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 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 of the formula

—Ar(Y) j ;

wherein Ar is an aromatic or heteroaromatic moiety, and each Y is independently a non-interfering substituent and j is 0–3; and

“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;

in an amount effective to mobilize said progenitor and/or stem cell population in said subject; followed by

(b) harvesting said progenitor and/or stem cells.

2. The method of claim 1 wherein the compound of formula (1) is of the formula:

and salts and prodrug forms thereof

wherein:

Ring A optionally comprises a heteroatom selected from N, O and S;

the dotted lines represent optional unsaturation;

R1, R2 and R3 are non-interfering substituents;

k is 0–4;

l is 0, 1, or 2;

X is unsubstituted or substituted C or N; or is O or S;

Ar is the residue of an aromatic or heteroaromatic moiety;

each n is independently 0–2;

each R is independently H or alkyl (1–6C);

j is 0–3; and

each Y is independently halo, OH, SH, SO, SO 2 , or an organic moiety of 1–20C atoms that does not contain N wherein two such Y may be connected to form a fused ring with Ar, or is selected from the group consisting of

—(CR 2 ) m CN,

—(CR 2 ) m NR 5 2 ,

—(CR 2 ) m NR(CR 2 ) m NRR 4 ,

—(CR 2 ) m NR(CR 2 ) m NR(CR 2 )mNR 5 2 ,

—(CR 2 ) m CO(CR 2 ) m NR 5 2 ,

—(CR 2 ) m CO(CR 2 ) m NR(CR 2 ) m NRR 4 ,

—(CR 2 ) m CO(CR 2 ) m NR(CR 2 ) m NR(CR 2 ) m NR 5 2 ,

—(CR 2 ) m NRCO(CR 2 ) m NRR 4 ,

—(CR 2 ) m NRCO(CR 2 ) m NR(CR 2 ) m NR 5 2 ,

—(CR 2 ) m NRCO(CR 2 ) m NR(CR 2 ) m NR(CR 2 ) m NR(CR 2 ) m NR 5 2 ,

—CH═N—Z″,

—(CR 2 ) m Z″,

—NR (CR 2 ) m Z″,

—(CR 2 ) m NROH,

(CR 2 ) m CONROH, and

(CR 2 ) m CR═NOH,

wherein Z″ is an optionally substituted aromatic or heteroaromatic moiety containing 5–12 ring members; and

wherein R is as defined above, each m is independently 0–4, and R 4 and each R 5 is independently H, alkyl (1–6C), alkenyl (1–6C), alkynyl (1–6C), or acyl (1–6C), each optionally substituted by one or more nonaromatic, nonheterocyclic substituent(s), and wherein two R 5 may be connected to form a cyclic amine, optionally containing one or more additional heteroatoms selected from N, O, and S.

3. The method of claim 2 wherein ring E is coupled to the remainder of the molecule at position 2.

4. The method of claim 3 wherein R 2 and R 3 taken together form a benzo substituent.

5. The method of claim 4 wherein X is N and ring E comprises a pi bond coupled to one N.

6. The method of claim 2 wherein ring A is saturated and l is 1.

7. The method of claim 6 wherein k is 0–1.

8. The method of claim 7 wherein the ring system which includes A is tetrahydroquinoline or a substituted form thereof.

9. The method of claim 2 wherein one of (CR 2 ) a n and (CR 2 ) b n is CH 2 and the other is a bond.

10. The method of claim 9 wherein (CR 2 ) a n is a bond and (CR 2 ) b n is CH 2 .

11. The method of claim 2 wherein at least one Y is —CH 2 NH 2 .

12. The method of claim 2 wherein Ar is the residue of benzene, benzimazole, benzothiazole, imidazole, oxazole, benztriazole, thiazole, pyridine, or pyrimidine.

13. The method of claim 1 wherein formula (1) is in the form of its acid addition salt.

14. The method of claim 13 wherein the acid addition salt is a hydrochloride.

15. The method of claim 1 wherein the subject is a healthy stem cell donor.

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

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

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

19. The method of claim 1 which further includes the step of administering G-CSF to said subject prior to performing the method.

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

21. The method of claim 1 wherein the harvesting is by apheresis.