Methods to mobilize progenitor/stem cells

• US 20030130250A1
• Filed: 07/30/2002
• Published: 07/10/2003
• Est. Priority Date: 07/31/2001
• Status: Active Grant

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: AnorMED, Inc. (Sanofi )
• Inventors: Abrams, Michael J., Bridger, Gary J., Calandra, Gary B., MacFarland, Ronald Trevor, Henson, Geoffrey W.
• Granted Patent: US 6,987,102 B2
• Time in Patent Office: Days
• US Class Current: 514/183
• CPC Class Codes: A61K 2035/124 the cells being hematopoietic, bone marrow derived or blood cells
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/33 Heterocyclic compounds
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61K 31/4427 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61K 35/28 Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/195 Chemokines, e.g. RANTES
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C12N 5/0647 : Haematopoietic stem cells; Uncommitted or multipotent progenitors

Abstract

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)—(CR₂)_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.

Claims

1. A method to enhance the population of progenitor and/or stem cells, in a subject, which method comprises

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′

may be embodied in a form as defined by Z above, or alternatively may be of the formula

—

N(R)—

(CR₂)_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;

in an amount effective to elevate said progenitor and/or stem cell population in said subject;

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 contains 10-24 members and contains 4 nitrogen atoms.

5. The method of claim 1 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 the hydrochloride.

12. The method of claim 1 wherein the subject exhibits a hematopoietic deficit from chemotherapy or radiation therapy.

13. The method of claim 1 wherein the subject has a condition selected from the group consisting of aplastic anemia, leukemia and drug-induced anemia.

14. The method of claim 1 wherein the subject is a transplantation recipient.

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

16. The method of claim 1 wherein said progenitor and/or stem cells enhance wound healing.

17. The method of claim 1 wherein said progenitor and/or stem cells ameliorate bacterial inflammation.

18. The method of claim 1 wherein said progenitor and/or stem cells restore damaged organ tissue.

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

20. The method of claim 1 wherein the compound of formula (1) is administered to said subject in the dosage range of about 0.1 μ

g/kg-5 mg/kg of body weight.

25. A pharmaceutical composition comprising an effective amount of the compound of formula (1) as set forth in claim 1 in unit dosage form for elevating progenitor and/or stem cell population in a subject.

26. A pharmaceutical composition comprising an effective amount of the compound of formula (1) as set forth in claim 1 in unit dosage form for elevating progenitor and/or stem cell population in a subject, used in single or multiple combinations with granulocyte-macrophage colony stimulating factor (GM-CSF), Interleukin-1 (IL-1), Interleukin-3 (IL-3), Interleukin-8 (IL-8), PIXY-321 (GM-CSF/IL-3 fusion protein), macrophage inflammatory protein, stem cell factor, thrombopoietin, and/or growth related oncogene.

21. A method to enhance the population of progenitor and/or stem cells in peripheral blood or bone marrow which method comprises treating said peripheral blood or bone marrow with 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′

may be embodied in a form as defined by Z above, or alternatively may be of the formula

—

N(R)—

(CR₂)_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;

in an amount effective to elevate said progenitor and/or stem cell population in said peripheral blood or bone marrow.

22. The method of claim 21 which further comprises treating said peripheral blood or bone marrow with macrophage inflammatory protein.

23. The method of claim 21 wherein said treating is ex vivo.

24. The method of claim 21 wherein said peripheral blood or bone marrow is derived from a subject who has been treated with G-CSF.

27. A method to elevate progenitor and/or stem cell population in a subject which method comprises administering to said subject an amount of a compound that binds to the chemokine receptor CXCR4 sufficient to elevate said progenitor and/or stem cell population.

28. A method to elevate progenitor and/or stem cell population in peripheral blood or bone marrow which method comprises treating said peripheral blood or bone marrow with an amount of a compound that binds to the chemokine receptor CXCR4 sufficient to elevate the progenitor and/or stem cell population in said peripheral blood or bone marrow.

29. A method to effect regeneration of cardiac tissue in a subject which method comprises administering to a subject in need of such regeneration an amount of a compound that binds to the chemokine receptor CXCR4 sufficient to regenerate said tissue.