Plerixafor

White SolidPlerixafor (AMD3100) is a chemokine receptor antagonist for CXCR4 and CXCL12-mediated chemotaxis with IC50 of 44 nM and 5.7 nM in cell-free assays, respectively. Autologous hematopoietic stem cell (HSC) transplantation, a standard treatment for hematological malignancies, such as non-Hodgkin’s lymphoma or multiple myeloma, involves collection of HSCs from the patient, chemo- or radiotherapy of the patient to eliminate malignant cells, and retransplantation of the stored HSCs.

Solid

Plerixafor is an azamacrocycle consisting of two cyclam rings connected by a 1,4-phenylenebis(methylene) linker. It is a CXCR4 chemokine receptor antagonist and a hematopoietic stem cell mobilizer. It is used in combination with grulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the perpheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma. It has a role as an immunological adjuvant, an antineoplastic agent, an anti-HIV agent and a C-X-C chemokine receptor type 4 antagonist. It is an azamacrocycle, a crown amine, a secondary amino compound, an azacycloalkane, a tertiary amino compound and a member of benzenes. It derives from a 1,4,8,11-tetraazacyclotetradecane.|Plerixafor is a hematopoietic stem cell mobilizer. It is used to stimulate the release of stem cells from the bone marrow into the blood in patients with non-Hodgkin lymphoma and multiple myeloma for the purpose of stimulating the immune system. These stem cells are then collected and used in autologous stem cell transplantation to replace blood-forming cells that were destroyed by chemotherapy. Plerixafor has orphan drug status in the United States and European Union; it was approved by the U.S. Food and Drug Administration on December 15, 2008.|Plerixafor is a Hematopoietic Stem Cell Mobilizer. The physiologic effect of plerixafor is by means of Increased Hematopoietic Stem Cell Mobilization.|Plerixafor is a small molecular antagonist of the cell-surface CXCR4 receptor that plays an important role in mobilization of hematopoietic stem and progenitor cells to the stroma of the bone marrow; blocking the receptor helps to mobilize stem cells from the marrow to peripheral blood allowing for collection of these cells by apheresis for hematopoietic cell transplantation. Plerixafor is generally well tolerated and has not been linked to serum enzyme elevations or to clinically apparent liver injury.|Plerixafor is a bicyclam with hematopoietic stem cell-mobilizing activity. Plerixafor blocks the binding of stromal cell-derived factor (SDF-1alpha) to the cellular receptor CXCR4, resulting in hematopoietic stem cell (HSC) release from bone marrow and HSC movement into the peripheral circulation.

1, 1'-[1, 4-phenylenebis (methylene)]-bis-tris-(trifluoroacetyl)-1, 4, 8, 11-azatetradecane (3.30 g, 3.05 mmol) was dissolved in MeOH (6.0 mL). K2 CO3 (1.27 g, 9.1 mmol) was added in one portion. The suspension was heated at reflux for 3 h. Toluene (30 mL) was then added to the cooled mixture. MeOH was removed by forming an azeotrope with toluene. After all MeOH was removed, the hot toluene solution suspended with inorganic salt was filtered and concentrated to give AMD3100 free base (1.32 g, 86percent) as a white solid. All characteristics of this product are in good agreement with an authentic sample prepared according to reported methods.0.50 g of 1, 1'- [1, 4-phenylenebis (methylene)] bis (1, 4, 8, 11-tetraazacyclotetradecane-5, 7, 12-trione), 0.85 mmol, 1 eq), 0.42 g of sodium borohydride (12.24 mmol, 14.4 eq) was charged into a three-necked flask, Add 20mL of anhydrous tetrahydrofuran;Ice bath and 1.30 g iodine (5.1 mmol, 6 eq) in tetrahydrofuran (40 mL) was added dropwise with nitrogen protection;After the addition was complete, reflux for 42 hours;Under ice bath, 3N HCl (7 mL)Adjusted to pH = 1; the reaction solution was refluxed for 2 hours, Tetrahydrofuran was removed under reduced pressure, Extracted three times with 30 mL of dichloromethane, Under ice bath, The pH was adjusted to 12 with potassium hydroxide, extracted with dichloromethane (30 mL x 4)Recrystallization yielded 0.18 g of white solid Plerixa 1, 1 '- [1, 4-phenylenedi (methylene)] - di-1, 4, 8, 11-tetraazacyclotetradecane (42percent).1, 1'-[1, 4-phenylenebis (methylene)]-bis-tris-(trifluoroacetyl)-1, 4, 8, 11-azatetradecane (3.30 g, 3.05 mmol) was dissolved in MeOH (6.0 mL). K 2 CO 3 (1.27 g, 9.1 mmol) was added in one portion. The suspension was heated at reflux for 3 h. Toluene (30 mL) was then added to the cooled mixture. MeOH was removed by forming an azeotrope with toluene. After all MeOH was removed, the hot toluene solution suspended with inorganic salt was filtered and concentrated to give AMD3100 free base (1.32 g, 86%) as a white solid. All characteristics of this product are in good agreement with an authentic sample prepared according to reported methods.Commercially available AMD3100 (l-[[4-(l, 4, 8, l l-tetrazacyclotetradec-l- ylmethyl)phenyl] methyl] -1, 4, 8, 11-tetrazacyclotetradecane), compound 3, is dissolved into methylene chloride containing an excess of triethylamine and the solution is cooled and then maintained at about 0C. Approximately 0.3 equivalents of chloroformate, compound 2, is also dissolved in methylene chloride and added dropwise to the cooled solution while stirring vigorously. The use of 0.3 equivalent of compound 3 is to minimize multiple additions of compound 2 to compound 3. After reaction completion, unreacted chloroformate is quenched by conventional methods. [0083] The reaction mixture can then be purified by conventional methods such as chromatography, distillation, precipitation, high performance liquid chromatography (HPLC), and the like to provide for compound 4.1, 4, 8, 11-Tetraazacyclotetradecane 1 (0.205 mol) was dissolved in a mixture of water(160 mL) and chloroform (160 mL); sodium carbonate (0.205 mol) and a, a0-dibromop-xylene 2 (0.1mol) were added, followed by addition of 10% of TBAB catalyst(0.0205 mol). The solution was refluxed for 1-2 h, cooled to room temperature, pouredinto ice cold water and extracted with toluene (3x200 mL). The organic phases werecombined, dried over anhydrous MgSO4 and concentrated in vacuo to give a white solid3. The obtained solid material was dissolved in a minimum amount of dry methanol(250 mL) and dry HCl gas was gently passed through the solution to form a white precipitatewhich was filtered and dried to give 3 octahydrochloride. Yield 92% with 99.6% purity, free base mp 131-132C, lit mp 129-131C;16 HClsalt mp 240.0-245.5C, lit mp 232C.7Free Base IR (cm1): 3417, 3283, 2937, 2817, 1645, 1531, 1464, 751; 1H NMR(400 MHz, CDCl3) 7.28 (s, 4H), 4.08 (s, 4H), 3.36 (bb, 8H), 3.26 (bb, 8H), 3.18-3.17(m, 4H), 2.59-2.59 (m, 16H), 179-1.68 (m, 4H), 1.58-1.48 (m, 4H); 13C NMR (100 MHz, CDCl3): 26.4, 29.6, 47.9, 48.1, 49.2, 50.10, 50.4, 51.2, 52.2, 54.9, 58.3, 129.2. 137.2.HRMS (M1): Calcd for C28 H55N8, 502.78196; Found (HRMS (M1)), 503.44962.7 (See Figure 1)Anal. Calcd for C28 H55N8: C, 66.75; H, 11.00; N, 22.24. Found: C, 66.85; H, 10.81; N, 22.19.0.50 g of 1, 1'- [1, 4-phenylenebis (methylene)] bis (1, 4, 8, 11-tetraazacyclotetradecane-5, 7, 12-trione), 0.85 mmol, 1 eq), 0.42 g of sodium borohydride (12.24 mmol, 14.4 eq) was charged into a three-necked flask, Add 20mL of anhydrous tetrahydrofuran;Ice bath and 1.30 g iodine (5.1 mmol, 6 eq) in tetrahydrofuran (40 mL) was added dropwise with nitrogen protection;After the addition was complete, reflux for 42 hours;Under ice bath, 3N HCl (7 mL)Adjusted to pH = 1; the reaction solution was refluxed for 2 hours, Tetrahydrofuran was removed under reduced pressure, Extracted three times with 30 mL of dichloromethane, Under ice bath, The pH was adjusted to 12 with potassium hydroxide, extracted with dichloromethane (30 mL x 4)Recrystallization yielded 0.18 g of white solid Plerixa 1, 1 '- [1, 4-phenylenedi (methylene)] - di-1, 4, 8, 11-tetraazacyclotetradecane (42%).To a stirred solution of hydroxylamine hydrochloride (760g, 10.937 mole) in isopropyl alcohol (5000 ml) was added triethylamine (1071g, 10.584 mole) at room temperature and the reaction mixture was stirred for 1.5 hrs.

Plerixafor is a hematopoietic stem cell (HSC) mobilizer that inhibits the CXCR4 chemokine receptor and blocks binding of its ligand, stromal cell-derived factor-1-α (SDF-1-α).on Dec. 15, 2008, as treatment in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize HSCs to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM).

Molecular Weight:502.8
Hydrogen Bond Donor Count:6
Hydrogen Bond Acceptor Count:8
Rotatable Bond Count:4
Exact Mass:502.44714376
Monoisotopic Mass:502.44714376
Topological Polar Surface Area:78.7
Heavy Atom Count:36
Complexity:456
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes