Methods to mobilize progenitor/stem cells

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 pharmaceutically acceptable salt or prodrug form 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 by apheresis.

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-tetraazocyclotetradecane.

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 7 wherein the compound of formula (1) is 1,1′-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane.

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 formula (1) is in the form of its acid addition salt.

11. The method of claim 10 wherein the acid addition salt is hydrochloride.

12. The method of claim 1 wherein the compound is administered to said subject by an intravenous or subcutaneous route.

13. The method of claim 1 wherein the compound of formula (1) is administered to said subject in the dosage range of about 0.1 μg/kg–5 mg/kg of body weight.

14. The method of claim 1 which further comprises administering macrophage inflammatory protein to said subject.

15. The method of claim 1 which further comprises administering G-CSF to said subject prior to performing said method.

16. A method to obtain progenitor and/or stem cells from a subject which method comprises

(a) administering to said subject an amount of a compound that binds to the chemokine receptor CXCR4 sufficient 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 by apheresis.

17. The method of claim 4 wherein Z′ is

—N(R)—(CR 2 ) n —X

wherein each R, N and X are as defined in claim 1 .

18. The method of claim 17 wherein the linker is 1,4-phenylene-bis-(methylene).

19. The method of claim 18 wherein Z′ is 2-aminomethyl-pyridine.

20. The method of claim 19 wherein the compound of formula (1) is N[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylene-bis-(methylene)]-2-aminomethyl-pyridine.

21. The method of claim 1 wherein the subject is human.

22. The method of claim 16 wherein the subject is human.