Methods to mobilize progenitor/stem cells
View Patent ↗Methods to elevate progenitor and stem cell counts in animal subjects using compounds which bind to the chemokine receptor CXCR4 are disclosed. Preferred embodiments of such compounds are of the formula Z-linker-Z′ (1) or pharmaceutically acceptable salt thereof wherein Z is a cyclic polyamine containing 9-32 ring members of which 3-8 are nitrogen atoms, said nitrogen atoms separated from each other by at least 2 carbon atoms, and wherein said heterocycle may optionally contain additional heteroatoms besides nitrogen and/or may be fused to an additional ring system; or Z is of the formula wherein A comprises a monocyclic or bicyclic fused ring system containing at least one N and B is H or an organic moiety of 1-20 atoms, Z′ may be embodied in a form as defined by Z above, or alternatively may be of the formula —N(R)—(CR 2 ) n —X wherein each R is independently H or straight, branched or cyclic alkyl (1-6C), n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or is a mercaptan; “linker” represents a bond, alkylene (1-6C) or may comprise aryl, fused aryl, oxygen atoms contained in an alkylene chain, or may contain keto groups or nitrogen or sulfur atoms.
1. A method to obtain progenitor and/or stem cells from a subject which method comprises:
(a) administering to said subject a compound of the formula
Z-linker-Z′ (1)
or a pharmaceutically acceptable salt thereof
wherein Z is a cyclic polyamine containing 9-32 ring members of which 2-8 are nitrogen atoms, said nitrogen atoms separated from each other by at least 2 carbon atoms, and wherein said heterocycle may optionally contain additional heteroatoms besides nitrogen and/or may be fused to an additional ring system;
or Z is of the formula
wherein A comprises a monocyclic or bicyclic fused ring system containing at least one N and B is H or an organic moiety of 1-20 atoms,
Z′ is either embodied in a form as defined by Z above, or is of the formula
—N(R)—(CR 2 ) n —X
wherein each R is independently H or straight, branched or cyclic alkyl (1-6C), n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or is a mercaptan;
“linker” represents a bond, alkylene (1-6C) or may comprise aryl, fused aryl, and/or oxygen atoms contained in an alkylene chain, and/or may contain keto groups and/or nitrogen or sulfur atoms;
in an amount effective to mobilize said progenitor and/or stem cells into the peripheral blood of said subject; followed by
(b) harvesting said progenitor and/or stem cells.
2. The method of claim 1 wherein Z and Z′ are both cyclic polyamines.
3. The method of claim 1 wherein Z and Z′ are identical.
4. The method of claim 1 wherein Z is a cyclic polyamine that contains 10-24 members and contains 4 nitrogen atoms.
5. The method of claim 3 wherein Z and Z′ are both 1,4,8,11-tetraazacyclotetradecane.
6. The method of claim 1 wherein the linker comprises an aromatic ring bracketed by two methylene moieties.
7. The method of claim 6 wherein the linker is 1,4-phenylene-bis-methylene.
8. The method of claim 1 wherein the compound of formula (1) is 1,1′-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11- tetraazacyclotetradecane or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 wherein
Z is of the formula
wherein A comprises a monocyclic or bicyclic fused ring system containing at least one N and B is H or an organic moiety of 1-20 atoms.
10. The method of claim 1 wherein Z′ is
—N(R)—(CR 2 ) n —X
wherein each R, N and X are as therein defined in.
11. The method of claim 10 wherein the linker is 1,4-phenylene-bis-(methylene).
12. The method of claim 1 wherein Z′ is 2-aminomethyl-pyridine.
13. The method of claim 1 wherein the compound of formula (1) is N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylene-bis-(methylene)]-2-aminomethylpyridine, or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 wherein formula (1) is in the form of an acid addition salt.
15. The method of claim 14 wherein the acid addition salt is hydrochloride.
16. The method of claim 1 wherein the compound of formula (1) or a pharmaceutically acceptable salt thereof is administered to said subject by an intravenous or subcutaneous route.
17. The method of claim 1 wherein the compound of formula (1) or a pharmaceutically acceptable salt thereof is administered to said subject in the dosage range of about 0.1 μg/kg-5 mg/kg of body weight.
18. The method of claim 1 which further comprises administering G-CSF to said subject prior to administering the compound of formula (1) or a pharmaceutically acceptable salt thereof.
19. The method of claim 8 which further comprises administering G-CSF to said subject prior to administering the 1,1′-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane or a pharmaceutically acceptable salt thereof.
20. The method of claim 13 which further comprises administering G-CSF to said subject prior to administering the N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylene-bis-(methylene)]-2-aminomethylpyridine, or a pharmaceutically acceptable salt thereof.
21. The method of claim 1 wherein the subject is human.
22. The method of claim 18 wherein the subject is human.
23. The method of claim 8 wherein the compound of formula (1) is in the form of an acid addition salt.
24. The method of claim 23 wherein the acid addition salt is hydrochloride.
25. The method of claim 8 wherein the compound of formula (1) or a pharmaceutically acceptable salt thereof is administered to said subject by a subcutaneous route.
26. The method of claim 8 wherein the compound of formula (1) or a pharmaceutically acceptable salt thereof is administered to said subject in the dosage range of about 0.1 μg/kg-5 mg/kg of body weight.
27. The method of claim 8 wherein the subject is human.
28. The method of claim 1 which further comprises administering macrophage inflammatory protein to said subject.
29. The method of claim 8 which further comprises administering macrophage inflammatory protein to said subject.