WO2006037090A2 - Promedicaments contenant des conjugues de phosphate-medicament et des analogues de ceux-ci - Google Patents

Promedicaments contenant des conjugues de phosphate-medicament et des analogues de ceux-ci Download PDF

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WO2006037090A2
WO2006037090A2 PCT/US2005/034974 US2005034974W WO2006037090A2 WO 2006037090 A2 WO2006037090 A2 WO 2006037090A2 US 2005034974 W US2005034974 W US 2005034974W WO 2006037090 A2 WO2006037090 A2 WO 2006037090A2
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prodrug
drug
group
alkyl
phosphate
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WO2006037090A3 (fr
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Richard Frederic Borch
Irene George Boutselis
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Purdue Research Foundation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to intracellular delivery of phosphate-substituted therapeutic compounds and analogs thereof. More particularly, this invention relates to prodrugs of phosphorus containing compounds, and prodrugs of drug-phosphate conjugates and analogs of drug-phosphate conjugates.
  • phosphate-substituted compounds such as biologically active peptides and nucleotides.
  • phosphate-substituted compounds possess a relatively high localized negative charge that may lead to low cellular permeability.
  • protein tyrosine kinases are important regulators of cell cycle progression, and represent attractive targets for the rational design of novel anticancer agents. Protein tyrosine kinases are activated upon phosphorylation of specific tyrosine residues of the kinases and the phosphotyrosine residue along with the three adjacent amino acids (p Y-E-E-I) serve as a binding site for Src homology 2 (SH2) domains of intracellular signaling proteins.
  • SH2 Src homology 2
  • Interaction between an SH2 domain of an intracellular signaling molecule and an activated protein tyrosine kinase is essential for effective cell cycle progression.
  • molecules that mimic the phosphotyrosine moiety of protein tyrosine kinases and block the binding of protein tyrosine kinases to SH2 domains represent promising antiproliferative agents for the treatment of cancers.
  • the phosphate dianion on tyrosine-phosphorylated protein tyrosine kinases is implicated in the successful kinase-SH2 domain interaction.
  • the crystal structures of a number of ligand-SH2 domains have been reported, the interactions have been modeled, and many different inhibitors have been synthesized.
  • the phosphotyrosine residue is involved in a complex network of hydrogen bonding and charge-charge interactions that involve extensive interaction of the SH2 domain with the phosphate dianion of the tyrosine phosphate moiety.
  • Nucleotide analogs represent another class of promising agents for use in treating disease states caused by uncontrolled viral or cellular replication. Like tyrosine phosphate peptidomimetics, the phosphate dianion of nucleotide analogs is implicated in the capacity of these compounds to block viral or cellular replication.
  • General approaches for the use of nucleotide analogs as therapeutic agents involve delivering the nucleoside analog as a prodrug across the cell membrane and to rely on the cellular machinery to link a phosphate group to the sugar portion of the purine or pyrimidine base-containing nucleoside to form the corresponding nucleotide analog.
  • nucleosides with therapeutic promise are not converted to the corresponding nucleotide by existing cellular pathways.
  • tumor cells or virus-infected cells may become resistant to treatment by down-regulating the activity of nucleoside kinases, and, for many previously developed nucleotide prodrugs, the intracellular activation process may be so inefficient that effective nucleotide concentrations do not accumulate within the cell.
  • the invention described herein is directed to drugs or drug conjugates that include one or more phosphate fragments or analogs of phosphate fragments.
  • various linkers other than oxygen connecting the phosphate fragment to the remaining portion of the drug are included, such as but not limited to linkers forming phosphoramidates, phosphonates, difluorophosphonates, oxophosphonates, and the like.
  • the invention described herein is also directed to drugs that are phosphorylated after delivery. It is appreciated that those drugs that are phosphorylated after delivery may only become active as drugs following phosphorylation.
  • the invention described herein is also directed to analogs of drugs that are phosphorylated after delivery.
  • Analogs of drugs that are phosphorylated after delivery include phosphorylated drugs where the linker connecting the phosphate fragment to the drug fragment is other than oxygen, such as but not limited to linkers forming phosphoramidates, phosphonates, difluorophosphonates, oxophosphonates, and the like.
  • prodrugs of each of these drugs, drug-phosphate conjugates, and phosphate analogs thereof may enhance their efficacy and specificity.
  • prodrugs of drugs that include a phosphate fragment or phosphate fragment analog are described, hi another embodiment, analogs of prodrugs of drugs that include a phosphate fragment or phosphate fragment analog are described, hi this latter embodiment, the phosphate frgament or phosphate fragment analog that is generally associated with the drug is replaced with a phosphate fragment analog or another phosphate fragment analog, respectively.
  • prodrugs of drugs that are phosphorylated after delivery are described.
  • the prodrugs may be derived from phosphorylated versions of the drug and/or from analogs of phosphorylated versions of the drug, including but not limited to phosphoramidates, phosphonates, difluorophosphonates, oxophosphonates, and the like.
  • delivery is to be understood to include any in vitro, in vivo, or other in situ situation, condition, or set of conditions where the drug is introduced to the situation, condition, set of conditions, or reaction condition under which it is phosphorylated.
  • drug from which prodrugs as described herein are derived will refer both to drugs that include a phosphate moiety or analog thereof, and to drugs that do not include a phosphate moiety or analog thereof but are phosphorylated after delivery such as in vivo by an endogenous process. It will be understood by the context whether the term drug is referring to a drug that does not include a phosphate moiety or analog thereof or referring to a drug that ordinarily includes a phosphate moiety or analog thereof, but where that phosphate moiety or analog thereof has been replaced by a phosphate analog described herein. It is also to be understoon that the term “drug” includes derivatives of drugs and drug fragments described above. Such derivatives may be prepared to include additional atoms or functional groups that are used for attaching the phosphorus-containing portion of the prodrug.
  • the phosphate-substituted compound to be delivered intracellularly is synthesized to include a delivery group and a masking group.
  • the masking group is illustratively a (substituted alkyl)amino or bis(substituted alkyl) amino moiety that may be modified intracellularly.
  • such (substituted alkyl)amines may be secondary or tertiary amines, i.e., there may be remaining hydrogen on the amine, or it may be further substituted with alkyl as descrbied herein, hi one aspect, modification of the masking group occurs while retaining the delivery group. In another aspect, the delivery group is removed before modification of the masking group occurs. In another aspect, the masking group undergoes intramolecular cyclization and subsequent cleavage by hydrolysis. In another aspect, intramolecular cyclization occurs contemporaneously, or even simultaneously in a concerted or anchimerically-assisted process, with hydrolysis of the masking group.
  • the masking group is generally stable as long as the delivery group remains attached to the phosphorus atom.
  • the delivery group is generally a group that is subject to intracellular hydrolysis, such as a biologically labile ester-forming group, or an ester that is readily hydrolyzed intracellularly.
  • the delivery group includes nitrofuryl groups, perhydrooxazines, optionally substituted benzyl groups, and the like.
  • a mechanism of prodrug release of drug-phosphate, optionally substituted drug-phosphoramidate, or optionally substituted drug-phosphonate conjugates described herein is outlined in Scheme 2.
  • the masking group is illustratively a chlorobutylmethylamine.
  • the masking group undergoes intramolecular cyclization and P-N bond cleavage (i.e., spontaneous or via hydrolysis) in the intracellular environment, thus releasing the desired phosphate-containing compound, or phosphate analog thereof.
  • the sequence of steps leading to release of the drug or drug-conjugate free of both the masking and delivery groups may occur in a different order.
  • removal of the delivery group may precede any intracellular modification of the masking group, as shown above.
  • cyclization of the masking group may be followed by immediate P-N bond cleavage prior to removal of the delivery group. It is to be understood that further variation of the mechanisms of release of the drug or drug-conjugate are contemplated.
  • the (substituted alkyl)amine or bis(substituted alkyl)amine is a substituted ethylamine or bis(substituted ethyl)amine, such as an ethyl substituted with a leaving group including halo, alkoxy, acyloxy, optionally substituted alkylsulfonyloxy, optionally substituted arylsulfonyloxy, and the like.
  • the leaving group is understood to be any electrophilic group capable of being nucleophilically displaced from the carbon atom to which it is bound, either intermolecularly or intramolecularly.
  • nucleophilic lability of the leaving group can be exploited in a controlled fashion to facilitate the unmasking of the prodrug and ultimate release of the drug phosphate conjugate or analog thereof.
  • substituted ethylamine or bis(substituted ethyl)amine variants of the masking group including the haloethylamine or bis(haloethyl)amine derivatives, may also lead to irreversible adducts such as formation of cross-linked structures with nucleic acids like DNA and RNA, enzymes, and the like.
  • the (substituted alkyl)amine or bis(substituted alkyl)amine includes a longer chain (substituted alkyl)amine, such as a substituted butyl and/or substituted pentyl group.
  • the substitutions include leaving groups such as halo, alkoxy, acyloxy, optionally substituted alkylsulfonyloxy, optionally substituted arylsulfonyloxy, and the like.
  • the alkyl may have branching substituents, including additional alkyl groups, spiro-ring fusions, halo groups, such as fluoro, and the like.
  • the branching substituents are not also leaving groups.
  • the prodrugs described herein may be formed from a wide variety of drugs or drug fragments that include a phosphate or phosphate analog, or drugs that are phosphorylated, and analogs thereof.
  • prodrugs of nucleotide analogs, phosphotyrosine peptides and peptidomimetics, and other pharmaceutically significant compounds containing phosphate moieties are described.
  • prodrugs of phosphotyrosine peptides and peptidomimetics may be synthesized from protected phosphotyrosine precursor phosphoramidates as described herein.
  • the invention is also directed to protected phosphotyrosine precursors and related protected peptides, for example, with N-Boc (tert-butoxycarbonyl) and N-Fmoc (fluorenylmethoxycarbonyl) groups.
  • N-Boc tert-butoxycarbonyl
  • N-Fmoc fluorenylmethoxycarbonyl
  • prodrugs of phosphoserine and phosphothreonine analogs are described herein. Synthesis of these variants may be accomplished by conventional methods, and similarly to the syntheses described herein for phosphotyrosine analogs, which may be correspondingly adapted.
  • the prodrugs described herein are formed from drugs that are phosphorylated in vivo after delivery or administration to a patient being treated for a disease state for which the drug is useful.
  • the drug is more active, or activated only, after phosphorylation by a biological pathway in the patient. It is appreciated that the efficacy of the drug may be hampered by the dependence upon that additional endogenous functionalization pathway. Further, in some disease states, the necessary pathway is compromised, further minimizing the efficacy of the drug.
  • the prodrugs described herein include the necessary or desirable phosphorus-containing fragment at dosing to the patient being treated, and therefore do not require additional in vivo modification or activation.
  • the prodrugs described herein are illustratively prepared to mask the negative charge, or double negative charge of the phosphorus-containing fragment. It is appreciated that highly charged molecules often suffer from poor absorption and/or transport to the relevant tissues of cells that are desirably treated.
  • the prodrugs described herein are resistant to phosphatases, including intracellular phosphatases that may cleave the phosphorus-containing fragment from the prodrug conjugate or conjugate after the prodrug is converted into the phosphorus-containing drug or drug-conjugate analog.
  • phosphatases including intracellular phosphatases that may cleave the phosphorus-containing fragment from the prodrug conjugate or conjugate after the prodrug is converted into the phosphorus-containing drug or drug-conjugate analog.
  • the efficacy of many drugs are aided by or dependent upon phosphorylation.
  • prodrugs described herein include embodiments that are resistant to metabolic degradation and therefore have increased half-lives in the patient being treated. It is appreciated that phosphatases may be particularly abundant and their presence may hamper treatment efforts. hi another illustrative embodiment, the prodrugs described herein are formed from drugs containing phosphate or drug-phosphate conjugates, and are resistant to degradation by phosphatases or other enzymes that cleave phosphorus- oxygen bonds, including nucleotidases, endonucleases, exonucleases, and the like.
  • Such degradation resistance may be accomplished by the replacement of the oxygen atom linker that connects the phosphorus fragment with the rest of the drug or drug- phosphate conjugate with a one or more carbon atoms, each of which may be substituted, such as with alkyl, fluorine, and oxo substituents, and the like.
  • R 1 is alkyl, including C 1 -C 6 alkyl, or -(CR 2 ) n X; n is an integer from 2 to about 5; R 2 is -(CR 2 ) m X; m is an integer from 2 to about 5; R is in each instance an independently selected substituent, including hydrogen, alkyl, fluoro, and the like; or any geminal pair of such groups R can be taken together with the attached carbon to form a ring, including a carbocyclic ring, or heterocyclic ring; X is a nucleophilically labile group, including halo, alkoxy, phenoxy, acyloxy, sulfonyloxy, and the like; R 3 is a biologically labile ester forming group; Drug is a biologically active compound, the activity of which is increased upon phosphorylation after delivery, or a fragment of a biologically active compound-phosphate conjugate; and A and B are each independently selected substituents, including hydrogen,
  • R 1 is alkyl, including C 1 -C 6 alkyl, or -(CR 2 ) n X; n is an integer from 2 to about 5; R 2 is -(CR 2 ) m X; m is an integer from 2 to about 5; R is in each instance an independently selected substituent, including hydrogen, alkyl, fluoro, and the like; or any geminal pair of such groups R can be taken together with the attached carbon to form a ring, including a carbocyclic ring, or heterocyclic ring; X is a nucleophilically labile group, including halo, alkoxy, phenoxy, acyloxy, sulfonyloxy, and the like; R 3 is a biologically labile ester forming group; Drug is a biologically active compound, the activity of which is increased upon phosphorylation after delivery, or a fragment of a biologically active compound-phosphate conjugate; and R 4 is hydrogen, alkyl, acyl, and
  • R is alkyl, including C 1 -C 6 alkyl, or -(CR 2 ) n X; n is an integer from 2 to about 5; R 2 is -(CR 2 ) m X; m is an integer from 2 to about 5; R is in each instance an independently selected substituent, including hydrogen, alkyl, fluoro, and the like; or any geminal pair of such groups R can be taken together with the attached carbon to form a ring, including a carbocyclic ring, or heterocyclic ring; X is a nucleophilically labile group, including halo, alkoxy, phenoxy, acyloxy, sulfonyloxy, and the like; R 3 is a biologically labile ester forming group; and Drug is a biologically active compound, the activity of which is increased upon phosphorylation after delivery, or a fragment of a biologically active compound-phosphate conjugate.
  • the drug may be modified as is necessary to provide a suitable point of attachment or provide a suitable linking atom or atoms to allow conjugation of the drug with the phosphorus- containing portion of the prodrug conjugate to be prepared.
  • the phosphorus may be attached directly to a drug through a linker, such as methylene, difluoromethylene, carbonyl, and the like, on an aromatic portion of the drug.
  • the drug may be derivatized with, for example, a suitable heteroatom, such as optionally substituted amino, and the drug derivative is then attached to the phosphorus through an optional linker.
  • an optionally substituted amino that nitrogen may be directly attached to the phosphorus to form a prodrug including a phosphordiamidate.
  • the integers n and m are each 2. hi another illustrative aspect, the integers n and m are each 4 or 5. In another illustrative aspect, each R is hydrogen. In another illustrative aspect, X is halogen, such as chloro. In another illustrative aspect, both A and B are hydrogen or both A and B are fluoro.
  • R 3 is heteroarylalkyloxy, optionally substituted with an electron withdrawing group, such as nitro, alkylsulfonyl, cyano, halo, and the like, hi another illustrative aspect, R 3 is optionally substituted arylalkyloxy, such as optionally substituted benzyl, hi another illustrative aspect where R 3 is optionally substituted benzyl, that compound may be prepared as an intermediate in the synthesis of the prodrugs described herein where R 3 is converted into heteroarylalkyloxy, optionally substituted with an electron withdrawing group.
  • an electron withdrawing group such as nitro, alkylsulfonyl, cyano, halo, and the like
  • R 3 is optionally substituted arylalkyloxy, such as optionally substituted benzyl, hi another illustrative aspect where R 3 is optionally substituted benzyl, that compound may be prepared as an intermediate in the synthesis of the prodrugs described herein where R
  • R 3 is optionally substituted 1,3- heterocycloalkyl, such as an optionally substituted tetrahydro-l,3-oxazine alkyl.
  • Drug is a phosphotyrosine peptide or peptidomimetic, a nucleoside or nucleoside analog, and the like.
  • R 3 is 4 5 4,6-trimethyl-3,4,5,6-tetrahydro-l,3-[2H]-oxazin-2-ylethyl.
  • Prodrugs described herein that include R 3 as 4,4,6-trimethyl-3,4,5,6-tetrahydro-l,3-[2H]- oxazin-2-ylethyl may be prepared by conventional methods, including those described by Borch et al. in U.S. Patent No. 5,233,031, the synthetic methods of which are incorporated herein by reference.
  • the prodrugs described herein may be applied to increase cell permeability of the drug or drug-phosphate conjugate or analog thereof, by selective activation.
  • R 3 is optionally substituted heteroarylalkyloxy
  • one variation includes nitrofuryhnethyloxy.
  • the prodrug activation may be initiated by bioreductive elimination of the delivery group followed by spontaneous liberation of the masking group, as generally described by Meyers, C.L.F.; Hong, L.; Joswig, C; and Borch, R.F. in J. Med. Chem. 43:4313-4318 (2000), the disclosure of which is incorporated herein by reference.
  • the prodrugs described herein include a phosphonate linkage between the phosphorus and the drug or drug-conjugate fragment. In another aspect, the prodrugs described herein include a difluorophosphonate linkage between the phosphorus and the drug or drug-conjugate fragment. In another aspect, the prodrugs described herein include a carbonyl linkage between the phosphorus and the drug or drug-conjugate fragment.
  • Illustrative examples of the delivered component include one or more of the following
  • Drug is virtually any biologically active compound that may be phosphorylated after delivery or a fragment of any biologically active compound that would generally be delivered as a drug-phosphate conjugate, or analog thereof.
  • Illustrative biologically active compounds include enzyme inhibitors, receptor antagonists, receptor agonists, and the like.
  • an effective amount of the prodrug compound with respect to the treatment of cancer refers to an amount of the compound which, upon administration to a patient, inhibits growth or proliferation of tumor cells, kills malignant cells, reduces the volume or size of the tumors, or eliminates tumors in the treated patient.
  • the effective amount to be administered to a patient may be based on body surface area, patient weight, and patient condition.
  • the interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich, E.J., et al., Cancer Chemother. Rep., 50 (4): 219 (1966).
  • Body surface area may be approximately determined from patient height and weight (see e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, New York, pages 537-538 (1970)).
  • An effective amount of the prodrug compounds for use in treating cancer can range from about 0.05 mg/kg to about 100 mg/kg, about 0.25 mg/kg to about 50 mg/kg, and most typically about 0.1 to about 10 mg/kg per dose. Effective doses may also vary dependent on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments, including other chemotherapeutic agents, and radiation therapy.
  • compositions of the prodrugs described herein may be administered via any route, including a parenteral route, including subcutaneously, intraperitoneally, intramuscularly and intravenously.
  • parenteral dosage forms include aqueous solutions or suspensions of the active agent in isotonic saline, 5% glucose or other well-known pharmaceutically acceptable liquid carrier, hi one aspect of the pharmaceutical compositions described herein, the compound is dissolved in a saline solution containing 5% of dimethyl sulfoxide and about 10% Cremphor EL (Sigma Chemical Company).
  • solubilizing agents such as cyclodextrins, which can form more soluble complexes with the present compounds, or other solubilizing agents well-known to those familiar with the art, can be utilized as pharmaceutical excipients for delivery of the present compounds for cancer therapy.
  • the present compounds can be formulated into dosage forms for other routes of administration utilizing conventional methods.
  • the pharmaceutical compositions can be formulated, for example, in dosage forms for oral administration in a capsule, a gel seal or a tablet.
  • Capsules may comprise any well- known pharmaceutically acceptable material such as gelatin or cellulose derivatives. Tablets may be formulated in accordance with conventional procedure by compressing mixtures of the active prodrugs and solid carriers and lubricants well- known to those familiar with the art.
  • solid carriers examples include starch, sugar, bentonite.
  • the compounds described herein can also be administered in a form of a hard shell tablet or capsule containing, for example, lactose or mannitol as a binder and conventional fillers and tableting agents.
  • the electrophilic group X is illustratively halo, such as chloro, bromo, or iodo.
  • the nature of group X is flexible and encompasses a wide variety of electrophilic groups, provided that the group X can serve as a good leaving group to enable cyclization and concomitant quaternization of the phosphorous-bound nitrogen atom in vivo following administration of the phosphoramidite prodrugs to a patient.
  • electrophilic leaving groups such as acetoxy, haloacetoxy, alkyl and arylsulfonyloxy, each of which may be optionally substituted, such as methane sulfonyloxy, trifluoromethane sulfonyloxy, tosyloxy, brosyloxy, nosyloxy, and the like may also be used.
  • biologically labile ester forming group refers to those ester forming groups derived from alcohols that form ester derivatives that are stable under drug manufacture and storage conditions but are subject to hydrolysis when exposed to biological conditions in vivo.
  • the ester forming groups used herein exhibit minimal susceptibility to hydrolysis in the body fluids in the extracellular space but exhibit susceptibility to hydrolysis in the intracellular space where ester-degrading reductive conditions are prominent.
  • the biologically labile ester forming group on the prodrugs described herein are those ester forming groups that are susceptible to hydrolysis under mild reductive conditions which include those groups such as nitroaryl, including nitrofuryl, nitrothienyl, nitropyrroyl, nitroimidazoyl, and the like, indanyl, napthoquinolyl, perhydrooxazinyl, and the like.
  • the nature of the ester forming group R 3 is not critical provided that the group exhibits susceptibility to hydrolysis under intracellular conditions, typically biological conditions that exhibit reductive potential.
  • the therapeutic compounds that can be derivatized as described herein to form prodrugs include amino acids, illustratively in the form of their doubly protected (both carboxyl protected and amino protected) form, peptides, proteins, peptidomimetics, nucleotide analogs, and other drug compounds that can exhibit biological activity as their corresponding phosphates, optionally substituted phosphoramidates, or optionally substituted phosphonate analogs thereof. It is understood that for drugs that already include a phosphate radical, fragment, or analog thereof, such as a phosphonate analog of a phosphate, the drug fragment excluding the phosphate radical or analog thereof is used as described herein as the drug in preparing prodrugs.
  • the drug that is converted to a prodrug as described herein is a nucleotide or nucleoside analog, such as fluorodeoxyuridine, which exhibits anti-tumor activity as its corresponding monophosphate derivative, hi another embodiment the drug is an amino acid, a peptide or a peptidomimetic.
  • Drugs that are phosphorylated after delivery and therefore become biologically active or more biologically active include drugs such as antitumor nucleosides, phosphotyrosine peptides and peptidomimetics, and others.
  • any drag that is phosphorylated after delivery may be prepared as a prodrug described herein, as a drug-phosphate conjugate analog described herein, or as a prodrug of a drug-phosphate conjugate analog described herein.
  • the drug, or analog or derivative thereof is a substituted aromatic compound.
  • the phosphate analog is a carbonyl phosphonate.
  • Such compounds may be prepared according to the synthetic route shown in Scheme 3.
  • L is a leaving group, such as acyloxy, sulfonyloxy, halo, and the like;
  • R a is alkyl, aryl, or arylalkyl;
  • n is an integer from 1 to about 5, and is illustratively 4;
  • Ar is an optionally substituted aryl group, such as phenyl, furyl, thiophenyl, and the like, and R represents the balance of the drug, or analog or derivative thereof, including ring fusions, and one or more substitutents such as an amino acid, or peptide, and the like.
  • the reaction may be performed without solvent, or with solvent, such as dipolar solvents and polar aprotic solvents such as DMSO, DMF, CH 2 Cl 2 , (CH 2 Cl) 2 , and the like.
  • suitable solvents include dipolar solvents and polar aprotic solvents such as DMSO, DMF, CH 2 Cl 2 , (CH 2 Cl) 2 , and the like.
  • suitable solvents include dipolar solvents such as CH 2 Cl 2 , (CH 2 Cl) 2 , and the like; and suitable bases include amine bases such as Et 3 N, (i-Pr) 2 NEt, pyridine, collidine, lutidine, and the like.
  • suitable solvents for step (d) include ether, THF, DME, and the like; and suitable bases include organolithium bases such as n-BuLi, LiHMDS, sec-BuLi, and the like.
  • the phosphate analog is a difluorophosphonate.
  • Such compounds may be prepared according to the synthetic route shown in Scheme 4.
  • L is a leaving group, such as acyloxy, sulfonyloxy, halo, and the like;
  • R a is alkyl, aryl, or arylalkyl;
  • n is an integer from 1 to about 5, and is illustratively 4;
  • Ar is an optionally substituted aryl group, such as phenyl, furyl, thiophenyl, and the like, and R represents the balance of the drug, or analog or derivative thereof, including ring fusions, and one or more substitutents such as an amino acid, or peptide, and the like.
  • the reagent BrCdCF 2 P(O)(OR a ) 2 is prepared according to the method of Qabar, et. al, Tetraheron, 53:11171-11178 (1997), the synthetic disclosure of which is incorporated herein by reference; and suitable solvents include dipolar solvents and polar aprotic solvents such as DMSO, DMF, CH 2 Cl 2 , (CH 2 Cl) 2 , and the like.
  • suitable solvents include dipolar solvents and polar aprotic solvents such as DMSO, DMF, CH 2 Cl 2 , (CH 2 Cl) 2 , and the like.
  • suitable solvents include dipolar solvents such as CH 2 Cl 2 , (CH 2 Cl) 2 , and the like; and suitable bases include amine bases such as Et 3 N, (i-Pr) 2 NEt, pyridine, collidine, lutidine, and the like.
  • suitable solvents for step (d) include ether, THF, DME, and the like; and suitable bases include organolithium bases such as n-BuLi, LiHMDS, sec-BuLi, and the like.
  • the difluorophosphonate functional group may be prepared according to Scheme 5.
  • the group R includes an ester, acid, or amide
  • such functional groups may be interconverted prior to or after variations of the steps shown in Schemes 3-5.
  • the group R is a carboxylic acid, or analog or derivative thereof or an amino acid, or analog or derivative thereof, having any of the formulae shown in Scheme 6.
  • Ester-acid, acid-ester, and acid-amide interconversion may be performed on any of the above formulae using conventional procedures. See generally, Larock in “Comprehensive Organic Transformations,” VCH Publishers, Inc. (New York, 1989); Greene & Wuts in “Protective Groups in Organic Synthesis,” 2d Ed., John Wiley & Sons (New York, 1991), the synthetic disclosures of which are incorporated herein by reference.
  • L and R a are as defined in Schemes 1-3;
  • R b is hydroxy, alkoxy, aryloxy, arylalkoxy, or amino, each of which is optionally substituted or protected with a protecting group;
  • Rc is hydrogen, or alkyl, aryl, arylalkyl, or amino, each of which may be optionally substituted or protected with a protecting group, or the balance of a peptide; and
  • m is an integer from 0 to about 3.
  • the starting compound is an acid, ester, or amide, where R b is hydroxy, alkoxy, aryloxy, arylalkoxy, or amino, each of which is optionally substituted or protected with a protecting group, and the product is a different acid, ester, or amide.
  • esters and amides may be formed from the corresponding acid using coupling reactions, such as carbodiimide, activated acid derivative, and like coupling reactions.
  • Activated acid derivatives include acid halides, pentafiorophenyl esters, N-hydroxybenzotriazole (HOBt) esters, N- hydroxysuccinimide (NOS) esters, and the like.
  • esters such as fluorenylmethyl esters may be prepared with conventional procedures, such as by reacting with Fmoc- Cl and DMAP in the presence of a base, such as an amine base like Et 3 N, (i-Pr) 2 NEt, pyridine, collidine, lutidine, and the like, in an appropriate solvent, such as a dipolar solvent like CH 2 Cl 2 or (CH 2 Cl) 2 .
  • a base such as an amine base like Et 3 N, (i-Pr) 2 NEt, pyridine, collidine, lutidine, and the like
  • an appropriate solvent such as a dipolar solvent like CH 2 Cl 2 or (CH 2 Cl) 2 .
  • acids may be prepared from the corresponding esters by hydrolysis, such as with LiOH/THF/H 2 O, and the like.
  • Fluorenylmethyl esters may be hydrolyzed to the corresponding acids with conventional procedures, such as by treatment with bases including DBU, and the like, in an appropriate solvent, such as a dipolar solvent like CH 2 Cl 2 or (CH 2 Cl) 2 .
  • an appropriate solvent such as a dipolar solvent like CH 2 Cl 2 or (CH 2 Cl) 2 .
  • the compounds shown in Tables 1-2 maybe prepared according to Schemes 3-5.
  • the drug is a peptidomimetic of the formula:
  • the prodrugs are prepared from drug and derivatives of amino acids and amino acid esters of the formula
  • tyrosine or tyrosine analogs are useful for the preparation of peptides or peptidomimetic compounds capable of facile transmembrane delivery as an intracellular corresponding source of the peptide phosphate or peptidomimetic phosphate.
  • R is hydrogen or a carboxy protecting group, particularly an ester forming group.
  • tyrosine or tyrosine analogs are useful for the preparation of peptides or peptidomimetic compounds capable of facile transmembrane delivery as an intracellular corresponding source of the peptide phosphate or peptidomimetic phosphate.
  • such compounds can themselves provide an intracellular source of the corresponding amino acid or amino acid analog.
  • the drug fragment is a compound of formula
  • R 6 is hydrogen, alkyl, acyl, an amide protecting group, or an amino acid, peptide, or peptidomimetic; and the (*) carbon is attached to phosphorus, or the optional linker Q, such as a substituted phosphonate carbon.
  • the prodrug is a compound of formulae I, II, or III group
  • R 7 is in each case hydrogen, or one or more optional substituents, each of which is independently selected, including halo, alkyl, alkoxy, cycloalkoxy, cycloalkylalkoxy, and the like; and R 8 is in each case hydroxy, an hydroxy protecting group, such as -O-Fmoc, alkoxy, such as C 1 -C 6 alkoxy, alkenyloxy, such as C 2 -C 6 alkenyloxy, unsubstituted or substituted amino, and the like.
  • R 8 is monosubstituted amino such as an optionally substituted benzylamino.
  • an illustrative intermediate V in the bioreduction of the prodrug IV is prepared, as shown in Scheme 8.
  • compound XIb includes a chiral center, and that both possible optical isomers are contemplated to be included in the invention described herein. Further, it is also to be understood that various mixtures, including a racemic mixture, of the two optical isomers may be used in one or more embodiments.
  • Base refers to the nucleoside bases present on guanine, cytosine, uracil, adenine, thymine, inosine, and analogs and derivatives thereof, such as the uracil analogs described herein; and phosphorus is attached to the (*) carbon, or attached to the (*) carbon through the optional linker Q, such as a linker like -C(AB)-, where A and B are each independently selected from hydrogen, alkyl, fluoro, and the like; or A and B are taken together with the attached carbon to from a carbocycle or a carbonyl group or analog thereof.
  • Additional analogs of bases useful in nucleoside analogs as described herein include substituted imidazoles, substituted triazoles, and the like. Substitutions include nitro, optionally substituted amino, carboxylic acid derivatives, including acids, esters, and optionally substituted amides, cyano, alkyl, alkenyl, and alkynyl, including ethenyl.
  • prodrugs described herein may include more than one prodrug feature.
  • Such multiple prodrug features may be included in any prodrug that may be derived from a drug or drug fragment, or analog or derivative thereof, the biological activity or properties of which might be improved by having multiple phosphate or phosphate analogs conjugated thereto.
  • drugs that are phosphorylated after delivery at more than one location are contemplated to be advantageously modified with more than one prodrug features capable of delivering a phosphate conjugate or phosphate conjugate analog.
  • the prodrugs described herein are useful in methods to treat various disease states.
  • any disease state that is responsive to changes in the biological pathways leading to the formation or cleavage of phosphorus-oxygen bonds in substrates may be treated using the prodrugs described herein. It is to be understood that disease states arising from the dysfunction of enzymes that use ATP as a substrate or co-factor and account for that disease state may be treated with the prodrugs described herein.
  • phosphorylation of tyrosine residues is regulated by protein-tyrosine kinases (PTKs), and such protein kinases have been implicated in solid tumor treatment, hi addition, phosphorylated tyrosine leads to interaction with SH2 domain-containing proteins to trigger a signal response in tumors.
  • the prodrugs described herein may be useful in for delivering HIV drugs, such as ribavirin, acyclovir, didanosine, ganciclovir, foscarnet zalcitabine, gemcitabine, EICAR, NAIR, and nucleoside reverse transcriptase inhibitors.
  • HIV drugs are phosphoryled in vivo by nucleoside kinases, such as thymidine kinases.
  • prodrugs are formed from zidovudine, stavudine, and abacavir, all of which are phosphorylated in vivo, such as by peripheral blood mononuclear cells.
  • the prodrugs described herein may be used to treat cancer.
  • the cancer cell is a B 16 melanoma cell
  • the cancer cell is an L1210 leukemia cell.
  • the cells are separated, washed, and resuspended in MEM medium supplemented with 10% fetal bovine serum.
  • the cells are plated in 60-mm culture dishes at a density of 50-50,000 cells/plate (depending upon the drug concentration to be used initially) and then incubated for 8 days in a CO 2 incubator at 37 0 C.
  • the colonies are fixed and stained with 0.5% crystal violet in ethanol and counted.
  • EXAMPLE 2 Biological Activity.
  • Stock solutions of the compounds are prepared in 95% ethanol, and serial dilutions of drug are prepared in ethanol such that 50 ⁇ of drug solution added to 10 ml of cell suspension give the desired final concentration.
  • L1210 cells in exponential growth are suspended in Fischer's medium supplemented with 10% horse serum, 1% glutamine, and 1% antibiotic-antimycotic solution to give 10-ml volumes of cell suspension at a final density of 3-6 x 10 4 /ml.
  • Appropriate volumes of the solutions of each compound are transferred to the cell suspensions, and incubation is continued for 2, 8, 24, or 48 hr.
  • the cells are spun down, resuspended in fresh drug-free medium, and returned to the incubator, then counted with a Coulter Counter 48 hr after treatment with the compound.
  • EXAMPLE 3 Biological Activity.
  • J77 cells (2 X 10 7 cells in 500 niL of FBS-free RPMI media) are transfected with 15 mg of NF-AT-Luciferase plasmid. Cells are transferred to a flask with 10 mL of complete RPMI media and incubated for 24 hours. After this time cells are spun down, resuspended in 12 mL of complete RPMI media and divided into a 6-well plate (2 mL/well).
  • Drug stock solutions in DMSO are made and each well is treated with a different concentration and incubated for 2 hours. Each well is then treated with 10 mL of a mixture of 1.25 mg of PMA and 9 mg of Ionomycin in 115 mL of FBS-free RPMI, followed by the addition of 2 mg of Anti-CD3. Cells are incubated for 6 hours, spun down, washed with PBS, lysed for 15 min and centrifuged. Supernantant is collected and stored at -78 0 C overnight. Luciferase activity is measured using a luminometer with a mixture of 50 mL of luciferase substrate and 10 ml of supernatant.
  • EXAMPLE 5 Biological Activity.
  • LM and LM(TK-) Cells Stock solutions of drugs are prepared in absolute ethanol. L1210 cells are suspended in Fisher's medium, LM and LM (TK-) cells are suspended in minimum essential medium to give a final density of 11.24 X lO 6 cells/mL. Aliquots (445 mL) of the cell suspension are placed in ependorf tubes, followed by addition of 5 mL of drug solution and incubated at 37°C for 2 hours. Tritium release reaction is started by the addition of 50 mL of serum free media containing 1 mCi [5- 3 H]dCyt in a 0.5 mM dCyt solution.
  • DRUG is illustratively selected from one or more of the following:
  • EXAMPLE 7 Diethyl benzoylphosphonate. This Example was prepared according to the general method of Terauchi & Sakurai, Bull. Chem. Soc. Jpn. 43:883-90 (1970), the synthetic disclosure of which is incorporated herein by reference, hi particular, benzoyl chloride (3.65 mL, 4.42 g, 31.4 mmol) was added dropwise to stirring P(OEt) 3 (7.0 mL, 6.8 g, 41 mmol) at 0 °C under an Ar atmosphere. The reaction mixture was warmed to ambient temperature over 1 h, and the title compound was distilled from the reaction mixture (147-172 °C, in vacuo) to give 4.85 g (64%).
  • EXAMPLE 8 Diethyl difluorobenzylphosphonate. This Example was prepared according to the general method of Burke et al, Tetrahedron Letters 34:4125-4128 (1993), the synthetic disclosure of which is incorporated herein by reference. Li particular, diethyl benzoylphosphonate (EXAMPLE 7, 2.85g, 10.65 mmol) and (diethylamino)sulfur trifluoride (DAST) (6.0 mL, 45.41 mL, 4.26 eq) were stirred together at O 0 C under an Ar atmosphere. The reaction was warmed to ambient temperature over 1 h and continued to stir for 20 h.
  • DAST diethylamino)sulfur trifluoride
  • the reaction mixture was then cooled again to O 0 C and it was added to a 25% solution OfNaHCO 3 in H 2 O (100 mL) cooled to O 0 C.
  • the suspension was stirred for 15 min, 150 mL of H 2 O was added and the aqueous phase was extracted with four-50 mL portions of CHCl 3 .
  • the combined organic extracts were washed with brine, dried over Na 2 SO 4 and concentrated to a dark oil.
  • the crude material was purified by flash column chromatography using 10% EtOAc/hexane. The product was isolated as an amber oil 1.18g (42%).
  • EXAMPLE 9 This Example was prepared according to the general method of Qabar, et. al, Tetraheron, 53:11171-11178 (1997), the synthetic disclosure of which is incorporated herein by reference, hi particular, cadmium powder (3.7g, 33.31 mmol, 3.2 eq) was stirred in dry DMF (36 mL) under an atmosphere of Ar. Chlorotrimethylsilane (0.13 mL, 1.04 mmol, 0.1 eq) was added dropwise to activate the metal. After 5 min, diethyl bromodifluoromethylphosphonate (5.7 niL, 32.27 mmol, 3.1 eq) was added dropwise from an addition funnel. The reaction mixture became warm and cloudy.
  • EXAMPLE 1OA This example was prepared according to the general method of Landry, et al, JAm Chem Soc 118:5881-5890 (1996), the synthetic disclosure of which is incorporated herein by reference.
  • diethyl phosphonate from EXAMPLE 9 (3.06g, 5.21 mmol) in 50 mL dry CH 2 Cl 2 was treated with bromotrimethylsilane (2.40 mL, 15.6 mmol 3 eq) and the mixture was stirred under a drying tube for 18h. Solvent was removed under reduced pressure and the residue was co-evaporated twice with CH 2 Cl 2 (30 mL) to remove excess bromotrimethylsilane.
  • EXAMPLE 11 Diethyl difluorobenzylphosphonate (EXAMPLE 8) (0.25g, 0.95 mmol) was dissolved in thionyl chloride (5 mL) and the mixture was refluxed under an atmosphere of Ar for 5 days. Thionyl chloride was removed under reduced pressure and the residue was taken up in dry CH 2 Cl 2 (12 mL) and was cooled to -78 0 C with stirring under an Ar atmosphere. N-methyl-N-(2-chlorobutyl)amine hydrochloride (0.13g, 0.88 mmol, 0.93 eq) was added followed by the addition of triethylamine (0.27 mL, 1.94 mmol, 2.2 eq).
  • EXAMPLES 12A, 12B, 12C, 12D, 12F 5 12G and 12H listed below were also prepared by the method described for EXAMPLE 12E.
  • Analytical Data for EXAMPLES 12A - 12H are as follows:
  • N-Fluorenylmethyloxycarbonyl-4-iodophenylalanine was suspended in MeOH (16 niL) under a drying tube.
  • Thionyl chloride (1.4 mL, 19.79 mmol, 2 eq) was added dropwise by syringe. The reaction stirred at ambient temperature and became a solid mass over two days. The solid mass was treated with 100 mL EtOAc and was sonicated until a solution was obtained. The solution was washed with saturated NaHCO 3 (50 mL), water (5OmL), and brine (5OmL). The organic phase was dried over Na 2 SO 4 and was concentrated to give a white solid which was used without purification. 5.21g, (99%).
  • EXAMPLE 15 Diethyl difluoromethyl phosphonate (EXAMPLE 16, 0.42g, 0.73 mmol, 1 eq) in dry CH 2 Cl 2 (6.0 mL) was stirred under an Ar atmosphere and was treated with propargyl alcohol (0.21 mL, 3.64 mmol, 5 eq) and dimethylaminopyridine (0.004g, 0.03 mmol, 0.05 eq). The reaction mixture was cooled to 0 0 C, diisopropylcarbodiimide (0.11 mL, 0.73 mmol, 1 eq) was added, and stirring continued for 20 h. SiO 2 (Ig) was added and solvent was removed under reduced pressure. The compound adhered to silica gel was purified by flash column chromatography using gradient elution (0%, 20%, 40% EtOAc/hexane) to provide the product as an oil 0.38g (85%).
  • EXAMPLE 17 Process A. The corresponding Fmoc ester (0.2Og, 0.30mmol, 1 eq) in CH 2 Cl 2 (4.0 mL) was stirred under an Ar atmosphere and was cooled to 0 0 C. A 0.17 M solution of DBLVCH 2 Cl 2 (1.96 mL, 0.33 mmol, 1.1 eq) was added dropwise. After 25 min the reaction was quenched with saturated NH 4 Cl solution. The phases were separated and the aqueous phase was extracted four times with EtOAc (5 mL each).
  • EXAMPLE 18 Methyl ester from EXAMPLE 12E (0.58g, 0.76 mmol, 1 eq) in THF (11 mL) and H 2 O (2 mL) was stirred at O 0 C. A solution of 0.3M LiOHTH 2 O (5.1 mL, 1.52 mmol, 2 equiv) was added dropwise in the following increments: 2.55 mL, 0.85 mL, 0.85 mL and 0.85 mL. The reaction was monitored by TLC after each addition. After the final addition the reaction was quenched with 10% aqueous citric acid, and the aqueous phase was extracted four times with EtOAc (1O mL each). The combined organic phases were washed with brine, dried over
  • EXAMPLE 19 Carboxylic acid from EXAMPLE 18 (0.07g, 0.10 mmol, 1 eq) in THF (ImL) was stirred at 0 0 C under an Ar atmosphere and was treated with N-hydroxysuccinimide (0.0 Ig, 0.10 mmol, 1 eq). Diisopropylcarbodiimide (0.02 mL, 0.14 mmol, 1.5 eq) was added. After stirring at 0 0 C for 2h a IM solution OfNH 4 HCO 3 (0.48 mL. 0.48 mmol, 5 eq) was added and the reaction mixture allowed to reach ambient temperature as it stirred for 2Oh.
  • reaction mixture was diluted with CH 2 Cl 2 (3 mL) and the organic phase was washed successively with 5 mL each of IM HCl, saturated NaHCO 3 solution and brine. Solvent was removed under reduced pressure and the crude material was purified by flash column chromatography using gradient elution (50%, 75% EtOAc/hexane) to give the product as an oil 0.05g (71%).
  • EXAMPLE 20 4-Iodophenylacetic acid (2.Og, 7.6 mmol, 1 eq) in CH 2 Cl 2 (30 mL) was treated with diisopropylethylamine (1.32 mL, 7.6 mmol, 1 eq) and the mixture was cooled to 0 0 C with stirring under an atmosphere of Ar. 9- Fluorenylmethyl chloroformate (2.16g, 8.36 mmol, 1.1 eq) dissolved in CH 2 Cl 2 (7.6 mL) was added followed by the addition of dimethylaminopyridine (0.14g, 1.14 mmol, 0.1 eq).

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Abstract

L'invention concerne des composés thérapeutiques substitués par des phosphates et des analogues de ceux-ci pouvant servir de promédicaments. Ces promédicaments peuvent comprendre des composés contenant du phosphore, des conjugués de phosphate-médicament ainsi que des analogues de conjugués de phosphate-médicaments. L'invention se rapporte également à des analogues de médicaments, dont des médicaments phosphorylés, dans lesquels le lieur reliant le fragment de phosphate au fragment de médicament n'est pas de l'oxygène, tels que, entre autres, des lieurs formant des phosphoramidates, des phosphonates, des difluorophosphates, des oxophosphonates et similaire.
PCT/US2005/034974 2004-09-28 2005-09-28 Promedicaments contenant des conjugues de phosphate-medicament et des analogues de ceux-ci WO2006037090A2 (fr)

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