US2018319815A1PendingUtilityA1
Hetero-substituted cyclic lactone analogues and uses thereof
Est. expiryNov 5, 2035(~9.3 yrs left)· nominal 20-yr term from priority
Inventors:Monica L. GuzmanCesar M. CompadrePaola E. OrdonezMariano MartinezMichael J. BalickDarin E. JonesFlavio G. Gaudio
C07D 493/10C07D 493/04C07D 493/18C07D 493/08C07D 307/93
47
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Claims
Abstract
The present disclosure provides SL and SL derivatives comprising a polar substituent adjacent to the lactone ring. Additionally, the present disclosure provides methods of using the SL and SL derivatives to inhibit the growth of leukemic cancer cells.
Claims
exact text as granted — not AI-modified1 . A compound comprising Formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
X is a polar substituent;
R 4 and R 5 are independently selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
is a single or double bond; and
is a SL ring structure, minus the lactone ring, from the class of SLs including germacranolides, heliangolides, guaianolides, pseudoguaianolides, hypocretenolides, and eudesmanolides.
2 . The compound of claim 1 , wherein X is a substituent comprising an atom selected from the group consisting of fluorine, oxygen, nitrogen, chlorine, bromine, and iodine.
3 . The compound of claim 1 , wherein X is selected from the group consisting of —NR 18 R 19 , —OR 18 , and —NHC(O)R 18 , wherein R 18 and R 19 are independently selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl.
4 . The compound of claim 1 , wherein R 4 and R 5 are independently selected from the group consisting of hydrogen, —OCOCH 3 , alkoxy, hydroxyalkyl, carbonylalkyl, carbonyl substituted alkyl, carbonylalkoxy, carbonylaminoalkyl, alkyl, substituted alkyl, ester, substituted ester, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl.
5 .- 9 . (canceled)
10 . A compound comprising Formula (Ia) or a pharmaceutically acceptable salt thereof:
wherein:
X is a polar substituent;
R 4 and R 5 are independently selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
is a single or double bond; and
R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl.
11 . The compound of claim 10 , wherein X is a substituent comprising an atom selected from the group consisting of fluorine, oxygen, nitrogen, chlorine, bromine, and iodine.
12 . The compound of claim 10 , wherein X is selected from the group consisting of —NR 18 R 19 , —OR 18 , and —NHC(O)R 18 , wherein R 18 and R 19 are independently selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl.
13 . The compound of claim 10 , wherein R 4 and R 5 are independently selected from the group consisting of hydrogen, —OCOCH 3 , alkoxy, hydroxyalkyl, carbonylalkyl, carbonyl substituted alkyl, carbonylalkoxy, carbonylaminoalkyl, alkyl, substituted alkyl, ester, substituted ester, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl.
14 . (canceled)
15 . The compound of claim 10 , wherein the lactone ring does not contain a double bond, comprises an α-methylene group and R 4 and R 5 are hydrogen.
16 . The compound of claim 10 , wherein R 6 is a C 1 -C 6 alkyl and R 7 and R 8 form a double bond.
17 . The compound of claim 16 , wherein R 9 , R 10 , and R 11 are hydrogen.
18 . The compound of claim 17 , wherein R 12 forms an epoxide ring.
19 . A compound comprising Formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
R 4 and R 5 are independently selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
is a single or double bond; and
is a SL ring structure, minus the lactone ring, from the class of SLs including germacranolides, heliangolides, guaianolides, pseudoguaianolides, hypocretenolides, and eudesmanolides.
20 . The compound of claim 19 , wherein R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, CH 3 , CH 2 OH, alkoxy, hydroxyalkyl, carbonylalkyl, carbonyl substituted alkyl, carbonylalkoxy, carbonylaminoalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl.
21 . The compound of claim 19 , wherein R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, CH 3 , CH 2 OH, alkyl and substituted alkyl.
22 . The compound of claim 19 , wherein R 1 is CH 3 and R 2 and R 3 are hydrogen. Alternatively, R 1 and R 2 are CH 2 OH and R 3 is hydrogen.
23 . The compound of claim 19 , wherein R 4 and R 5 are independently selected from the group consisting of hydrogen, —OCOCH 3 , alkoxy, hydroxyalkyl, carbonylalkyl, carbonyl substituted alkyl, carbonylalkoxy, carbonylaminoalkyl, alkyl, substituted alkyl, ester, substituted ester, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl.
24 . (canceled)
25 . The compound of claim 19 , wherein the lactone ring contains a double bond, does not comprise an α-methylene group, R 4 is hydrogen and R 5 is selected from the group consisting of —OCOCH 3 , alkyl, substituted alkyl, ester and substituted ester.
26 . The compound of claim 19 , wherein the lactone ring contains a double bond, does not comprise an α-methylene group, R 4 is hydrogen and R 5 is OCOCH 3 .
27 . The compound of claim 19 , wherein the SL ring structure, minus the lactone ring is from the germacranolide class or the guaianolide class.
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