US2013184229A1PendingUtilityA1
Heterobifunctional inhibitors of e-selectins and cxcr4 chemokine receptors
Est. expiryMay 1, 2029(~2.7 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 35/00A61P 29/00A61K 31/7034C07H 15/22C07H 15/207A61K 31/7064A61K 31/7052C07H 15/26
50
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Claims
Abstract
Compounds, compositions and methods are provided for treating cancer and inflammatory diseases, and for releasing cells such as stem cells (e.g., bone marrow progenitor cells) into circulating blood and enhancing retention of the cells in the blood. More specifically, heterobifunctional compounds that inhibit both E-selectins and CXCR4 chemokine receptors are described.
Claims
exact text as granted — not AI-modifiedWe claim the following:
1 . A heterobifunctional compound for inhibition of E-selectin and the CXCR4 chemokine receptor, comprising E-selectin inhibitor-Linker-CXCR4 chemokine receptor inhibitor, or a physiologically acceptable salt thereof.
2 . The compound of claim 1 wherein the E-selectin inhibitor consists of:
wherein:
L=end of bond to Linker;
R 1 =H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, halogenated C 1 -C 8 alkanyl, aryl which may be substituted with one or more of Me, OMe, halide, OH, or NHX where X═H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, halogenated C 1 -C 8 alkanyl, aryl which may be substituted with one or more of Me, OMe, halide, or OH; C(═O)OX, alkanyl substituted with C(═O)OX, C(═O)NHX, alkanyl substituted with C(═O)NHX, where X═H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, halogenated C 1 -C 8 alkanyl, aryl which may be substituted with one or more of Me, OMe, halide, or OH; C(═O)X, OX, NHX, NHC(═O)X, where X═H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, halogenated C 1 -C 8 alkanyl, aryl which may be substituted with one or more of Me, OMe, halide, or OH;
R 2 =—OH,
—O—C(═O)—X, —NH 2 , —NH—C(═O)—NHX, or —NH—C(═O)—X where n=0-2 and X is independently selected from C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl,
where Q is H or a physiologically acceptable salt, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, aryl, (CH 2 ) m -aryl where m is 1-10, and where n=0-10, and any of the above ring compounds may be substituted with one to three independently selected of Cl, F, CF 3 , C 1 -C 8 alkoxy, NO 2 , C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, C 1 -C 14 aryl, or OY, C(═O)OY, NY 2 or C(═O)NHY where Y is H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, or C 1 -C 14 aryl;
R 3 =H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, CN, CH 2 CN, C(═O)X where X is H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, NHOH, NHOCH 3 , NHCN, or NX 2 , or C(═O)OY where Y is H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl or C 1 -C 8 alkynyl; and
where the cyclopropane ring may be substituted with one to two, and the cyclohexane ring may be substituted with one to three, independently selected of Cl, F, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C alkynyl or OY where Y is H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl or C 1 -C 14 aryl.
3 . The compound of claim 2 wherein the E-selectin inhibitor consists of:
wherein L=end of bond to Linker.
4 . The compound of claim 2 wherein the E-selectin inhibitor consists of:
wherein L=end of bond to Linker.
5 . The compound of claim 2 wherein the E-selectin inhibitor consists of:
wherein L=end of bond to Linker.
6 . The compound of claim 2 wherein the E-selectin inhibitor consists of:
wherein L=end of bond to Linker.
7 . The compound of claim 1 wherein the CXCR4 chemokine receptor inhibitor consists of:
wherein L=end of bond to Linker.
8 . The compound of claim 1 having the formula:
wherein:
R 1 =H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, halogenated C 1 -C 8 alkanyl, aryl which may be substituted with one or more of Me, OMe, halide, OH, or NHX where X═H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, halogenated C 1 -C 8 alkanyl, aryl which may be substituted with one or more of Me, OMe, halide, or OH; C(═O)OX, alkanyl substituted with C(═O)OX, C(═O)NHX, alkanyl substituted with C(═O)NHX, where X═H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, halogenated C 1 -C 8 alkanyl, aryl which may be substituted with one or more of Me, OMe, halide, or OH; C(═O)X, OX, NHX, NHC(═O)X, where X═H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, halogenated C 1 -C 8 alkanyl, aryl which may be substituted with one or more of Me, OMe, halide, or OH;
R 2 =—OH,
—O—C(═O)—X, —NH 2 , —NH—C(═O)—NHX, or —NH—C(═O)—X where n=0-2 and X is independently selected from C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl,
where Q is H or a physiologically acceptable salt, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, aryl, (CH 2 ) m -aryl where m is 1-10, and where n=0-10, and any of the above ring compounds may be substituted with one to three independently selected of Cl, F, CF 3 , C 1 -C 8 alkoxy, NO 2 , C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, C 1 -C 14 aryl, or OY, C(═O)OY, NY 2 or C(═O)NHY where Y is H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, or C 1 -C 14 aryl;
R 3 =H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, CN, CH 2 CN, C(═O)X where X is H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, NHOH, NHOCH 3 , NHCN, or NX 2 , or C(═O)OY where Y is H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl or C 1 -C 8 alkynyl; and
where the cyclopropane ring may be substituted with one to two, and the cyclohexane ring may be substituted with one to three, independently selected of Cl, F, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl or OY where Y is H, C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl or C 1 -C 14 aryl.
9 . The compound of claim 1 having the formula:
10 . The compound of claim 1 having the formula:
11 . The compound of claim 1 having the formula:
12 . The compound of claim 1 having the formula:
13 . The compound of claim 1 wherein the Linker is —C(═O)—NH—(CH 2 ) 2 —NH—, —CH 2 —NH—CH 2 —, or —C(═O)—NH—CH 2 —.
14 . The compound of claim 2 wherein the Linker is —C(═O)—NH—(CH 2 ) 2 —NH—, —CH 2 —NH—CH 2 —, or —C(═O)—NH—CH 2 —.
15 . The compound of claim 7 wherein the Linker is —C(═O)—NH—(CH 2 ) 2 —NH—, —CH 2 —NH—CH 2 —, or —C(═O)—NH—CH 2 —.
16 . A method for the treatment of a cancer in which cancer cells may leave the primary site in an individual who is in need of such treatment, said method comprising administering to the individual the compound of claim 1 in an amount effective for treatment.
17 . A method for the treatment of a cancer in which it is desired to mobilize cancer cells from a site into the bloodstream and retain the cancer cells in the bloodstream in an individual who is in need of such treatment, said method comprising administering to the individual the compound of claim 1 in an amount effective for treatment.
18 . A method for releasing cells into circulating blood and enhancing retention of the cells in the blood of an individual who is need of such treatment, said method comprising administering to the individual the compound of claim 1 in an amount effective for treatment.
19 . The method of claim 18 , further including the step of collecting the cells released.
20 . The method of claim 19 wherein the step of collecting utilizes apheresis.
21 . The method of claim 18 wherein the cells are bone marrow progenitor cells.
22 . A method for the treatment of an inflammatory disease in which the adhesion or migration of cells occurs in the disease in an individual who is in need of such treatment, said method comprising administering to the individual the compound of claim 1 in an amount effective for treatment.
23 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.Join the waitlist — get patent alerts
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