5 is CH, R 5 is H, and X 10 is CH 2 , when the bond between X 5 and X 10 is a single bond; or
X 5 is C, R 5 is defined below, and X 10 is CH, when the bond between X 5 and X 10 is a double bond;
R 1 —R 3 and R 6 —R 8 represent a lone pair or O when each respective X 1 —X 3 and X 6 —X 8 is N; or
when X 1 —X 3 or X 6 —X 8 is C, each respective R 1 —R 3 and R 6 —R 8 is independently selected from the group consisting of:
a) H, substituted or unsubstituted C(1-8) alkyl, halogen, azido, cyano, nitro, or NR 21 R 22 , wherein R 21 represents H or C(1-8) alkyl, and R 22 represents H, substituted or unsubstituted C(1-8) alkylcarbonyl, substituted or unsubstituted arylcarbonyl, heterocycle, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted C(1-8) alkylaminocarbonyl, substituted or unsubstituted arylaminocarbonyl;
b) OR 23 , wherein R 23 is H, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl;
c) SR 23 , wherein R 23 is defined as in b);
d) O(CH 2 ) j —R 24 , O(CH 2 ) j —O—R 24 , or O(CH 2 ) j —S—R 24 , wherein j is an integer from 1 to 8, and R 24 is selected from the group consisting of H, substituted or unsubstituted C(1-8) alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
e) S(CH 2 ) j R 24 , S(CH 2 ) j —O—R 24 , or S(CH 2 ) j —S—R 24 , wherein j and R 24 are defined as in d);
f) C≡C—R 25 , C≡C—OR 25 , or C≡C—CO 2 R 25 , wherein R 25 is H, substituted or unsubstituted C(1-8) alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
g) CH═CH—R 25 , CH═CH—OR 25 , or CH═CH—CO 2 R 25 , having a stereochemistry of E or Z, and R 25 is defined as in f);
h) C≡C—NR 25 R 26 or C≡CCONR 25 R 26 , wherein R 25 is defined as in f), and R 26 is defined as R 25 , and R 25 and R 26 are selected independently;
i) CH═CH—NR 25 R 26 or CH═CHCONR 25 R 26 , having a stereochemistry of E or Z, wherein R 25 and R 26 are independently defined as in h);
j) (CH 2 ) k R 25 , (CH 2 ) k —COOR 25 , or (CH 2 ) k —OR 25 , wherein k is an integer from 2 to 6 and R 25 is defined as in f);
k) (CH 2 ) k NR 25 R 26 , (CH 2 ) k CONR 25 R 26 , wherein R 25 and R 26 are selected independently, and R 25 and R 26 are defined as R 25 in f); and
l) CH 2 XR 27 , wherein X is O or S and R 27 is H, substituted or unsubstituted C(1-8) alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
R 4 is selected from the group consisting of:
m) H, substituted or unsubstituted C(1-8) alkyl; and
n)
wherein X═O, S, or NH, n=1 to 4; and wherein R 51 is H; R 52 and R 53 are independently chosen from the group consisting of H, substituted or unsubstituted C(1-8)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or R 51 and R 52 are combined to form a heteroalkyl, substituted heteroalkyl, heteroaryl, or substituted heteroaryl ring system;
R 5 is selected from the group consisting of:
o) a lone pair when X 5 is N; or
when X 5 is C, R 5 is selected from the group consisting of:
p) H, substituted and unsubstituted C(1-8) alkyl; and
q)
wherein X═O, S, or NH, n=1 to 4; and wherein R 51 is H; R 52 and R 53 are independently chosen from the group consisting of H, substituted or unsubstituted C(1-8) alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or R 51 and R 52 are combined to form a heteroalkyl, substituted heteroalkyl, heteroaryl, or substituted heteroaryl ring system; or
wherein when R 1 —R 3 and R 5 —R 8 are H, and R 4 is H or CH 3 , then at least one of X 1 —X 9 represents a ring member other than carbon.
2 . A compound, according to claim 1 , in which X 1 —X 3 are independently C.
3 . A compound, according to claim 1 , in which X 4 is CH.
4 . A compound, according to claim 1 , in which X 6 —X 8 are independently C.
5 . A compound, according to claim 1 , in which X 9 is CH or N.
6 . A compound, according to claim 1 , in which X 5 is C, X 10 is CH and the bond between X 5 and X 10 is a double bond.
7 . A compound, according to claim 1 , in Which X 5 is N, R 5 is a lone pair, X 10 is CH and the bond between X 5 and X 10 is a double bond.
8 . A compound, according to claim 1 , in which X 5 is CH, R 5 is H, X 10 is CH 2 and the bond between X 5 and X 10 is a single bond.
9 . A compound having the following formula:
wherein X 5 is C or N, and X 1 —X 3 , X 4 , X 6 —X 8 , R 1 —R 3 , R 4 , R 5 and R 6 —R 8 are as defined in claim 1 .
10 . A compound having the following formula:
wherein X 1 —X 3 , X 4 , X 6 —X 8 , R 1 —R 3 , R 4 , R 5 and R 6 —R 8 are as defined in claim 1 .
11 . A compound having the following formula:
wherein X 1 —X 3 , X 4 , X 6 —X 8 , R 1 —R 3 , R 4 , R 5 and R 6 —R 8 are as defined in claim 1 .
12 . A compound having the following formula:
wherein X 1 —X 3 , X 4 , X 6 —X 8 , R 1 —R 3 , R 4 , R 5 and R 6 —R 8 are as defined in claim 1 .
13 . A compound, according to claim 1 , in which when X 1 —X 3 or X 6 —X 8 is C, each respective R 1 —R 3 and R 6 —R 8 is independently selected from the group consisting of:
a) H, halogen; b) OR 23 , wherein R 23 is H, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl; and d) O(CH 2 ) j —R 24 , O(CH 2 ) j —O—R 24 , or O(CH 2 ) j —S—R 24 , wherein j is an integer from 1 to 8, and R 24 is selected from the group consisting of H, substituted or unsubstituted C(1-8) alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
14 . A compound, according to claim 1 , in which R 4 is selected from the group consisting of:
m) H, substituted or unsubstituted C(1-8) alkyl; and n) wherein X═O, S, or NH, n=2; and wherein R 51 is H; R 52 and R 53 are independently chosen from the group consisting of H, substituted or unsubstituted C(1-8)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or R 51 and R 52 are combined to form a heteroalkyl, substituted heteroalkyl, heteroaryl, or substituted heteroaryl ring system.
15 . A compound, according to claim 14 , in which R 4 is selected from the group consisting of:
m) H, substituted or unsubstituted C(1-8) alkyl; and n) wherein X═S, n=2; and wherein R 51 is H; R 52 and R 53 are both H, or R 51 and R 52 are combined to form a heteroaryl ring system.
16 . A compound, according to claim 15 , in which R 4 is selected from the group consisting of: H, methyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 N 3 , CH 2 CH 2 CH 2 SC(═NH)NH 2 and
17 . A compound, according to claim 1 , in which X 5 is N and R 5 is a lone pair.
18 . A compound, according to claim 1 , in which X 5 is C or CH, and R 5 is selected from the group consisting of:
p) H, substituted and unsubstituted C(1-8) alkyl; and q) wherein X═S, n=2; and wherein R 51 is H; R 52 and R 53 are independently chosen from the group consisting of H, substituted or unsubstituted C(1-8) alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or R 51 and R 52 are combined to form a heteroalkyl, substituted heteroalkyl, heteroaryl, or substituted heteroaryl ring system.
19 . A compound, according to claim 18 , in which X 5 is C or CH, and R 5 is selected from the group consisting of H, methyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 SC(═NH)NH 2 , CH 2 CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH 2 CH 2 N 3 , CH 2 CH 2 CH 2 NH 2 , and
20 . A compound, according to the following formula
selected from the group consisting of:
Bond
between
Cpd.
X 5 /X 10
R 3
R 50
R 7
X 5 /R 5
X 9
X 10
121
Double
H
—OH
H
CH
CH
CH;
124
Double
BnO
—OH
H
CH
CH
CH;
125
Double
H
—OH
H
CMe
CH
CH;
126
Double
H
—OH
BnO
CH
CH
CH;
127
Double
H
—OH
H
CH
CH
CMe;
128
Double
H
—OH
H
N
CH
CH;
129
Double
BnO
—OH
H
CMe
CH
CH;
130
Double
H
—OH
H
CH
N
CH;
131
Double
BnO
—OH
H
CH
CH
CMe;
132
Double
H
—OH
F
CH
CH
CH;
133
Double
H
—N(CH 3 ) 2
H
CH
CH
CH;
136
Double
BnO
—N(CH 3 ) 2
H
CH
CH
CH;
137
Double
H
—N(CH 3 ) 2
H
CMe
CH
CH;
138
Double
H
—N(CH 3 ) 2
BnO
CH
CH
CH;
139
Double
H
—N(CH 3 ) 2
H
CH
CH
CMe;
140
Double
H
—N(CH 3 ) 2
H
N
CH
CH;
141
Double
BnO
—N(CH 3 ) 2
H
CMe
CH
CH;
142
Double
H
—N(CH 3 ) 2
H
CH
N
CH;
143
Double
H
—SC(═NH)NH 2
H
CH
CH
CH;
146
Double
H
—SC(═NH)NH 2
H
CMe
CH
CH;
147
Double
H
—SC(═NH)NH 2
BnO
CH
CH
CH;
148
Double
BnO
—SC(═NH)NH 2
H
CH
CH
CH;
149
Double
BnO
—SC(═NH)NH 2
H
CH
CMe
CH;
150
Double
BnO
—SC(═NH)NH 2
H
CH
CH
CMe;
151
Double
H
—SC(═NH)NH 2
H
CH
CH
CMe;
152
Double
H
—SC(═NH)NH 2
H
CH
N
CH;
153
Double
MeO
—SC(═NH)NH 2
H
CH
CH
CH;
154
Double
F
—SC(═NH)NH 2
H
CH
CH
CH;
155
Double
H
—SC(═NH)NH 2
F
CH
CH
CH;
156
Double
H
H
CH
CH
CH;
159
Single
H
—SC(═NH)NH 2
H
CH 2
CH
CH 2 ;
160
Double
OCH 2 S
—SC(═NH)NH 2
H
CH
CH
CH;
Ph
161
Double
H
—N 3
H
CH
CH
CH; and
162
Double
H
—NH 2
H
CH
CH
CH.
21 . A compound according to the following formula:
selected from the group consisting of:
Example
R 3
R 50
R 7
R 4
163
H
OH
H
H;
164
H
OH
H
Me;
165
BnO
OH
H
H;
166
H
SC(═NH)NH 2
H
H;
167
H
SC(═NH)NH 2
H
Me;
168
BnO
SC(═NH)NH 2
H
Me;
169
H
N(CH 3 ) 2
H
Me;
170
H
H
Me;
171
H
N 3
H
Me; and
172
H
NH 2
H
Me.
22 . A composition comprising a compound, according to claim 1 , in combination with carrier.
23 . The composition, according to claim 22 , further including a chemotherapeutic agent.
24 . The composition, according to claim 22 , further including a cytokine.
25 . The composition, according to claim 22 , further including anti-sense oligonucleotides.
26 . A method of treating an inflammatory disorder, the method comprising: administering to a subject in need thereof an effective amount of a compound or a composition, according to claim 1 or 22 , so as to treat the disorder.
27 . A method of treating cancer, the method comprising: administering to a subject in need thereof an effective amount of a compound or a composition, according to claim 1 or 22 , so as to treat the cancer.
28 . A method of treating a cell proliferative disorder, the method comprising: administering to a subject in need thereof an effective amount of a compound or a composition, according to claim 1 or 22 , so as to treat the disorder.
29 . A method of treating cancer, the method comprising: administering to a subject in need thereof an effective amount of a compound or a composition, according to claim 1 or 22 , in combination with another chemotherapeutic agent.
30 . Use of a compound or a composition, according to claim 1 or 22 , so as to induce apoptosis in Jurkat cells.
31 . Use of a compound or a composition, according to claim 1 or 22 , so as to induce apoptosis in cancer cell lines.
32 . The use, according to claim 31 , in which the cancer cell lines are prostate cancer and breast cancer cell lines
33 . A method of treatment or prevention of a condition resulting from loss of growth and cellular differentiation control, the method comprising: administration to a subject in need thereof an effective amount of a compound or a composition, according to claim 1 or 22 , so as to treat or prevent the condition.Cited by (0)
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