WO2008076826A1 - Agents d'alkylation pyrophosphoramide - Google Patents

Agents d'alkylation pyrophosphoramide Download PDF

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Publication number
WO2008076826A1
WO2008076826A1 PCT/US2007/087429 US2007087429W WO2008076826A1 WO 2008076826 A1 WO2008076826 A1 WO 2008076826A1 US 2007087429 W US2007087429 W US 2007087429W WO 2008076826 A1 WO2008076826 A1 WO 2008076826A1
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compound
group
pharmaceutically acceptable
pyrophosphoramide
alkylator
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PCT/US2007/087429
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English (en)
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Xiaohong Cai
Jian-Xin Duan
Hailong Jiao
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Threshold Pharmaceuticals, Inc.
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Publication of WO2008076826A1 publication Critical patent/WO2008076826A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/098—Esters of polyphosphoric acids or anhydrides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines

Definitions

  • the present invention provides compositions and methods for treating cancer and other hyperproliferative disease conditions with pyrophosphoramide alkylators alone and in combination with other anti-cancer agents and therapies, and so relates to the fields of medicine, pharmacology, chemistry, and biology.
  • Phosphoramidate alkylators used in treating cancer encompass a group of compounds that have in common the ability to alkylate biologically vital macromolecules such as DNA (Hardman et al., The Pharmacological Basis of Therapeutics, 2001 , 1389-1399, McGraw-Hill, New York, USA).
  • certain prodrugs currently used in cancer therapy that release phosphoramidate alkylators in vivo such as the drugs ifosfamide and cyclophosfamide, are problematic due to side effects arising in part from toxic metabolites such as acrolein.
  • a phosphoramidate alkylator prodrug, giufosfamide, that does not produce acrolein, has not yet been approved for treating cancer (see, US Pat. No. 5,622,936 incorporated herein by reference).
  • the present invention provides pyrophosphoramide alkylators that are anhydrides of phosphoramidate alkylators containing 1 -3 phosphoramidate alkylator moieties.
  • the present invention provides pyrophosphoramide alkylators containing two phosphoramidate alkylator moieties.
  • each of the phosphoramidate alkylator moieties is selected from the group consisting of an ifosfamide alkylator, a cyclophosfamide alkylator, an N,N,N',N'-tetrakis-2-haloalkyl phosphoramidate alkylator, and analogs of the foregoing.
  • the pyrophosphoramide alkylator is a bis-ifsofamide alkylator.
  • the present invention provides phosphoramidate alkylator anhydrides containing two phosphoramidate alkylator moieties joined by a phosphate or a phosphoramidate moiety.
  • the present invention provides a pyrophosphoramide alkylator having a structure of formula:
  • each R 1 - R 8 is independently selected from the group consisting of H, C- ⁇ -C- 6 alkyl, and the moiety:
  • each Rg- R 11 is O.
  • the present invention provides a pyrophosphoramide alkylator having structure of formula:
  • the present invention provides a pyrophosphoramide alkylator having structure of formula: H R 8
  • R 4 H "R 6 or a pharmaceutically acceptable salt thereof; wherein R 2 , R 4 , Re, and R 8 are defined as above.
  • the present invention provides a pyrophosphoramide alkylator having structure of formula:
  • R 12 is selected from the group consisting of halo and OSO 2 R I4 -
  • R 12 is selected from the group consisting of chloro and bromo.
  • R 12 is a 4-hydroxyphenylsulfonyloxy moiety:
  • the present invention provides a pyrophosphoramide alkylator of the present invention in substantially pure form.
  • the present invention provides methods of synthesizing novel pyrophosphoramide alkylators and known pyrophosphoramide compounds, comprising reacting a phosphoramidate alkylator or a phosphoramidate under Mitsunobu conditions.
  • the present invention provides methods of synthesizing novel pyrophosphoramide alkylators and known pyrophosphoramide compounds, comprising reacting a phosphoramidate alkylator or a phosphoramidate with a dialkyl or dicycloalkyl carbodiimide.
  • the present invention provides methods of synthesizing novel pyrophosphoramide alkylators and known pyrophosphoramide compounds, comprising reacting a compound having a structure of formula:
  • a pharmaceutically acceptable salt thereof with water and a base selected from the group consisting of a trialkyl amine and a pyridine.
  • the present invention provides a pharmaceutically acceptable formulation comprising a pyrophosphoramide alkylator and pharmaceutically acceptable diluents or excipients.
  • the present invention provides a method of treating cancer and other hyperproliferative diseases comprising administering a therapeutically effective amount of a pyrophosphoramide alkylator to a patient in need of such treatment.
  • Figure 1 Tumor growth delay in H460 tumor xenografts in mice, upon administration of compound 1 alone and in combination with cisplatin (CDDP)
  • Section I provides useful definitions
  • Section Il describes pyrophosphoramide alkylators of the present invention (part A) and methods of synthesizing novel and known pyrophosphoramide compounds (part B);
  • Section III describes various methods of treating cancer and other diseases of cellular hyperproliferation employing the pyrophosphoramide alkylators of the present invention;
  • Section IV provides illustrative examples for synthesizing pyrophosphoramide alkylators of the present invention and demonstrating in vitro and in vivo efficacy of a pyrophosphoramide alkylator of the present invention.
  • This detailed description is organized into sections only for the convenience of the reader, and disclosure found in any section is applicable to disclosure elsewhere in the specification.
  • C 1 -C 6 alkoxy refers to a Ci-C ⁇ alkyl covalently bonded to an oxygen atom.
  • a C-1-C 6 alkoxy group has the general structure -0-(Cr Ce)alkyl.
  • C I -C ⁇ alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
  • CrC ⁇ alkoxycarbonyl refers to a CrC 6 alkoxy group covalently bonded to a carbonyl.
  • C 1 -Ce alkyl refers to a substituted or unsusbstituted straight or branched chain alkyl groups having 1-6 carbon atoms.
  • C 1 -C- 6 alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2- pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl.
  • a C r C 6 alkyl substituent may be covalently bonded to an atom within a molecule of interest via any chemically suitable portion of the CrC 6 alkyl group.
  • CrC ⁇ alkylamino refers to a CrC ⁇ alkyl covalently bonded to -NH- .
  • a CrC 6 alkylamino group has the general structure -NH-(Cr C 6 )alkyl.
  • a di(C r C 6 )alkylamino group has the general structure -N-[(C r C 6 )alkyl] 2 .
  • CrC 6 alkylamino groups include, for example, methylamino, ethylamino, propylamine and butylamino.
  • CrCe alkylene refers to a linear saturated divalent substituted or unsubstituted hydrocarbon radical or a branched saturated divalent hydrocarbon radical having 1 - 6 carbon atoms.
  • An alkylene can be further substituted with Cr Ce alkyl and aryl groups.
  • Alkylene groups include, for example, methylene, ethylene, propylene, butylene, 2-methylpropylene, pentylene.
  • Cycloalkyl refers to a substitutued or unsubstitutued monovalent cyclic hydrocarbon group of three to seven ring carbons.
  • the cycloalkyl group can have one or more double bonds and can be further substituted with C 1 -C 6 alkyl and aryl groups.
  • the term cycloalkyl includes, for example, cyclopropyl, cyclohexyl, cyclohexenyl, phenylcyclohexyl, 4-carboxycyclohexyl, 2- carboxamidocyclohexenyl, 2-dimethylaminocarbonyl-cyclohexyl, and the like.
  • Aryl refers to a substituted or unsusbstituted moiety that includes one or more monocyclic or fused ring aromatic systems. Such moieties include any moiety that has one or more monocyclic or bicyclic fused ring aromatic systems, including but not limited to phenyl and naphthyl.
  • Halogen or halo refers to fluorine, chlorine, bromine, and iodine.
  • Heteroaryl refers to a substituted or unsusbstituted monocyclic aromatic system having 5 or 6 ring atoms, or a fused ring bicyclic aromatic system having 8 - 20 atoms, in which the ring atoms are C, O, S, SO, SO 2 , or N and at least one of the ring atoms is a heteroatom, i.e., O, S, SO, SO 2 , or N.
  • Heteroaryl groups include, for example, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothio- furanyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl
  • Heterocyclyl refers to a substituted or unsubstituted monocyclic or fused ring multicyclic cycloalkyl group at least a portion of which is not aromatic and in which one or more of the carbon atoms in the ring system is replaced by a heteroatom selected from the group consisting of O, S, SO, SO 2 , P, or N.
  • heterocyclyl groups include but are not limited to imidazolinyl, morpholinyl, piperidinyl, piperidin-2-only, piperazinyl, pyrrol id inyl, pyrrolidine-2- onyl, tetrahydrofuranyl, and tetrahydroimidazo [4,5-c] pyridinyl.
  • C 1 -C 6 heteroalkylene refers to a CrC 6 alkylene as defined above wherein 1 - 3 carbon atoms in the hydrocarbon radical or a branched saturated divalent hydrocarbon radical is replaced with a heteroatom.
  • Ci-C 6 heteroalkylene groups include, for example, -CH 2 CH 2 -O-CH 2 CH 2 - and -CH 2 CH 2 -S-CH 2 CH 2 -.
  • C 1 -C 6 heteroalkyl refers to a C 1 -C 6 alkyl as defined above wherein 1 - 3 carbon atoms in the hydrocarbon radical or a branched saturated divalent hydrocarbon radical is replaced with a heteroatom.
  • C 1 -C 6 heteroalkyl groups include, for example, -CH 2 CH 2 -O-CH 2 CH 3 and -CH 2 CH 2 -S-CH 2 CH 3 .
  • Phosphoramidate alkylators refer to phosphordiamidic acid compounds (or mustards) having up to four substituted or unsubstituted -CH 2 -CH 2 -X moieties, wherein X is selected from the group consisting of halo and an 0-SO 2 - Y moiety wherein Y is CrC 6 alkyl, CrC 6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • Phosphoramidate alkylators include, for example, ifosfamide alkylator, dibromoifosfamide alkylator, cyclophosfamide alkylator, and N, N, N', N' -tetrakis-2-haloalkyl phosphoramidate alkylators. Examples of other phosphoramidate alkylators are provided in PCT Patent App. Pub. No. WO 07/002931 and US Pat. No. 6,197,760 each of which is incorporated herein by reference.
  • “Pyrophosphoramide alkylators” refer to linear or cyclic anhydrides of phosphoramidate alkylators containing two or more phosphoramidate alkylator moieties.
  • Substituent refers to an atom or group, including, for example, amino, C-i-C ⁇ alkylamino or di(C- ⁇ -C 6 )alkylamino, C-i-C ⁇ alkoxy, C-1-C 6 alkylthio, aryl, - COOH, -CONH 2 , cyano, ethenyl, ethynyl, halo, heteroaryl, hydroxy, mono- or di(Ci-C 6 )alkylcarboxamido, mono or d ⁇ CrC ⁇ alkylsulfonamido, nitro, -OSO 2 -(Cr C 6 )alkyl, and -SO 2 NH 2 .
  • administering or “administration of” a drug to a patient (and grammatical equivalents of this phrase) refers to direct administration, which may be administration to a patient by a medical professional or may be self- administration, and/or indirect administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.
  • “About” refers to ⁇ 20% of a quantity and includes, but is not limited to, ⁇ 15%, ⁇ 10%, and ⁇ 5%.
  • Cancer refers to leukemias, lymphomas, and malignant tumors of potentially unlimited growth that can expand locally by invasion and systemically by metastasis.
  • cancers include, but are not limited to cancer of the adrenal gland, bone, brain, breast, bronchi, colon and/or rectum, gallbladder, head and neck, kidneys, larynx, liver, lung, neural tissue, pancreas, prostate, parathyroid, skin, stomach, and thyroid.
  • cancers include, acute and chronic lymphocytic and granulocytic tumors, adenocarcinoma, adenoma, basal cell carcinoma, cervical dysplasia and in situ carcinoma, Ewing's sarcoma, epidermoid carcinomas, giant cell tumor, glioblastoma multiforma, hairy-cell tumor, intestinal ganglioneuroma, hyperplastic corneal nerve tumor, islet cell carcinoma, Kaposi's sarcoma, leiomyoma, leukemias, lymphomas, malignant carcinoid, malignant melanomas, malignant hypercalcemia, marfanoid habitus tumor, medullary carcinoma, metastatic skin carcinoma, mucosal neuroma, myeloma, mycosis fungoides, neuroblastoma, osteo sarcoma, osteogenic and other sarcoma, ovarian tumor, pheochromocytoma, polycythemia vera, primary brain tumor, small-
  • Hyperproliferative disease refers to a disease characterized by cellular hyperproliferation (e.g., an abnormally increased rate or amount of cellular proliferation).
  • hyperproliferative diseases other than cancer include, but are not limited to, allergic angiitis and granulomatosis (Churg-Strauss disease), asbestosis, asthma, atrophic gastritis, benign prostatic hyperplasia, bullous pemphigoid, coeliac disease, chronic bronchitis and chronic obstructive airway disease, chronic sinusitis, Crohn's disease, demyelinating neuropathies, dermatomyositis, eczema including atopic dermatitis, eustachean tube diseases, giant cell arteritis, graft rejection, hypersensitivity pneumonitis, hypersensitivity vasculitis (Henoch-Schonlein purpura), irritant dermatitis, inflammatory hemolytic anemia, inflammatory neutropenia, inflammatory bowel disease
  • “Pharmaceutically acceptable carrier, excipient, or diluent” refers to a carrier, excipient, or diluent that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier, excipient, or diluent that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable carrier, excipient, or diluent” includes one and more than one such carrier, excipient, or diluent.
  • Prodrug refers to a compound that, after administration, is metabolized or otherwise converted to a biologically active or more active compound (or drug) with respect to at least one property.
  • a prodrug, relative to the drug is modified chemically in a manner that renders it, relative to the drug, less active or inactive, but the chemical modification is such that the corresponding drug is generated by metabolic or other biological processes after the prodrug is administered.
  • a prodrug may have, relative to the active drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor (for example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference).
  • a prodrug may be synthesized using reactants other than the corresponding drug.
  • Reduction of a symptom or symptoms refers to decreasing the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • “Therapeutically effective amount" of a drug refers to an amount of a drug that, when administered to a subject with cancer or another hyperproliferative disease, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of cancer or another hyperproliferative disease in the subject.
  • the full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations.
  • Treating" a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms of cancer or another hyperproliferative disease; diminishment of extent of disease; delay or slowing of disease progression; amelioration, palliation, or stabilization of the disease state, or other beneficial results described more particularly below.
  • Phosphoramidate alkylators have been used in treatment of cancer. Because of the reactivity and instability of the phosphoramidate alkylators, these alkylators are administered as prodrugs that are more stable than their corresponding alkylators. Upon administration, the phosphoramidate alkylator prodrugs are metabolized, releasing the alkylator, which kills cancer cells. For example, cyclophosfamide, a prodrug of cyclophosfamide alkylator, and ifosfamide, a prodrug of ifosfamide alkylator, are used in cancer treatment.
  • cyclophosfamide and ifosfamide prodrugs are problematic, because when metabolized, they produce the toxic byproduct acrolein, which can cause unwanted side effects.
  • the present invention arises in part out of the discovery that anhydrides of phosphoramidate alkaylators such as pyrophosphoramides are excellent prodrugs.
  • an ionizable hydroxyl group, "P-OH” is converted into a "P-O-P” type, charge neutral, oxygen atom.
  • the pyrophosphoramide alkylator is more stable to hydrolysis, aminolysis, and/or thiolysis, compared to the corresponding phosphoramidate alkylator.
  • the "P-O-P" linker is hydrolyzed and the phosphoramidate alkylator is released and can kill cancer cells.
  • the present invention provides anhydrides of phosphoramidate alkylators containing two or more phosphoramidate alkylator moieties. In one embodiment, the present invention provides pyrophosphoramide alkylators containing two phosphoramidate alkylator moieties. In another embodiment, the present invention provides pyrophosphoramide alkylators wherein each of the phosphoramidate alkylator moieties is the same. In another embodiment, the present invention provides pyrophosphoramide alkylators wherein each of the alkylator moieties is different.
  • each of the alkylator moieties is an ifosfamide alkylator, a dibromoifosfamide alkylator, a cyclophosfamide alkylator, an N,N,N',N'-tetrakis-2-haloalkyl phosphoramidate alkylator, or an analog of one of the foregoing.
  • the pyrophosphoramide alkylator is a bis-ifsofamide alkylator.
  • the present invention provides a pyrophosphoramide alkylator having structure of formula:
  • each R 1 - R 8 is independently selected from the group consisting of H, C 1 -Ce alkyl, and the moiety:
  • each Rg- R 1 I is O.
  • the present invention provides a pyrophosphoramide alkylator having structure of formula:
  • the present invention provides a pyrophosphoramide alkylator having structure of formula:
  • R 2 , R 4 , R 6 , and Rs are defined as above.
  • the present invention provides a pyrophosphoramide alkylator having structure of formula:
  • R 12 is selected from the group consisting of halo and OSO 2 R 14 .
  • R 12 is selected from the group consisting of chloro and bromo.
  • R 12 is a 4-hydroxyphenylsulfonyloxy moiety:
  • n O - 4 and R 16 is selected from the group consisting of halo, cyano, nitro, C 1 -C 6 alkyl, CrC 6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • a 4-hydroxyphenylsulfonyloxy moiety can be ionized to a phenoxide anion at neutral pH and be charge neutral at lower pH. Extracellular regions of tumors reportedly have lower pH compared to that of normal tissue.
  • a pyrophosphoramide alkylator containing a 4- hydroxyphenylsulfonyloxy moiety as a leaving group can exist in the extracellular region of a tumor in its charge neutral form.
  • the charge neutral form can permeate through the cell membrane more easily than the ionized anionic form and thus, pyrophosphoramide alkylators containing one or more 4-hydroxyphenylsulfonyloxy moieties can selectively enter into and kill tumor cells compared to normal cells.
  • pyrophosphoramide alkylators of the present invention examples include:
  • the present invention provides pharmaceutically acceptable formulations comprising the pyrophosphoramide alkylators of the present invention.
  • the pharmaceutically acceptable formulations further comprise a suitable carrier, excipient, or diluent.
  • the pyrophosphoramide compounds of the present invention can be synthesized by reacting a phosphoramidate alkylator with a trisubstitutued phosphine and a dialkylazdicarboxylate under Mitsunobu reaction conditions.
  • the present invention provides methods of synthesizing novel pyrophosphoramide alkylators and known pyrophosphoramide compounds comprising, reacting a phosphoramidate alkylator or a phosphoramidate; a trisubstituted phosphine; and a dialkylazodicarboxylate.
  • the method comprises reacting a phosphoramidate alkylator having a structure of formula:
  • R-i - R 4 is defined as above, under reaction conditions described as above.
  • R 1 and R 3 are hydrogen.
  • each R 2 and R 4 is independently selected from the group consisting of 2-chloroethyl, 2-bromoethyl, and -CH 2 - CH 2 -OSO 2 R 14 wherein R 14 is defined as above.
  • the trisubstitued phosphine is selected from the group consisting of from triphenyl phosphine, tributyl phosphine, and a resin bound triphenyl phosphine.
  • the dialkylazodicarboxylate is selected from diethylazodicarboxylate and diisopropylazodicarboxylate.
  • pyrophosphoramide alkylators are synthesized by reacting phosphoramidate alkylators, a dicycloalkyl or dialkylcarbodiimide, and optionally, amines such as a trialkylamine and/or a 4-dialkylaminopyridine.
  • amines such as a trialkylamine and/or a 4-dialkylaminopyridine.
  • the pyrophosphoramide alkylators are synthesized by reacting a compound having a structure of formula:
  • a pyrophosphoramide alkylator of the present invention in accordance with this method of the present invention is schematically shown below and can be used for synthesizing other pyrophosphoramide alkylators of the present invention:
  • Suitable bases useful in the method include, but are not limited to trialkyl amines and pyridines.
  • Other pyrophosphoramide alkylator of the present invention can be synthesized following the method described above by appropriate substitution of starting material.
  • the present invention provides a method of synthesizing a pyrophosphoramide alkylator of the present invention having a structure of formula:
  • Ri 2 is selected from the group consisting of halo and OSO 2 R 14 wherein R 14 is selected from the group consisting of C 1 -C 6 alkyl, C-i-C ⁇ heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl comprising reacting a compound having a structure of formula: or a pharmaceutically acceptable salt thereof; a base selected from the group consisting of a trialkylamine and a pyridine analog, and water to yield the compound having a structure of formula:
  • R-12 is chloro. In another embodiment, R 12 is bromo. In another embodiment, the amine is triethyl amine. In one embodiment, the pyridine analog is a 4-N,N-dialkylaminopyridine. The synthesis of Compound 2 according to this method is described in Section IV.1. B.
  • Compounds 1-4 can be synthesized by a Mitsunobu reaction employing triphenyl phosphine and diisopropyl or diethyl azodicarboxylate.
  • Pyrophosphoramide alkylators of the present invention can also be synthesized following synthetic methods reported, for example, in PCT Patent App. Pub. No. WO 07/002931 ; US Pat. No. 4,518,413; and GB 985,996 (each of which is incorporated herein by reference), modified in accordance with the teachings herein and appropriate substitution of starting material.
  • Compound 1 a pyrophosphoramide alkylator of the present invention, was effective in treating cancer as demonstrated by treating various xenograft solid tumors in mice, when administered alone and in combination with a variety of other anticancer agents.
  • Suitable anticancer agents, useful in combination with Compound 1 included, CDDP and gemcitabine.
  • Various modes of administration and dosing schedules were found to be effective in the treatment of cancer. These and other monotherapies and combination therapies for administering Compound 1 are described in Examples 5.A - C below.
  • the present invention provides a method of treating cancer and other hyperproliferative diseases comprising administering a therapeutically effective amount of a pyrophosphoramide alkylator of the present invention to a patient in need of such treatment.
  • the present invention provides a method of treating cancer and other hyperproliferative diseases comprising administering a therapeutically effective amount of a pyrophosphoramide alkylator of the present invention having structure of formula:
  • the pyrophosphoramide alkylator administered has the structure of formula:
  • the pyrophosphoramide alkylator administered is compound 1.
  • the pyrophosphoramide alkylators of the present invention are administered in the form of pharmaceutically acceptable formulations.
  • the pharmaceutical formulations are administered parenteraliy or orally (p.o.).
  • the pharmaceutical formulations are administered by i.v. or i.p. injection or by infusion.
  • the pyrophosphoramide alkylators of the present invention can be administered in accordance with any of a variety of dosing schedules including but not limited to daily or once every other day or once a week to the patient. Multiple daily administrations of a pyrophosphoramide alkylator of the present invention can also be employed in the methods of the invention. Depending on the dose selected by the practitioner and the convenience of the patient, the entire daily dose may be administered once daily or the daily dose may be administered in multiple smaller doses throughout the course of a day.
  • the pyrophosphoramide alkylators of the present invention need not, however, be administered daily; for example a daily dose used for some patients or indications may be, in other patients or for other indications, given every other day, or less frequently.
  • the daily dose is repeatedly administered over a period of time.
  • the administration of the therapeutically effective daily dose is continued for multiple days, typically for at least three consecutive days, or for at least a week, or for several weeks, or for several months, or for several years, or until cancer (or another hyperproliferative disease) or one or more of its symptoms disappears or substantially abates, or up to the rest of the patient's life.
  • cancer or another hyperproliferative disease
  • treatment can be suspended temporarily if toxicity is observed or for the convenience of the patient without departing from the scope of the invention.
  • the pyrophosphoramide alkylators of the present invention are administered qd, bid, tid, qid, qod, q2d, twice weekly, q7d, or qweek, and treatment is continued for a period ranging from three days to the longer periods enumerated above.
  • the methods of the present invention can be used for treatment of any cancer.
  • the compound of the present invention is administered for the treatment of cancer in combination with other anti cancer agents or other anti cancer therapies.
  • Suitable anticancer therapies useful in accordance with the present methods include, but are not limited to, radiation therapy and surgery.
  • the present invention provides a method of treating hyperproliferative diseases characterized by cellular hyperproliferation (e.g., an abnormally increased rate or amount of cellular proliferation) other than cancer, by administering a therapeutically effective amount of a pyrophosphoramide alkylator to a patient in need of such treatment.
  • hyperproliferative diseases characterized by cellular hyperproliferation (e.g., an abnormally increased rate or amount of cellular proliferation) other than cancer, by administering a therapeutically effective amount of a pyrophosphoramide alkylator to a patient in need of such treatment.
  • This example describes the synthesis of compound 1 , a novel pyrophosphoramide alkylator of the present invention, from dibromoifosfamide alkylator (Br-IPM) and DCC.
  • a mixture of Br-IPM (1.24 g, 4 mmol) and dicyclohexylcarbodiimide (DCC, 1.24 g, 6 mmol) in THF (20 ml_) was stirred at room temperature (rt). After 2 h, thin layer chromatography (15:1 (v/v) ethyl acetate/methanol) of the reaction mixture showed that the reaction was completed.
  • Compound 1 can be synthesized employing this method and substituting 2-chloroethylamine hydrochloride with 2-bromoethylamine hydrobromide.
  • H460 cells ATCC HTB-177 (NCI- H460), 20,000 cells/well/500 ⁇ l_
  • RPMI medium Invitrogen Corp.
  • the cells in the treatment group were rinsed to remove compound 1 , further incubated for 3 days, and then stained with Alamar blue for 2 h.
  • the cells were stained with Alamar blue for 2 h.
  • the IC 50 of compound 1 was calculated from the plot as the concentration of compound 1 at which there was a 50% reduction in cell proliferation compared to the control group. See Biosource International Inc., Tech Application Notes, Use of Alamar Blue in the Measurement of Cell Viability and Toxicity, Determining IC 50 .
  • the antiproliferative activity of compound 1 was determined in HT29, PC3, and MiaPaCa-2 cell lines in the same way as described above for the H460 cell line.
  • test compound 1 can be incubated with the test compound, compound 1 , at various concentrations for 3 days and the antiproliferation activity of the test compound determined as described above for the 2h treatment group.
  • the results from these tests are tabulated below (Table 1 , average value of IC 50 presented, if multiple tests were done with one cell line). This method can be employed to measure the antiproliferative activities of other compounds of the present invention.
  • This example demonstrates the cytotoxic property of compound 1 by determining clonogenic cell survival.
  • Exponentially growing human colon cancer HT29 cells obtained from the ATCC
  • HT29 cells obtained from the ATCC
  • RPMI medium supplemented with 10 % fetal bovine serum for 2 days prior to initiating drug treatment.
  • solutions of Compound 1 of known concentration were prepared in complete medium, 2 mL of the desired solution added to each plate, and the cells were incubated under an atmosphere of 95% air and 5% carbon dioxide for 2 h at 37°C. Then, the cells were rinsed to remove compound 1.
  • the glass plates were washed with phosphate buffered saline and a solution of trypsin-EDTA and then trypsinized at 37 0 C for 5 min. Detached cells were neutralized with medium and serum, collected by centrifugation at 100xg for 5 min, resuspended at approximately 1x10 6 cells/mL, and diluted 10 fold to yield stock concentrations of treated cells for plating. The concentration of each stock was determined by counting with a Coulter Z2 particle counter. Known numbers of cells were plated, and the plates were placed in an incubator for between 7 and 10 days. Colonies were fixed and stained with a solution of 0.25% crystal violet in 95% ethanol. Colonies of greater than 50 cells were counted.
  • the surviving fraction of treated cells was measured by comparison with colony numbers obtained from untreated cells, and the concentration of compound 1 at which 10% cells survived (or 90% cell death), or IC 90 determined. See Table 1 below. This method can be employed to measure the cytotoxicities of other compounds of the present invention. Table 1
  • cancer such as, non small cell lung cancer
  • a compound of the present invention can be administered in an amount in a range of about 0.01 mg/kg - about 60 mg/kg and about 0.06 mg/kg - about 6 mg/kg for treating cancer in humans.
  • H460 xenograft tumor bearing mice were treated with Compound 1 orally at 200 mg/kg once or at 50 mg/kg, everyday for 5 days.
  • the monotherapy, i.e., a single agent administration, of Compound 1 at 50 mg/kg daily dosing demonstrated similar tumor growth inhibition as CDDP alone.
  • the monotherapy of Compound 1 at 200 mg/kg single dose demonstrated a higher tumor growth inhibition than Compound 1 dosed once daily.
  • the combination therapy administering Compound 1 at 200 mg/kg single dose and at 50 mg/kg once daily dosing resulted in a similar tumor growth inhibition.
  • the TGDs as compared to vehicle treated tumors, to reach 500 mm 3 , were 6 and 7 days respectively, when Compound 1 was administered alone at 200 mg/kg and 50 mg/kg; they were 12 and13 days respectively when Compound 1 was administered at the same amount and in combination with CDDP. Tumor growth was inhibited 56% and 64% when Compound 1 was administered alone at 200 mg/kg and 50 mg/kg, and 84% and 85% when Compound 1 administered at the same amount was co-administered with CDDP. Animals in the drug treated groups lost weight during the treatment period, but recovered after dosing stopped, demonstrating that the administration of Compound 1 , in accordance with the present methods is effective and safe for the treatment of cancer. C.
  • Compound 1 when administered orally, to treat xenografted H460 lung tumor in nude mice, by administering Compound 1 as a monotherapy, and in combination with gemcitabine.
  • Compound 1 was formulated (2.5, 5, and 20 mg/ml_) in a vehicle (2% DMSO, 0.5% Tween ⁇ O, and 0.5% carboxymethyl cellulose (CMC) in water).
  • Gemcitabine (6 mg/mL) was formulated in saline. The drug formulations were prepared weekly, stored at 4 0 C, and diluted prior to administration.
  • H460 cells were prepared in 50% matrigel and 50% PRIM medium and were implanted (1 x 10 6 . 0.2 mL/mouse) subcutaneously on the right flank of the mice. Tumor lumps were measurable on the seventh day post-implantation and were about 100 mm 3 on the eleventh day.
  • Mice with similar tumor size were randomized for treatment and treated as follows: Compound 1 was administered orally (p.o.), once every day for 5 days/week for 2 weeks (qd x 5 x 2 weeks) at amounts of 25 and 50 mg/kg, and once every week for 2 weeks at amounts of 200 mg/kg, alone, and in combination with gemcitabile (i.p., 60 mg/kg, q3dx4); in all 6 groups of 10 mice each were thus treated. A group of 10 tumor bearing mice were used as no-treatment control. The results of tumor growth inhibition upon administration of Compound 1 alone and in combination are tabulated below.
  • T/C (Tn-Ti)/(Cn-Ci)
  • Tn tumor volume in treatment group at Day 31
  • Ti is the initial tumor volume in the treatment group
  • Cn tumor volume in the vehicle control group at Day 31
  • Ci is the initial tumor volume in the vehicle control group.
  • TGI tumor growth inhibition
  • the drug treated groups showed weight loss during the treatment period, but recovered after drug administration was stopped.
  • the administration of Compound 1 according to the present methods was effective and safe to treat the tumors.
  • Compound 1 was administered to mice bearing HT29 xenograft tumor, alone and in combination with CPT-11 , the results indicated that Compound 1 was more effective in treating mice bearing H460 xenograft tumor than mice bearing HT29 tumor.
  • human equivalent doses can be estimated from doses administered to mice by dividing the mouse dose by -12.
  • a compound of the present invention can be administered in a daily dose in the range of about 0.02 mg/kg - about 1700 mg/kg and about 0.2 mg/kg - about 170 mg/kg for treating cancer in humans.

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Abstract

L'invention concerne des agents d'alkylation pyrophosphoramide utiles dans le traitement du cancer et d'autres maladies hyperprolifératives.
PCT/US2007/087429 2006-12-13 2007-12-13 Agents d'alkylation pyrophosphoramide WO2008076826A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8003625B2 (en) 2005-06-29 2011-08-23 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US8299088B2 (en) 2003-03-28 2012-10-30 Threshold Pharmaceuticals, Inc. Compositions and methods for treating cancer
US8552048B2 (en) 2006-12-26 2013-10-08 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs for the treatment of cancer

Citations (4)

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Publication number Priority date Publication date Assignee Title
US4203977A (en) * 1977-10-13 1980-05-20 Basf Aktiengesellschaft Phosphoric acid esters, composition and use
US4661509A (en) * 1982-09-28 1987-04-28 Gordon Arnold Z Methods for treating leukopenia
US20050239054A1 (en) * 2002-04-26 2005-10-27 Arimilli Murty N Method and compositions for identifying anti-HIV therapeutic compounds
WO2006103568A2 (fr) * 2005-03-22 2006-10-05 Innate Pharma Nouvelle classe d'activateurs de cellules g? t et utilisation correspondante

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4203977A (en) * 1977-10-13 1980-05-20 Basf Aktiengesellschaft Phosphoric acid esters, composition and use
US4661509A (en) * 1982-09-28 1987-04-28 Gordon Arnold Z Methods for treating leukopenia
US20050239054A1 (en) * 2002-04-26 2005-10-27 Arimilli Murty N Method and compositions for identifying anti-HIV therapeutic compounds
WO2006103568A2 (fr) * 2005-03-22 2006-10-05 Innate Pharma Nouvelle classe d'activateurs de cellules g? t et utilisation correspondante

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8299088B2 (en) 2003-03-28 2012-10-30 Threshold Pharmaceuticals, Inc. Compositions and methods for treating cancer
US8003625B2 (en) 2005-06-29 2011-08-23 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US8507464B2 (en) 2005-06-29 2013-08-13 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US8664204B2 (en) 2005-06-29 2014-03-04 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US9226932B2 (en) 2005-06-29 2016-01-05 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US8552048B2 (en) 2006-12-26 2013-10-08 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs for the treatment of cancer

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