WO1992017185A1 - Targeted drug delivery via mixed phosphate derivatives - Google Patents

Targeted drug delivery via mixed phosphate derivatives Download PDF

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Publication number
WO1992017185A1
WO1992017185A1 PCT/US1992/002239 US9202239W WO9217185A1 WO 1992017185 A1 WO1992017185 A1 WO 1992017185A1 US 9202239 W US9202239 W US 9202239W WO 9217185 A1 WO9217185 A1 WO 9217185A1
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WIPO (PCT)
Prior art keywords
compound according
drug
residue
alkyl
group
Prior art date
Application number
PCT/US1992/002239
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French (fr)
Inventor
Nicholas S. Bodor
Original Assignee
University Of Florida
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Publication date
Application filed by University Of Florida filed Critical University Of Florida
Priority to JP4508920A priority Critical patent/JPH06510020A/en
Priority to AU16748/92A priority patent/AU668506C/en
Publication of WO1992017185A1 publication Critical patent/WO1992017185A1/en

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    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • 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
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Definitions

  • the present invention relates to an anionic sequestration type of drug modification designed to enhance delivery of the active drug species to the desired site of action, especially to the brain. More especially, the present invention relates to the discovery that a biologically active compound coupled to a lipophilic carrier moiety of the acyloxyalkyl mixed phosphate type readily penetrates biological membranes such as the blood-brain barrier (BBB) and enters the target organ; cleavage of the mixed phosphate carrier/drug entity in vivo provides a hydrophilic, negatively charged intermediate which is "locked in” the brain or other organ and which provides significant and sustained delivery of the active drug species to the target organ.
  • BBB blood-brain barrier
  • the delivery of drug species to the brain and other organs is often seriously limited by transport and metabolism factors, including biological membranes; specifically, in the case of the brain, delivery is limited by the functional barrier of the endothelial brain capillary wall, i.e. the blood-brain barrier or BBB.
  • BBB blood-brain barrier
  • a brain-targeted approach is a desirable means of delivery for a wide diversity of drugs, including neurotransmitters, stimulants, dopaminergic agents, tranquilizers, antidepressants, narcotic analgesics, narcotic antagonists, sedatives, hypnotics, anesthetics, antiepileptics/anticonvulsants, hormones such as the male and female sex hormones, peptides, anti-inflammatory steroids, non-steroidal anti-inflammatory agents/non-narcotic analgesics, memory enhancers, antibacterials/antibiotics, antineoplastics (anticancer/antitumor agents) and antiviral agents.
  • drugs including neurotransmitters, stimulants, dopaminergic agents, tranquilizers, antidepressants, narcotic analgesics, narcotic antagonists, sedatives, hypnotics, anesthetics, antiepileptics/anticonvulsants, hormones such as the male
  • Viruses are submicroscopic pathogens which depend on the cellular nucleic acid and protein synthesizing mechanisms of its host for
  • viruses invade cells by first interacting at a recognizable surface protein, penetrating the cell membrane and
  • the heart of these pathogens is genetic material, either DNA or RNA, and the type of nucleic acid gives rise to the system'of nomenclature for these entities.
  • the viral DNA and RNA can interact with cellular components to produce daughter genetic material as well as various structural or enzymatic proteins. After assembly and release, the viral progeny may infect other cells, yielding disease or ultimately death.
  • DNA viruses are subdivided into five families and include the pathogens responsible for labial and genital herpes, herpes encephalitis, human cytomegalovirus infection, chicken pox, shingles and mononucleosis.
  • RNA viruses are present in more numerous forms and are subdivided into ten families. These viruses are unusual in that they reverse the usual DNA ⁇ RNA ⁇ protein sequence which occurs in higher life forms. RNA viruses are unusually dangerous for several reasons, including their lethality and the lack of effective treatments. RNA viral diseases include acquired immune deficiency syndrome, hemorrhagic fevers of various descriptions, Dengue fever, Lassa fever, and numerous encephalitic maladies including Japanese B encephalitis.
  • Ribavirin has a broad range of activity against both DNA and RNA viruses. This riboside, which contains an unnatural triazole base, significantly suppresses the infectivity and cytopathicity of several viral pathogens by mechanisms which are as of yet unclear.
  • Ribavirin is active against several influenza viruses and respiratory syncytial virus and as such is used in an aerosol form to treat these diseases. Ribavirin is also used in the treatment of Lassa fever which rages in epidemic proportions in Sierra Leone. Unfortunately, while peripheral viral infections can be successfully treated with ribavirin and other riboside derivatives, encephalitis is immune to the action of these drugs. The inability of antiviral drugs, which are highly potent in vitro, to exert activity in the CNS is attributable to their exclusion from the brain. The basis of this impermeability is the blood-brain barrier (BBB), which effectively separates the systemic circulation from the brain parenchyma. As this barrier is lipoidal in nature, the BBB restricts the entry of materials which do not have high affinity for the phospholipid matrix and
  • antiherpetic agents exhibit poor penetration across biological barriers such as the BBB and the ocular and skin barriers, achieving concentrations well below therapeutic levels. Improved delivery of an antiherpetic agent across these barriers would offer a significant advantage in the treatment of such serious and debilitating diseases as encephalitis, ophthalmic infections caused by herpes simplex such as herpetic uveites, keratitis etc. and cutaneous herpes infections such as genital and orofacial herpes.
  • Vidarabine (9- ⁇ -D-arabinofuranosyladenine, Ara-A, adenine arabinoside) is a purine nucleoside analog with a broad spectrum of antiviral activity against a number of DNA viruses, including HSV-1 and 2, cytomegaiovirus and varicella zoster virus.
  • the drug has been shown useful in the treatment of brain biopsy-proven herpes simplex encephalitis (HSE), resulting in a statistically significant reduction in mortality.
  • HSE herpes simplex encephalitis
  • Ara-A has demonstrated clinical utility as a topical agent for herpes keratitis of the eye. However, when applied locally to the skin, vidarabine has provided no benefit in genital or orafacial HSV infection. In immunocompromised patients with localized herpes zoster, Ara-A has demonstrated a beneficial effect in accelerating cutaneous healing and decreasing the rate of cutaneous dissemination.
  • vidarabine The essential mechanism of inhibition of viral replication by vidarabine, although not precisely defined, appears to be a consequence of the incorporation of the drug into viral DNA.
  • vidarabine To exert its antiviral action, vidarabine must first be phosphorylated by cellular enzymes to the triphosphate, which competitively inhibits HSV DNA polymerase.
  • Some investigators have found that the viral DNA polymerase activity is more sensitive to inhibition than that of cellular DNA polymerases, an observation that could explain some of the selective toxicity of the drug and its dose-related toxicity.
  • Vidarabine triphosphate is incorporated into both cellular and viral DNA, where it may act as a chain terminator for newly synthesized HSV nucleic acid.
  • Ara-A does suffer from a number of limitations, including low lipophilicity as evidenced by a negative log P (octanol/ water), which results in a failure to be adequately transported across biological membranes.
  • Herpes simplex virus is a causative factor for encephalitis. Its involvement in the CNS represents the most common cause of nonepidemic fatal encephalitis in the United States. An estimated 1,000 to 5,000 cases occur each year in the U.S., with death in over one half of those who are untreated. Herpes simplex virus type 2 causes encephalitis in patients with thymic dyplasia and other severe immunodeficiency states. Encephalitis also is a common opportunistic infection associated with AIDS.
  • the acute severe encephalitis due to herpes simplex type 1 in humans may represent a primary infection, a reinfection or an activation of latent infection.
  • the primary mode of viral transport into the CNS has not been clearly established.
  • the virus gained access to the CNS by both hematogenous and neural pathways.
  • the neural pathway of transport in man is supported by the fact that the virus can be isolated from explants of both trigeminal ganglia in the majority of routine autopsies.
  • Herpes simplex encephalitis is the most common cause of sporadic fatal encephalitis. Both the high mortality rate and the risk of severe sequelae in the survivor have prompted attempts at therapy with antiviral compounds. In order for the antiencephalitic agent to exert its effect, it is necessary for the drug to be present in the CNS where the virus is lodged, at an optimum concentration and for a sufficient period of time.
  • Maintaining a therapeutic level of the drug over a prolonged period at the site of action is essential in optimal reduction of viral concentrations.
  • the main reason for the lack of successful treatment is the inefficient method of drug delivery to the brain, the major impediment to drug delivery to the brain being the blood-brain barrier.
  • Antiviral agents such as iododeoxyuridine and vidarabine exhibit little activity and high toxicity in the treatment of encephalitis. This is primarily due to their inability to cross the blood-brain barrier at optimum concentrations. In the case of other antivirals such as acyclovir, drug resistance has been observed. To overcome such problems, a new family of fluorinated nucleoside analogs has been synthesized.
  • This family includes 1-(2'-deoxy-2'-fluoro- ⁇ -D-arabinofuranosyl) derivatives of 5-methyluracil (FMAU), 5-iodocytosine (FIAC) and 5-iodouracil (FIAU).
  • FMAU 5-methyluracil
  • FIAC 5-iodocytosine
  • FIAU 5-iodouracil
  • FIAU is a metabolite of FIAC.
  • FMAU considered the most potent antiviral agent of its class (therapeutic index greater than 3,000) in treating encephalitis, produces irreversible neurological damage at doses greater than 32 mg; other side effects include diarrhea, nausea and blood count depression.
  • FIAU cardiac fibrosis, myelosuppression and lymphoid depletion.
  • significant reduction in body weight or death has also been noted at higher doses. Further, sustained therapeutic levels have not been achieved, even at these higher doses.
  • FIAC Fluorescence-Activated Cell Culture
  • the major metabolites of FIAC include the deaminated species FIAU, the deiodinated species 2'-fluoroarbinosylcytosine (FAC) and 2'-fluoroarabinosyluracil (FAU) and their glucuronides.
  • FAC fluoroarbinosylcytosine
  • FAU 2'-fluoroarabinosyluracil
  • FMAU Two metabolites of FMAU have been isolated from the urine of mice. These include 2'-fluoro-5-hydroxymethylarabinosyluracil (FHMAU) and a glucuronide of FMAU.
  • FMAU, FIAU and FIAC have been found to exhibit more potent antiviral activity than acycl ⁇ vir.
  • BVDU (E)-5-(2-bromovinyl)deoxyuridine
  • E is also a polar antiviral agent effective against encephalitis caused by herpes zoster virus and HSV-1. This agent crosses the BBB in low levels only at very high
  • DHPG Dihydroxypropoxymethylguanine
  • acyclovir Dihydroxypropoxymethylguanine
  • herpes virus-specific thymidine kinase phosphorylates DHPG to its monophosphate, which is further phosphorylated to its di- and triphosphate by cellular guanylate kinase and other cellular enzymes, respectively.
  • DHPG is transported to the brain only at high doses, which in mm produce high plasma levels of the drug which exert cytotoxic effects on normal human mycloid cells. Studies have shown that acyclovir crosses the BBB poorly, and at higher doses causes problems such as renal blockage.
  • HCMV Human cytomegalovirus
  • herpes group which includes herpes simplex I and II, Epstein-Barr virus, and varicella zoster virus.
  • infection with HCMV leads to a latent state in which the viral genome becomes incorporated in the host DNA, and in which recurrent infections are common.
  • Viral infection with HCMV is quite widespread, with
  • HCMV in the fetus or neonate can result in severe clinical manifestations.
  • the virus in these cases is acquired congenitally, often from asymptomatic mothers.
  • the virus has been said to be the single most frequent cause of viral infections in newborns.
  • the occurrence of HCMV in neonates is from 0.5 % to 4% of all live births, but only 10% to 20% of these will have clinical manifestations of cytomegalic disease, which mainly involve the CNS and which can result in permanent, debilitating brain damage or auditory degeneration.
  • HCMV When the host immune system is suppressed, HCMV becomes a much more serious infective agent. In this state, a latent HCMV infection may recur, or a primary infection may be unusually severe.
  • Immunosuppression can occur in several circumstances, for example, during use of immunosuppressive drugs, such as corticosteroids, azathioprine, and thymocyte immune globulin which are given to prevent rejection of a transplanted organ when a patient has undergone organ transplant surgery.
  • immunosuppressive drugs such as corticosteroids, azathioprine, and thymocyte immune globulin which are given to prevent rejection of a transplanted organ when a patient has undergone organ transplant surgery.
  • immunosuppressive drugs such as corticosteroids, azathioprine, and thymocyte immune globulin which are given to prevent rejection of a transplanted organ when a patient has undergone organ transplant surgery.
  • cytomegalic disease is a common and sometimes especially serious problem which can follow successful kidney, bone marrow, and heart transplantation.
  • the manifestations of cytomegalic disease following transplant surgery can include, but are not limited to, retinitis and pneumonias.
  • HCMV immunodeficiency syndrome
  • HIV immunodeficiency virus
  • Ocular involvement is presented as a hemorrhagic retinitis, first evidenced by blurring of vision. This retinitis is so common that it has been proposed that it be the primary diagnostic evidence for the presence of AIDS.
  • Neural involvement resulting in viral encephalitis is also common and presents itself post-mortem in the microglial nodules which are typical of HCMV infection. In AIDS, this neural involvement is concomitant with HIV infection of the CNS, often manifesting as subacute encephalopathy.
  • DHPG An antiviral agent which has shown promise in the treatment of HCMV infections in immunosuppressed states is DHPG.
  • DHPG is structurally similar to acyclovir (ACV), a safe and efficacious antiherpetic agent.
  • the primary mechanism of DHPG action against CMV is inhibition of the replication of viral DNA by DHPG-triphosphate. This inhibition includes a selective and potent inhibition of the viral DNA polymerase.
  • HCMV does not encode a virus-specific thymidine kinase
  • phosphorylation of DHPG is presumably accomplished by the host-cell enzymes, primarily various nucleoside kinases, which have been shown to be elevated in HCMV-infected cells.
  • the markedly increased activity of DHPG toward CMV compared with ACV appears to be due in part to the efficient intracellular metabolism of DHPG to its mono and triphosphate in CMV-infected cells.
  • DHPG vs ACV activities, as measured by the IC 50 values of DHPG vs ACV are of the same order against herpes simplex virus (HSV), namely 0.2 to 0.8 ⁇ M.
  • HSV herpes simplex virus
  • DHPG has significant activity against HCMV in vitro.
  • cytomegalic infection As mentioned above, one of the first clinical signs of AIDS infection is a retinitis which is caused by HCMV.
  • One of the most dramatic recent clinical demonstrations of antiviral activity has been in a study of the effects of intravenous DHPG in AIDS patients who were suffering from progressive blindness caused by cytomegalic infection of the retina. In these patients, not only did viral titers drop to an unobservable level, but clinically observable improvement in sight was achieved. In other studies, significant improvement in other areas of cytomegalic infection was shown. These included improvement in the cytomegalic pneumonias and encephalitis, as well as gastrointestinal infections.
  • DHPG obviously, has very high intrinsic activity but, as with most useful drugs, has a number of inherent undesirable properties as well.
  • bioavailability of DHPG is only 3-4.6% based on urinary excretion, with
  • pharmacoknetic disposition of intravenous DHPG in humans is similar to that observed in rats and dogs, with the finding of a biphasic elimination with an ⁇ -phase half-life of 0.23 hours and a ⁇ -phase of 2.53 hours. These values are quite similar to those for acyclovir, and show that repeated dosing is necessary to maintain effective plasma concentration.
  • Neutropenia is the most frequent dose-dependent toxicity associated with DHPG therapy.
  • DHPG is a hydroxymethyl analog of acyclovir and consequently is more polar and is expected to pass through the blood brain barrier (BBB) even less readily.
  • BBB blood brain barrier
  • acyclovir distributes into most organs, with the highest levels found in renal tissue and the lowest levels found in brain tissue.
  • Pharmacolrinetic studies of DHPG in the rat and dog have demonstrated behavior similar to acyclovir.
  • Human pharmacokinetics of intravenous DHPG indicate cerebrospinal fluid
  • CSF cerebral spastic syndrome
  • AIDS Acquired immune deficiency syndrome
  • HIV-1 human immunodeficiency virus
  • helper/ inducer T-cells are responsible for containing and eliminating various types of infection including those precipitated by Pneumocystis carinii, Toxoplasma gondii, Cryptococcus neoformans, Candida , Mycobacterium aviumintracellular and others.
  • HIV-1 causes the normally benign infections resulting from the above mentioned pathogens to run more fulminate courses. These opportunistic infections are generally the causes of death in patients with AIDS.
  • the CNS In AIDS, the CNS, like the periphery, is susceptible to opportunistic infections and unusual neoplasms. Several of these have been identified, including cerebral toxoplasmosis, cryptococcal infection, candidiasis, cerebral tuberculosis, progressive multifocal leukoencephalopathy, cytomegalovirus encephalitis and primary brain lymphomas. Interestingly, these occur in less than 30% of neurologically-impaired AIDS patients. In addition, symptoms caused by these pathogens are generally focal in nature and are expressed as seizures. In the majority of AIDS patients, neuropsychiatric changes are characterized as an insidious, progressive dementia related to diffuse parenchymal brain dysfunction.
  • Gross changes include decreased brain weight and general cerebral atrophy. Histopathologically, several unique abnormalities are consistently seen in demented AIDS patients. Most of these are white matter changes and include a diffuse pallor, perivascular and parenchymal sites that contain lymphocytic and macrophage infiltrates and vacuolation.
  • azidothymidine also known as zidovudine or AZT
  • ZT zidovudine
  • AZT inhibits retroviral transcriptase, the enzyme responsible for initiating viral replication.
  • AZT has been shown to improve the immunological picture in AIDS patients.
  • T-cell lymphocytes T4 +
  • opportunistic infections spontaneously disappeared, and patients gained weight due to increased appetite.
  • fever subsided and skin hypersensitivity returned.
  • viremia disappeared and T-cell function was restored.
  • the bioavailability is about 60%.
  • the drug is generally well-tolerated, but several untoward side effects occurred, including headache and abdominal discomfort. The most severe side effect was anemia, which proved to be dose-limiting in several cases.
  • AZT has been used in large clinical trials, the results of which are very exciting.
  • AZT was shown to improve immunoiogical and neurologic functioning. T4 + cells increased in number, motor symptoms improved, gait became less ataxic and muscle strength returned. Attention span increased in one case and verbal skills improved. Unfortunately, when the drug was stopped in cases of anemia, all improvements disappeared and mental function declined. This initial report indicated that AZT can at least partially reverse neurological dysfunction. The authors noted at the end of the paper that "even modest enhancement of BBB penetration might have very important clinical consequences.” These limited improvements in neurological symptomatology are consistent with the similarly limited ability of AZT to pass into the CSF. Unfortunately, CSF levels of a drug may be a poor indication of brain tissue levels.
  • Increasing brain levels of the nucleoside is possible by administering lipophilic esters of AZT leading to an increase in brain concentration of the nucleoside.
  • lipophilic esters of AZT are, however, not optimized in terms of pharmacokinetics and tissue distribution.
  • the drug will more easily pass the BBB and enter the CNS, the increased lipophilicity will increase the distribution of the compound in general, leading to an even greater tissue burden in all locations. This has ramifications in terms of peripheral toxicity such as anemia, i.e. a bad situation is made even worse.
  • a dihydropyridine ⁇ pyridinium salt redox carrier system has recently been successfully applied to brain-targeted delivery of a variety of drug species. Generally speaking, according to that system, a
  • dihydropyridine carrier moiety is covalently bonded to a biologically active compound, which derivative can enter the CNS through the blood-brain barrier following its systemic administration. Subsequent oxidation of the dihydropyridine species to the corresponding pyridinium salt leads to delivery of the drug to the brain.
  • the redox carrier system provides for brain-targeted drug delivery by means of carrier-drugs, which in their reduced form, which is the form intended for administration, can be represented by the formula wherein [D] is a centrally acting drug species and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating, lipoidal form of a dihydropyridine ⁇ pyridinium salt redox carrier.
  • the carrier-drugs can be represented by the formula
  • [D-QC] + X- wherein X- is the anion of a non-toxic pharmaceutically acceptable acid, [D] is a centrally acting drug species and [QC] + is the hydrophilic, positively charged ionic pyridinium salt form of a dihydropyridine ⁇ pyridinium salt redox carrier.
  • redox carrier-drugs provided by the earlier chemical delivery system are dihydropyridine/pyridinium salt derivatives of dopamine, testosterone, phenytoin, GABA, valproic acid, tyrosine, methicillin, oxac ⁇ lin, benzyipemcillin, cioxacillin, dicloxacillin, desipramine, acyclovir, trifluorothymidine, zidovudine, hydroxy-CCNU, chlorambucil, tryptamine, dexamethasone, hydrocortisone, ethinyl estradiol, norethindrone, estradiol.
  • ethisterone norgestrel, estrone, estradiol 3-methyl ether, estradiol benzoate, norethynodrel, mestranol, indomethacin, naproxen, FENU, HENU, 5-FU and many others.
  • the dihydropyridine redox carrier system has achieved remarkable success in targeting drugs to the brain in laboratory tests.
  • the dihydropyridine-containing derivatives suffer from stability problems, since even in the dry state they are very sensitive to oxidation as well as to water addition. Such problems have significantly complicated attempts to commercialize the system.
  • a different earner approach to brain-targeted drug delivery which would not include the inherently unstable dihydropyridine system would be desirable.
  • R 1 is, for example, -CH 3 or -C(CH 3 ) 3
  • R is phenyl (as a model residue).
  • R is a 5'-linked nucleoside and R' is a group designed to possess suitable hydrolytic properties.
  • thymidin-5-yl was selected for R and several substituted phenyl groups as R', i.e. 4-(methylthio)phenyl, 4-chlorophenyl, 2-chlorophenyl, 4-(methylsulfonyl)phenyl, 2,5-dichlorophenyl and 4-nitrophenyl.
  • the following 5'-5'-linked triester derivatives of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and acyclovir (ACV) were then synthesized and studied for their antiviral effects:
  • R' is 4-(methylthio)phenyl or 4-(methylsulfonyl)phenyl or 2- chlorophenyl and R" is H or Ac.
  • the present invention provides novel mixed phosphate derivatives, adapted for targeted drug delivery, which have the formula
  • [D] is the residue of a drug having a reactive functional group, said functional group being attached, directly or through a bridging group, via an oxygen-phosphorus bond to the phosphorus atom of the , moiety;
  • R 1 is C 1 -C 8 alkyl, C 6 -C 10 aryl or C 7 -C 12 aralkyl, with the proviso that when [D] is the residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the ,
  • R 1 taken together with the adjacent oxygen atom, can also be the residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the ,
  • R 2 is hydrogen, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 4 -C 9 heteroaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl or C 7 -C 12 aralkyl; and R 3 is selected from the group consisting of C,-C, alkyl; Q-C 3 alkenyl having one or two double bonds; (C 3 -C 7 cycloalkyl)-C 1 H 2r - wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C 1 -C 4 alkyl substituents on the ring portion; (C 6 -C 10 aryloxy)C 1 -C 8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-C 1 H 2r -
  • alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms.
  • the invention further provides a generic method for target-enhanced delivery to the brain and other organs of a wide variety of drug species via the bidirectional transport of the drug species into and out of the organ by anio ⁇ ic sequestration via novel mixed phosphate derivatives.
  • the present invention provides novel mixed phosphate derivatives of hydroxy-containing drugs, which derivatives have the formula
  • D-O- is the residue of a drug having a reactive hydroxyl functional group, the oxygen atom of said functional group being bonded to the phosphorus atom of the
  • the present invention provides novel mixed phosphate derivatives of mercapto-containing drugs, which derivatives have the formula
  • D-S- is the residue of a drug having a reactive mercapto functional group, the sulfur atom of said functional group being bonded to the phosphorus atom of the
  • the present invention further provides novel mixed phosphate derivatives of carboxyl-containing drugs, which derivatives have the formula
  • R 2 is defined as is R 2 with formula (I); or wherein
  • Z is C 3 -C 8 cycloalkylene in which two adjacent ring carbon atoms are each bonded to a different oxygen atom in the -O-Z-O- bridging group; and wherein R 1 and R 3 are as defined with formula (I).
  • the invention provides novel mixed phosphate derivatives of drugs containing imide or amide functional groups, which derivatives have the formulas
  • R 4 is preferably H but may also be C 1 -C 7 alkyl or combined with to form a cvciic amide; and wherein the R 2 groups in formulas (Id) and (Ie), which can be the same of different, are as defined with formula
  • the present invention also provides novel mixed phosphate derivatives of amino-containing drugs, which derivatives have the formula
  • R" 2 is defined as is R 2 with formula (I); and wherein R 1 and R 3 are as defined with formula (I).
  • lipoidal as used here is intended to mean lipid-soluble or lipophilic.
  • drug means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and conditions in man or animal.
  • centrally acting drug drug species, active agent or compound as used herein, there is of course intended any drug species or the like, a significant (usually, principal) pharmacological activity of which is CNS and a result of direct action in the brain.
  • Centrally acting drugs are preferred for derivation in accord with the present invention, brain-targeted drug delivery being the preferred goal of the invention.
  • drug having a reactive functional group means that the drug possesses at least one functional group which is capable of covalently bonding to the phosphorus atom in the phosphate moiety, either directly or through a bridging group, in such a manner that an active drug species will ultimately be released at the desired site of action, e.g. the brain.
  • reactive functional groups include hydroxyl, carboxyl, mercapto, amino, amide and imide functions.
  • hydroxyl means an -OH function
  • mercapto means an -SH function
  • amino means a primary or secondary amino function, i.e. -NH 2 or -NHR 4 .
  • the secondary amino function is also represented herein as -NH-, particularly since the exact identity of the R 4 portion of -NHR 4 is immaterial, R 4 being a part of the drug residue itself which is left unchanged by conversion of the drug to the phosphate carrier system.
  • amide means a carbamoyl (-CONH 2 ) or substituted carbamoyl (-CON ⁇ R 4 ) or a sulfamoyl (-SO 2 NH 2 ) or substituted sulfamoyl (-SO 2 NHR 4 ) functional group.
  • the -CONHR 4 and -SO 2 NHR 4 groups may also be represented herein as -CONH- and -SO 2 NH-, respectively, since the identity of R 4 is immaterial, R 4 being a pan of the drug residue itself which is left unchanged by conversion of the drug to the phosphate carrier system.
  • imide means a functional group having the structure
  • the structure which characterizes imides i.e. compounds having a succinimide-type or phthalimide-type structure.
  • a bridging group refers to a bivalent group used to attach the mixed phosphate carrier moiety to the drug when the drug does not contain a functional group susceptible to direct bonding to the phosphorus atom to form a linkage which will ultimately cleave to release an active drug species in the target organ.
  • Drugs containing reactive hydroxyl and mercapto groups are capable of direct bonding to the phosphorus atom to form the desired linkage; other reactive functional group require appropriate bridging groups, for example as shown in structures (Ic), (Id), (Ie) and (If) hereinabove.
  • C 1 -C 8 alkyl as used herein includes straight and branched-chain lower alkyl radicals having up to eight carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
  • C 6 -C 10 aryl includes aromatic radicals having the indicated number of carbon atoms, e.g. phenyl and naphthyl.
  • C 7 -C 12 aralkyl designates radicals of the type
  • aryl portion is phenyl or naphthyl and the alkylene portion, which can be straight or branched, can contain up to 6 carbon atoms, e.g. methylene, ethylene, propylene, trimethylene, 1,2-butylene, 2,3-butylene, tetramethylene and the like.
  • a typical aralkyl group is benzyl.
  • C 4 -C 9 heteroaryl refers to aromatic radicals having the indicated number of carbon atoms and additionally containing 1 or 2 hetero atoms in the ring(s) selected from the group consisting of N, O and S.
  • Illustrative radicals of this type include furyl, pyrrolyl, imidazolyl, pyridyl, indolyl, quinolyl and the like.
  • C 3 -C 7 cycloalkyl designates saturated alicyclic hydrocarbon radicals containing the indicated number of carbon atoms, e.g. cyclopentyl and cyclohexyl.
  • C 3 -C 7 cycloheteroalkyl refers to saturated alicyclic hydrocarbon radicals having the indicated number of carbon atoms and additionally containing 1 or 2 hetero atoms in the ring selected from the group consisting of N, O and S. Examples include morpholino, piperazinyl and pyrrolidinyl.
  • C 2 -C 8 alkenyl designates unsaturated aliphatic hydrocarbon radicals, or olefinic groups, which contain one or two double bonds and the indicated number of carbon atoms, e.g. 1-propen-1-yl, 1,3- pentadien-1-yl and the like.
  • (C 6 -C 10 aryloxy)C 1 -C 8 alkyl includes aryloxyalkyl radicals such as phenoxymethyl, i.e. the aryl portion contains 6 to 10 carbon atoms, e.g. phenyl or naphthyl, while the alkyl portion contains 1 to 8 carbon atoms, e.g. methyl or ethyl.
  • C 3 -C 7 cycloalkyl-C r H 2r - includes cycloalkyl and cycloalkyl-alkylene- radicals containing the indicated number of carbon atoms and bearing 0 to 2 C 1 -C 4 alkyl groups as ring substituents.
  • Illustrative radicals include cyclopentyl, cyclohexyl, cyclohexylmethyl, 1-methylcyclohex-1-yl, 2,2,3,3-tetramethylcycloprop-1-yl and the like.
  • phenyl-C r H 2r - includes phenyl and phenyl-alkyleneradicals containing the indicated number of carbon atoms, e.g. benzyl, any of which can bear 0 to 3 substituents as defined above.
  • the substituents can be selected from C 1 -C 4 alkyl, which can be straight or branched, e.g. methyl, ethyl, propyl, isopropyl; C 1 -C 4 alkoxy, which can be straight or branched, e.g.
  • halo which includes bromo, chloro, iodo and fluoro; trifluoromethyl; C 2 -C 8 dialkylamino, e.g. dimethylamino and diethylamino; and C 2 -C 6 alkanoylamino, e.g. acetamido and propionamido.
  • Substituted phenyl-C r H 2r - radicals include such radicals p-tolyl, 2,4,6-trimethylphenyl and m-trifluoromethylbenzyl.
  • alkylene when used in conjunction with the Z term herein refers to bivalent radicals of the type -(CH 2 ) n - where n is 1, 2 or 3, and the corresponding branched-chain groups.
  • die alkylene grouping can only be unsubstituted methylene if the drug residue is sufficiently hindered; otherwise, it should be substituted methylene or unsubstituted or substituted C 2 -C 3 alkylene.
  • C 3 -C 8 cycloalkylene designates radicals of the type where m is 1 to 6 and the corresponding branched-chain groups.
  • non-toxic pharmaceutically acceptable salts as used herein generally includes the non-toxic salts of compounds of formula
  • the salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, giucolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyciic, sulfanilic, fumaric, methanesulfonic, toluenesulfonic and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, giucolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,
  • hydroxyl protecting group as used herein is intended to designate a group (Y) which is inserted in place of a hydrogen atom of an OH group or groups in order to protect the OH group(s) during synthesis and/or to improve lipoidal characteristics and prevent premature metabolism of the OH group(s) prior to the compound's reaching the desired site in the body.
  • protected hydroxy substituent designates an OY group wherein Y is a "hydroxyl protecting group” as defined above.
  • Typical hydroxyl protecting groups contemplated by the present invention are acyl groups and carbonates.
  • the hydroxyl protecting group is acyl (i.e., when it is an organic radical derived from a carboxylic acid by removal of the hydroxyl group), it can be selected from the same group of radicals as those encompassed by the portion of formula (I) hereinabove.
  • the hydroxyl protecting group preferably represents an acyl radical selected from the group consisting of alkanoyl having 2 to 8 carbon atoms; alkenoyl having one or two double bonds and 3 to 8 carbon atoms; wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three; phenoxyacetyl; pyridinecarbonyl; and
  • r is zero, one, two or tiiree and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, tnfluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms.
  • unbranched and branched alkanoyl for example, acetyl, propionyl butyryl, isobutyryl, valeryl, isovaleryl, 2-methylbutanoyl, pivalyl (pivaloyl), 3-methylpentanoyl, 3,3-dimethylbutanoyl, 2,2-dimethylpentanoyl, hexanoyl and the like.
  • Pivalyl, isobutyryl, isovaleryl and hexanoyl are especially preferred, both groupings and as hydroxyl protective groups.
  • acyl group is alkenoyl
  • alkenoyl there are included, for example, crotonyl, 2,5-hexadienoyl and 3,6-octadienoyl.
  • cycloalkanecarbonyl and cycloalkanealkanoyl groups wherein the cycloalkane portion can optionally bear 1 or 2 alkyl groups as substituents, e.g. cyclopropanecarbonyl, 1-methylcyclopropanecarbonyl, cyclopropaneacetyl, ⁇ -methylcyclopropaneacetyl, 1-methylcyclopropane acetyl, cyclopropanepropionyl, ⁇ -methylcyclopropanepropionyl,
  • acyl group is pyridinecarbonyl
  • picoiinoyl (2-pyridinecarbonyl) nicotinoyl (3-pyridinecarbonyl) and isonicotinoyl (4-pyridinecarbonyl).
  • benzoyl phenylacetyl, ⁇ -phenylpropionyl, ⁇ -phenylpropionyl, p-toluyl, m-toluyl, o-toluyl, o-ethylbenzoyl, p-tert-butylbenzoyl, 3,4-dimethylbenzoyl, 2-methyl-4-ethylbenzoyl, 2,4,6-trimethylbenzoyl, m-methylphenylacetyl, p-isobutylphenylacetyl, ⁇ -(p-ethylphenyl)propionyl, p-anisoyl, m-anisoyl, o-anisoyl, m-isopropoxybenzoyl, p-methoxyphenylacetyl, m-isobutoxyphenylacetyl, m-diethylaminobenzoyl, 3-
  • hydroxyl protecting group When the hydroxyl protecting group is a carbonate grouping, it has the structural formula i.e., it is an organic radical which can be considered to be derived from a carbonic acid by removal of the hydroxyl group from the COOH portion.
  • Y' preferably represents alkyl having 1 to 7 carbon atoms; alkenyl having one or two double bonds and 2 to 7 carbon atoms; cycloalkyl-C r H 2r - wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three; phenoxy; 2-, 3-, or 4-pyridyl; or phenyl-C r H 2r - wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, tnfluoromethyl, dialkylamino having
  • carboxyl protecting group as used herein is intended to designate a group (W) which is inserted in place of a hydrogen atom of a COOH group or groups in order to protect the COOH group(s) during synthesis and/or to improve lipoidal characteristics and prevent premature metabolism of said COOH group or groups prior to the compound's reaching the desired site in the body.
  • carboxyl protecting groups W are the groups encompassed by Y' above, especially C 1 -C 7 alkyl, particularly ethyl, isopropyl and t-butyl. While such simple alkyl esters and the like are often useful, other carboxyl protectmg groups may be selected, e.g. in order to achieve greater control over the rate of in vivo hydrolysis of the ester back to the acid and thus enhance drug delivery.
  • carboxyl protecting groups W such as the following may be used in place of the hydrogen of the -COOH group: ,
  • alk is C 1 -C 6 straight or branched alkylene and the alkyl radical is straight or branched and contains 1 to 7 carbon atoms (e.g. -
  • carboxyl protecting groups W which can be used in place of the hydrogen of the -COOH group and which are especially useful herein are the following:
  • X 4 is S, SO or SO 2 and R a is C 1 -C 7 alkyl or C 3 -C 12 cycloalkyl;
  • R a is defined as above;
  • R b is C 1 -C 7 alkyl and R c is C 1 -C 7 alkyl or wherein R b and R c taken together represent -(CH 2 ) m' - wherein m' is 3 or 4 and -(CH 2 ) m' - is optionally substituted by one to three C 1 -C 7 alkyl;
  • R d is hydrogen or C 1 -C 7 alkyl and R c is unsubstituted or substituted C 1 -C 12 alkyl [e.g. cycloalkyl -C p H 2p -wherein p is defined as above, C 3 -C 12 cycloalkenyl-C p H 2p - wherein p is defined as above or C 2 -C 1 alkenyl, the substituents bemg selected from the group consisting of halo, C 1 -C 7 alkoxy, C 1 -C 7 aikylthio, C 1 -C 7 alkylsulfinyl, C 1 -C 7 alkylsulfonyl,
  • R a is unsubstituted or substituted phenyl or benzyl
  • substituents being selected from the group consisting of C 1 -C 7 alkyl, C 1 -C 7 alkoxy, halo, carbamoyl, C 2 -C 1 alkoxycarbonyl, C 2 -C 8 alkanoyloxy, C 1 -C 7 haloalkyl, mono(C 1 -C 7 alkyl)amino, di(C 1 -C 7 alkyl)amino, mono(C 1 -C 7 alkyl)carba moyl, di(C 1 -C 7 alkyl)carbamoyl, C 1 -C 7 aikylthio, C 1 -C 7 alkylsulfinyl and C 1 -C 7 alkylsulfonyl, or R a is C 6 -C 28 polycycloalkyl-C p H 2p - or C 6 -C 2g poiycycloalkenyl-C p H 2p - wherein p is defined as
  • R d and R a are defined as above; and wherein R d is defined as above and R f and R g , which can be the same or different, are each hydrogen, C 1 -C 7 alkyl, C 3 -C 12 cycloalkyl-C p H 2p -, C 3 -C 12 cycloalkenyl-C p H 2p -, phenyl or benzyl, or one of R f and R b is hydrogen.
  • R f and R b are C 6 -C 28 polycycloalkyl-C P H- 2p - or C 6 - C 2g polycycloalkenyl-C p H 2p -, or R f and R g are combined such that -NR R g represents the residue of a saturated monocyclic secondary amine.
  • the carboxyl protecting group is C 3 -C 12 cycloalkyl-C p H 2p - or otherwise contains a C 3 -C 12 cycloalkyl group
  • the cycloalkyl groups contain 3 to 8 ring atoms and may optionally bear one or more, preferably one to four, alkyl substituents. Exemplary such cycloalkyl groups are
  • the carboxyl protecting group is C 3 -C 12 cycloalkenyl-C p H 2p - or otherwise contains a C 3 -C 12 cycloalkenyl group
  • the corresponding unsaturated radicals such as cyclopentenyl and cyclohexenyl and the like are contemplated.
  • the polycycloalkyl-C p H 2p - radicals which can serve as carboxyl protecting groups, or as portions of carboxyl protecting groups, are bridged or fused saturated alicyclic hydrocarbon systems consisting of two or more rings, optionally bearing one or more alkyl substituents and having a total of 6 to 28 carbon atoms in the ring portion.
  • the corresponding bridged or fused unsaturated alicyclic hydrocarbon systems are intended by the term "C 6 -C 28 polycycloalkenyl-C p H 2p -".
  • polycycloalkenyl radicals are exemplified by adamantyl (especially 1- or 2-adamantyl), adamantylmethyl (especially 1-adamantylmethyl),
  • adamantylethyl especially 1-adamantylethyl
  • bomyl norbonyl, (e.g. exonorbornyl or endo-norbomyl), norbomenyl (e.g. 5-norbornen-2-yl), norbornylmethyl (e.g. 2-norbomylmethyl) and norbornylethyl (e.g. 2-norbornylethyl)
  • p is defined as above and the steroi residue is the portion of a steroidal alcohol which remains after removal of a hydrogen atom from a hydroxy group therein.
  • the steroi residue is preferably that of a pharmacologically inactive steroid, e.g. cholesterol, a bile acid (cholic acid or related compound) or the like.
  • a pharmacologically inactive steroid e.g. cholesterol, a bile acid (cholic acid or related compound) or the like.
  • p is preferably 0, 1 or 2.
  • -NR f R g represents the residue of a saturated monocyclic secondary amine, such monocycles preferably have 5 to 7 ring atoms optionally containing another hetero atom (-O-, -S- or -N-) in addition to the indicated nitrogen atom, and optionally bear one or more substituents such as phenyl, benzyl and methyl.
  • residues of saturated monocyclic secondary amines which are encompassed by the -NR f R g term are morpholino, 1-pyrrolidinyl, 4-benzyl-1-piperazinyl, perhydro-1,2,4-oxathiazin-4-yl, 1- or
  • an appropriate carboxyl protecting group will depend upon the reason for protection and the ultimate use of the protected product. For example, if the protecting group is intended to be present in a pharmaceutically useful end product, it will be selected from those protecting groups described hereinabove which offer low toxicity and the desired degree of lipophilicity and rate of in vivo cleavage. On the other hand, if the protecting group is used solely for protection during synthesis, then only the usual synthetic requirements will generally apply.
  • amino protecting group as used herein is intended to designate a group (T) which is inserted in place of a hydrogen atom of an amino group or groups in order to protect the amino group(s) during synthesis and/or to improve lipoidal characteristics and prevent premature metabolism of said amino group or groups prior to me compound's reaching the desired site in the body.
  • amino protecting groups T selection of a suitable amino protecting group will depend upon the reason for protection and the ultimate use of the protected product. When the protecting group is used solely for protection during synthesis, then a conventional amino protecting group may be employed. When the amino protecting group is intended to be present in a pharmaceutically useful end product, then it will be selected from among amino protecting groups which offer low toxicity and the desired degree of lipophilicity and rate of in vivo cleavage. Especially suitable for in vivo use as amino protecting groups T are activated carbamates, i.e. the protecting group T has the structure wherein R h is hydrogen, C 1 -C 7 alkyl or phenyl and R i can be selected from the groups indicated as suitable carboxyl protecting groups W hereinabove.
  • R i is preferably a polycycloalkyl or polycycloalkenyl-containing group, such as adamantyl or a steroi residue, especially a cholesterol or bile acid residue.
  • the drugs which can be derivatized in accord with the present invention must contain at least one functional group capable of bonding to the phosphorus atom in the mixed phosphate carrier moiety, directly or through a bridging group. Drugs which are capable of direct bonding are generally preferred because directly-bonded derivatives are more readily synthesized and their in vivo cleavage to the active drug species is likewise less complex. When a linking or bridging group is required, such must be chosen judiciously so that in vivo cleavage will occur in the desired sequence.
  • the mixed phosphate derivatives of formula (I) are designed to be cleaved in vivo in stages after they have reached the desired site of action. The first cleavage, by esterase, provides a negatively charged "locked-in" intermediate of the type
  • the drug is activated in vivo by phosphorylation; such activation may occur in the present system by enzymatic conversion of the "locked-in” intermediate with phosphokinase to the active triphosphate and/or by phosphorylation of the drug itself after its release from the "locked-in” intermediate as described above.
  • the original nucleoside-type drug will be convened. via the derivatives of this invention, to the active phosphorylated species according to the sequence:
  • the instant invention provides derivatives which need only a two-step in vivo phosphorylation to amve at the active tri-phosphorylated species, while the original drug requires a tiiree-step activation in vivo to the triphosphate.
  • (lb) can be any of the groups defined as R 2 values with formula (I) hereinabove.
  • the derivatives of formulas (Id) and (Ie), like those of formulas (la) and (Ib), are thus first cleaved by esterase to give the negatively charged intermediate; subsequent cleavage by alkaline
  • -O-Z- can be -OCH 2 - in formula (Ic), because that bond will be less susceptible to esterase than the bond linking to the rest of the molecule, due to steric considerations.
  • the compounds are designed so that the bonds will cleave in the proper sequence.
  • Drugs containing a reactive hydroxyl or mercapto function for use herein include, but are not limited to, steroid sex hormones, antivirals, tranquiUzers, anticonvulsants, antineoplastics (anticancer/antitumor agents), hypotensives, antidepressants, narcotic analgesics, narcotic antagonists and agonist/antagonists, CNS anticholinergics, stimulants, anesthetics, antiinflammatory steroids, nonsteroidal antiinflammatory agents/analgesics, antibiotics and CNS prostaglandins.
  • Preferred drugs of this type are antivirals, antineoplastics and steroids.
  • male sex hormones/androgens such as testosterone and methyl testosterone
  • female sex hormones including estrogens, both semisynthetic and natural, such as mestranol, quinestrol, ethinyl estradiol, estradiol, estrone, estriol, estradiol 3-methyl ether and estradiol benzoate, as well as progestins, such as norgestrel, norethindrone, ethisterone, dimethisterone, allylestrenol, cingestol, ediynerone, lynestrenol, norgesterone, norvinisterone, ethynodiol, oxogestone, tigestol and norethynodrel.
  • the mixed phosphate moiety will be bonded to the steroid via a hydroxyl in the 3- or 17-position, with the
  • nucleoside type examples include those of the nucleoside type, glycosides, phenyl giucoside derivatives and others.
  • nucleoside type i.e. a purine or pyrimidine base-type structure, including analogs of purines and pyrimidines, bearing a singly or multiply hydroxylated substituent, which may be a natural or unnatural sugar, hydroxy-bearing alkyl group or similar substituent.
  • nucleoside-type antivirals include zidovudine (AZT);
  • ribavirin (S)-9-(2,3-dihydroxypropyl)adenine, 6-azauridine, acyclovir (ACV), 5,6-dichloro-1- ⁇ -D-ribofuranosylbenzimidazole, 5,7-dimethyl-2- ⁇ -D-ribofuranosyl-s-trizoole (1,5-a) pyrimidine, 3-deazauridine, 3-deazaguanosine, DHPG (ganciclovir), 6-azauridine, idoxuridine, dideoxycytidine (DDC), trifluridine
  • nucleoside-type antivirals suitable for derivatization in accord with the present invention have been descnbed in the literature. See, for example, Van Aerschot et al, J. Med. Chem. 1989, 32, 1743-1749; Mansuri et al, J. Med. Chem. 1989. 32, 461-466; Kumar et al, J. Med. Chem. 1989. 32, 941-944; Lin et al, J, Med, Chem. 1989, 32, 1891-1895; Kim et al, J. Med. Chem. 1987, 30, 862-866; Lin et al, J. Med. Chem. 1987. 30, 440-444; Herdewijn et al, J, Med, Chem.
  • the mixed phosphate moiety will be bonded to the
  • Non-nucleoside antivirals for possible derivatization herein include hydroxy-containing giycosides such as 2-deoxy-D-glucose and 2-deoxy-2- fluoro-D-mannose, phenyl glucosides such as phenyl-6-chloro-6-deoxy- ⁇ -D-glucopyranoside and benzimidazole analog type antivirals such as the syn and anti isomers of 6[[(hydroxylmino)phenyl]methyl]-1-[(1-methylethyl)sulfonyl]-1H-benzimidazol-2-amine.
  • hydroxy-containing benzodiazepine tranquilizers for example oxazepam, lorazepam and temazepam
  • tranquilizers of the butyrophenone group such as haloperidol
  • tranquilizers of the diphenylmethane group for example hydroxyzine
  • phenothiazine-type tranquilizers for example acetophenazine, caxphenazine, fluphenazine, perphenazine and
  • piperacetazine and tranquilizer analogs of phenothiazines, e.g.
  • hydroxy-containing anticonvulsants there can be mentioned, for example, the metabolites of valproic acid, i.e. 5 -hydroxy- 2-n-propylpentanoic acid, 4-hydroxy-2-n-propylpentanoic acid and 3-hydroxy- 2-n-propylpentanoic acid.
  • antineoplastics i.e. anticancer and/or antitumor agents
  • antineoplastics i.e. anticancer and/or antitumor agents
  • hormonal agents i.e. anticancer and/or antitumor agents
  • antineoplastics podophyllotoxins (e.g. teniposide, etoposide), antibiotic-type antibiotics, nitrosourea-type alkylating agents and, especially, purine and pyrimidine antagonists.
  • the punne and pyrimidine antagonist-type antineoplastics include simple purine and pyrimidine base-type structures, e.g. thioguanine and 6-mercaptopurine, as well as those of the nucleoside-type, e.g.
  • Ara-AC pentostatin, dihydro-5-azacytidine, tiazofurin, sangivamycin, Ara-A (vidarabine), 6-MMPR, 5-FUDR (floxuridine), cytarabine (Ara-C; cytosine arabinoside), 5-azacytidine (azacitidine), uridine, thymidine, idoxuridine, 3-deazauridine, cyclocytidine, dihydro-5-azacytidine, triciribine and fiudrabine.
  • Many nucleoside-type compounds have utility both as antineoplastics and as antiviral agents. Such are typically derivatized as described hereinabove with reference to the nucleoside-type antivirals.
  • antibiotics there can be mentioned lincomycin type antibiotics such as clindamycin and lincomycin.
  • narcotic analgesics there can be mentioned those of the meperidine type such as meptazinol, profadol and myfadol; and those which can be considered morphine derivatives.
  • the morphine derivatives include those of the morphine series, such as hydromorphone,
  • oxymorphone apomorphine, levorphanol, morphine and metopon
  • benzomorphan series such as pentazocine, cyclazocine and
  • phenazocine and those of the codeine series, such as codeine, oxycodone, drocode and pholcodine.
  • narcotic antagonists and mixed agonist/antagonists include such compounds as nalbuphine, naloxone, nalorphine, buprenorphine, butorphanol, levallorphan, naltrexone, naimefene, alazocine, oxilorphan and nalmexone.
  • the antiinflammatory steroids include such compounds as cortisone, hydrocortisone, betamethasone, dexamethasone, flumethasone,
  • fluprednisolone methyl prednisolone, meprednisone, prednisolone, prednisone, triamcinolone, triamcinolone acetonide, cortodoxone.
  • fludrocortisone flurandrenolone acetonide (flurandrenolide) and
  • nonsteroidal antiinflammatory agents/non-narcotic analgesics there can be mentioned, for example, clonixeril, sermatacin and naproxol.
  • both [D] and OR 1 is formula (I) can be drug residues. While virtually any of the hydroxyl-containing drugs disclosed above could be used to prepare a compound of formula (I) in which [D] and OR 1 are the same or different drug residues, specific utility classes and specific hydroxyl-containing drugs within those classes lend themselves especially to this type of derivatization.
  • nucleoside-type drugs which are especially useful as antivirals and antineoplastics, and are known to be activated in vivo by phosphorylation, are particularly desirable targets for this type of derivatization; the bioavailability of drugs of this type may be enhanced by providing two identical drug residues in the compound of formula (I), in essence providing for faily rapid release of the first drug residue and its conversion to active species, followed by a sustained release of the second drug residue and its activation.
  • botii [D] and -OR represent AZT (zidovudine) residues or in which both represent DDI (dideoxylnosine) residues.
  • the possibility of including two different drug residues within a system for targeted drug delivery is of particular interest when it is desired to deliver two drugs to the same target organ, especially when the drugs may have a synergistic, rather than a simply additive, effect when co-administered.
  • Of particular interest in this connection are combinations of two antineoplastics or two antivirals, especially two nucleoside-type antivirals. Nevertheless, even when the combined effect is no more than additive, it may be convenient to incorporate residues of two different drugs in the same molecule, as may be the case for certain antineoplastic-antineoplastic or antiviral-antiviral combinations, antineoplastic-antiviral combinations, antibiotic-antiinflammatory combinations and estrogen-progestin combinations.
  • -OR 1 represents a drug residue in formula (I)
  • it may be a substance which functions wholly or partially as an enhancer or activator when used in combination with the drug whose residue is represented by [D], or to prevent deactivation thereof, e.g. an enzyme inhibitor for use with an antiviral agent, or it may function as a transport facilitator, in which case it may not be a "drug" residue in its normal sense but simply a protective residue which functions to enhance transport or delivery of the drug whose residue is represented by [D], principally by improving lipophilicity. It must, however, be a group which is enzymatically much less sensitive to cleavage in vivo than the
  • acyloxyalkyl group -OCH(R 2 )OCOR 3 It is not an acyloxyalkyl group in any event. Preferred protective residues are discussed in more detail hereinbelow.
  • an estrogen such as estradiol may be paired with a progestin such as norediindrone, or norgestrel, for contraceptive use or other use known for an estrogen/progestin combination.
  • pairs of hydroxy-containing drugs whose residues may be combined in a single compound of formula (I) are combinations of antiviral drugs with enzyme inhibitors and combinations of two antiviral agents.
  • the rationale for such combination in a single molecule includes the fact that the antivirals and antivirals/enzyme-inhibitors have themselves been co-administered. See, for example,
  • Antiviral Agents The Development and Assessment of Antiviral
  • Adenosine-containing nucleoside antivirals are susceptible to adenosine deaminase metabolism. Deamination appears to substantially decrease activity. Incorporation of an deaminase inhibitor residue into the same molecule as a nucleoside antiviral susceptible to such an inhibitor is thus designed to alleviate inactivation of the antiviral by the widespread
  • adenosine deaminase enzyme adenosine deaminase enzyme.
  • Antiviral drugs susceptible to such inactivation include vidarabine (adenine arabinoside or Ara-A), 3-deoxyadenosine (3-dA, cordycepin) and 2',3'-dideoxyadenosine.
  • Adenosine deaminase inhibitors include coformycin, 2'-deoxycoformycin, EHNA [erythro-9-(2-hydroxy-3-nonyl)adenine], acyclo-coformycin, DHPA
  • Combination of such an antiviral drug and such an enzyme inhibitor in a single molecule of formula (I) may be of particular use in combating DNA viruses such as vaccinia virus, varicella-zoster, HSV-1, HSV-2, adenoviruses, etc.
  • 2'-Deoxycytidine and many cytidine analogs are substrates for cytidine-deoxycytidine deaminase, which is widely occurring. Deamination by cytidine-deoxycytidine deaminase may lead to enhanced cytotoxicity and/or reduced activity.
  • Antiviral nucleosides susceptible to this enzyme include the 5-iodo- and 5-bromo-2'-deoxycytidines, Ara-C and FIAC [1- (2'-deoxy-2'-fluoro- ⁇ -D-arabinofuranosyl)-5-iodocytosine], while the enzyme inhibitors includes tetrahydrouridine (THU) and
  • DNA viruses such as HSV-1 and -2, VZV and HCMV may be particularly susceptible to such combination in formula (I).
  • Thymidine, uridine and many pyrimidine nucleoside analogs are subject to cleavage by phosphorylases. By inhibiting phosphorylysis, it may be possible to increase drug half-life and enhance plasma levels of drug.
  • Antivirals susceptible to cleavage of this sort include idoxuridine (IUdR or 5-iodo-2'-deoxyuridine), 5-ethyl-2'-deoxyuridine (EtUdR), trifluridine (TFT or 5-trifluoromethyl-2'-deoxyuridine), 5-E-(2-bromovinyl)- 2'-deoxyuridine (BVDU) and 5-(2-chloroethyl)-2'-deoxyuridine (CEDU).
  • Thymidine and uridine phosphorylase inhibitors include 5-benzyl acyclouridine, 2'-deoxyglucosyl thymine and 5-methyl acyclouridine. Again, combination of antiviral and inhibitor in a single compound of formula (I) may be of particular interest in treating inflections caused by DNA viruses.
  • Selection of two different antiviral agents for incorporation of their residues into formula (I) may be made, by way of illustration, from among virus-specific agents which act on or via DNA polymerase, from
  • DNA virus-specific agents such as acyclovir (ACV), 5-E- (2-bromovinyl)-2'-deoxyuridine (BVDU), 9-(2-hydroxy-1- (hydroxymethyl)ethoxymethyl)guanine (DHPG), spongothymidine (Ara-T) and 5-ethyl-2'-deoxyuridine (EtUdR) may be selected, e.g. residues of ACV and BVDU, DHPG and BVDU, ACV and DHPG, Ara-T and ACV, and Ara-T and EtUdR combinations as the [D] and OR 1 moieties.
  • ACCV acyclovir
  • BVDU 5-E- (2-bromovinyl)-2'-deoxyuridine
  • DHPG 9-(2-hydroxy-1- (hydroxymethyl)ethoxymethyl)guanine
  • Rha-T spongothymidine
  • EtUdR 5-ethyl-2'-deoxyuridine
  • Combinations of DNA- specific with less specific nucleosides include, for example, selection of a specific agent such as ACV, EtUdR,
  • MMUdR (5-methoxymethyl-2'-deoxyuridine), BVDU or Ara-T, together with a less specific agent such as Ara-A, IUdR, TFT, FUdR, FMAU, FIAC or Ara-C.
  • a less specific agent such as Ara-A, IUdR, TFT, FUdR, FMAU, FIAC or Ara-C.
  • [D] and -OR 1 are the residues of ACV/Ara-A, ACV/FIAC, ACV/IUdR, ACV/TFT and
  • TFT, FUdR, FMAU, FIAC, Ara-C can also be selected for derivatization in accord with the present invention. Such combination may lead to lower doses and thus to lower toxicity.
  • residues include those of Ara-A with IUdR, Ara-A with Ara-C, IUdR with FUdR, Ara-A with FIAC, Ara-A with FMAU, Ara-A with TFT.
  • choice of one of these agents for derivatization may be combined with a choice of a selective inhibitor such as 5' -amino-5'-deoxythymidine (5' -AdThd) or with a selective protector such as deoxythymidine (dThd).
  • An objective of selective inhibition may be to inhibit enzymes responsible for undesired activation of the antiviral drug in uninfected cells, while an objective of selective protection may be to provide a competitive substrate for enzymes which are responsible for cellular toxicity.
  • RNA virus-specific agents whose residues can be combined as [D] and -OR 1 in a compound of the present invention include selenazofurin, ribavirin, 3-deazaguanosine, 3-deazauridine, tiazofurin, 2-deoxy-D-glucose, 6-mercapto-9-tetrahydro-2-furylpurine (6-MPTF), zidovudine (AZT), dideoxylnosine (DDI), dideoxyadenosine, DDC, D4T and the like.
  • the R 1 group can be many of the groups defined as carboxyl protecting groups hereinabove, from simple alkyl groups such as ethyl to carbocylic and polycarbocyclic groups (cycloalkyl-C p H 2p -, polycycloalkyl- C p H 2p - and so forth, especially the polycycloalkyl-C p H 2p - groups as defined and exemplified hereinabove), just so long as it is enzymatically much less sensitive to cleavage in vivo man the -OCH(R 2 )OCOR 3 portion of the instant compounds. This is true regardless of the identity of the [D] residue.
  • a large lipophilic protective residue for -OR 1 is of particular interest when the drug is hydrophilic (e.g. a nucleoside); on the other hand, when the drug is lipophilic, R 1 can easily be one of the smaller, more simple residues (e.g. methyl) as there is no need to enhance lipophilicity.
  • the final compound of formula (I) will optimally have a log P of between about 1 and 5, preferably between about 2 and 3, and this can be controlled by appropriate selection of -OR 1 for a given drug residue [D].
  • derivatization herein include, but are not limited to, tranquilizers, sedatives, anticonvulsants/antiepileptics, hypnotics, antineoplastics, antivirals, antibiotics/antibacterial agents, barbiturate antagonists, stimulants, antihypertensives and antidepressant/psychotropic drugs.
  • tranquilizers and anticonvulsants/antiepileptics for example, phenytoin, mephenytoin and ethotoin; barbiturate sedatives/anticonvulsants/
  • antepileptics e.g. phenobarbital, amobarbital and butalbital
  • gultarimide or piperidine derivatives which are sedatives and hypnotics, for example, glutethimide, methyprylon and aminoglutethimide (also an anticonvulsant); benzodiazepine-type tranquilizers, such as nitrazepam, bromazepam, demoxepam, oxazepam
  • antidepressants/psychotropics e.g. sulpiride
  • GABAergic agents/antiepileptics for example progabide
  • valproic acid derivative-type anticonvulsants e.g. valpromide
  • barbiturate antagonists for example, bemegride
  • tetracycline-type antibiotics such as
  • antiinflammatory/ analgesic agents e.g. tesicam
  • antineoplastics for example alkylating agents of the nitrogen mustard-type, e.g. uracil mustard, spiromustine and cydophosphamide, alkylating agents of the nitrosourea type such as PCNU, purine/pyrimidine antagonists, e.g. 5-FU(5-fluorouracil), and various other antineoplastics, such as razoxane and
  • Drugs containing a reactive carboxyl function for derivatization in accord with the present invention include, but are not limited to, anticonvulsants, antineoplastics, antibiotics/antibacterials, diagnostics and nonsteroidal antiinflammatory agents/non-narcotic analgesics.
  • anticonvulsants e.g. valproic acid
  • antineoplastics for example, nitrogen mustard-type alkylating agents such as chlorambucil and folic acid antagonists such as methotrexate and dichloromethotrexate
  • penicillin-type antibiotics such as amoxicillin, phenoxymethylpenicillin (penicillin V), benzylpenicillin, dicloxacillin, carbenicillin, oxacillin, cloxacillin, hetacillin, methicillin, nafcillin, ticarcillin and epicillin
  • cephalosporin-type antibiotics e.g.
  • cephalothin cefoxitin, cefazolin and cephapirin; miscellaneous other antibiotics, e.g. oxolinic acid; nonsteroidal antiinflammatories/non-narcotic analgesics, including propionic, acetic, fenamic and biphenylcarboxylic acid
  • ibuprofen for example, ibuprofen, naproxen, flurbiprofen, zomepirac, sulindac, indomediacin, ketoprofen, fenbufen, fenoprofen, indoproxen, fluprofen, bucloxic acid, tolmetin, alclofenac, fenclozic acid, ibufenac, flufenisal, pirprofen, flufenamic acid, mefenamic add, clonixin,
  • meclofenamic acid flunixin, diclofenac, carprofen, etodolac, fendosal, prodolic acid, diflunisal and flutiazin; and diagnostics such as diohippuric acid and iothalamic acid.
  • Drugs containing a reactive amino function for use in accord with the present invention include, but are not limited to, GABAergics/antiepileptics, antineoplastics, cerebral stimulants, appetite suppressants, MAO inhibitors, tricyclic antidepressants, decongestants, narcotic analgesics, antivirals, neurotransmitters, small peptides, dopaminergic agents and antibiotics.
  • Illustrative drugs of this structural type include antiepileptics such as GABA, 7-vinyl GABA and ⁇ -acetylenic GABA; nitrogen mustard-type antineoplastics such as mdphalan; antibiotic-type antineoplastics, e.g. daunorubicin (daunomycin), doxorubicin (adriamycin), dactinomycin and mitomycin C; nitrosourea-type antineoplastics such as alanosine;
  • miscellaneous other antineoplastics e.g. bactobolin, DON and acivicin: sympathetic stimulants/appetite suppressants, such as methamphetamine. phentermine, phenmetrazine, dextroamphetamine, levamphetamine, amphetamine, phenethylamine, methyl phenidate, aletamine, cypenamine, fencamfamin and etryptamine; MAO inhibitors, e.g. tranylcypromine; tricyclic antidepressants, e.g.
  • protriptyline desipramine, nortriptyline, octriptyline and maprotiline
  • cerebral stimulants e.g. amedalin, bupropion. cartazolate, daledalin, difluanine and nisoxetine
  • antivirals such as glucosamine, 6-amino-6-deoxy-D-glucose, amantadine and rimantadine
  • amino adds/neutrotransmitters e.g. tryptophan
  • small peptides typically containing 2-20 amino acid units, e.g. the enkephalins (leu 5 -enkephalin, met 5 -enkephalin), endorphins and LHRH analogs
  • catecholamine e.g. the enkephalins (leu 5 -enkephalin, met 5 -enkephalin), endorphins and LHRH analogs
  • catecholamine e.g. the enkephalin
  • neurotransmitters e.g. norepinephrine, epinephrine and dopamine
  • other neurotransmitters e.g. serotonin, and related compounds such as tryptamine
  • penicillin-type antibiotics such as ampicillin
  • cephalosporin-type antibiotics e.g. cephalexin
  • sympatholytic agents such as guanethidine and debrisoquin.
  • metabolites of drugs are typified by hydroxylated metabolites of tricyclic antidepressants, such as the E- and Z-isomers of 10-hydroxynortriptyline, 2-hydroxylmipramine, 2-hydroxydesipramine and 8-hydroxychloripramine; hydroxylated metabolites of phenothiazine tranquilizers, e.g. 7-hydroxychlorpromazine; and desmethyl metabolites of N-methyl benzodiazepine tranquilizers, e.g.
  • tricyclic antidepressants such as the E- and Z-isomers of 10-hydroxynortriptyline, 2-hydroxylmipramine, 2-hydroxydesipramine and 8-hydroxychloripramine
  • hydroxylated metabolites of phenothiazine tranquilizers e.g. 7-hydroxychlorpromazine
  • desmethyl metabolites of N-methyl benzodiazepine tranquilizers e.g.
  • SL 75102 which is an active metabolite of progabide, a GABA agonist
  • hydroxy-CCNU which is an active metabolite of CCNU, an anticancer nitrosourea.
  • tiiese pharmacologically active metabolites have been identified as such in the sdentific literature but have not been administered as drugs themsdves.
  • the active metabolites are believed to be comparable in activity to their parent drugs; frequendy, however, the metabolites have not been administered per se because they are not themselves able to penetrate biological membranes such as the blood-brain barrier.
  • Diagnostic agents including radiopharmaceuticals. are encompassed by the expression "drug” or the like as used herein. Any diagnostic agent which can be derivatized to afford a mixed phosphate derivative of formula (I) which will penetrate biological membranes, e.g. the BBB, and concentrate in the target organ, e.g. the brain, in its negatively charged form and can be detected therein is encompassed by this invention.
  • the diagnostic may be "cold” and be detected by X-ray (e.g. radiopaque agents) or other means such as mass spectrophotometry, NMR or other non-invasive techniques (e.g. when the compound includes stable isotopes such as C13, N15, O18, S33 and S34).
  • the diagnostic alternatively may be
  • Typical "cold" diagnostics for derivation herein include o-iodohippuric acid, iothalamic acid, iopydol, iodamide and iopanoic acid.
  • radiolabelled diagnostics include diohippuric acid (I 125, I 131),
  • diotyrosine (I 125, I 131), o-iodohippuric acid (I 131), iothalamic acid (I 125, I 131), thyroxine (I 125, I 131), iotyrosine (I 131) and
  • iodometaraminol (I 123).
  • the "locked-in" negatively charged form will be the form that is imaged or otherwise detected, not the original diagnostic itself.
  • any of the drugs disdosed herein which are intended for the treatment or prevention of medical disorders but which can be radiolabelied, e.g. with a radioisotope such as iodine, or labelled with a stable isotope can thus be converted to a diagnostic for incorporation into the mixed phosphate of formula (I).
  • the drug sdected for derivatization according to the present invention is to be linked to the mixed phosphate moiety via a secondary or tertiary hydroxyl, or via a hindered hydroxyl, it may be desirable to use a bridging group as described above for linking amide and imide groups to the phosphate, rather than a direct bond between the drug's hydroxyl group and the phosphorus atom.
  • the compounds of formula (I) can be prepared by a variety of synthetic procedures tailored to the structure of the particular drug to be derivatized, particularly to the nature of the reactive functional group to be linked to the mixed phosphate moiety, the identity of the bridging group, if any, and the presence of other functional groups which may benefit from protection.
  • the drug contains a reactive hydroxyl group susceptible to direct bonding to the phosphorus atom in the mixed phosphate moiety. It is also preferred for simplicity's sake that the selected drug not require protection of other functional groups, although such groups can be protected when necessary.
  • the compounds of formulas (la) and (lb) can be synthesized by first converting the drug, D-OH or D-SH, respectively, to the corresponding mixed phosphate diester intermediate of the formula
  • the two steps can be combined in a single step utilizing two equivalents of D-OH to give the corresponding diester intermediate.
  • the diester intermediate can then be converted to the compound of formula (I) by one of the methods described in the preceding paragraph, preferably by reaction with cesuim fluoride and a compound of the formula such as
  • That intermediate can be isolated by column chromatography (although the 2-chlorophenyl moiety can be easily hydrolyzed on the column), then subjected to deprotection with pyridine-2-aldoxime and 1,1,3,3- tetramethylguanidine to give the corresponding diester intermediate.
  • the diester intermediate can then be converted to the compound of formula (I) as described immediately above.
  • the compounds of formula (Ic) can be synthesized by reacting the drug D-COOH with chloromethyl chlorosulfate or similar compound of the type Cl-Z-SO 3 Cl to give an intermediate of the type
  • That intermediate which contains a linking group bearing a reactive
  • aldehyde of the type R 2 CHO e.g. formaldehyde, chloral, acetaldehyde, furfural, benzaldehyde or the like, in the presence of a basic catalyst such as potassium carbonate, to give the corresponding aldehyde of the type R 2 CHO, e.g. formaldehyde, chloral, acetaldehyde, furfural, benzaldehyde or the like, in the presence of a basic catalyst such as potassium carbonate, to give the corresponding
  • the compounds of formula (If) can be synthesized by reacting the drug, DNHR 4 , with a halo(optionally substituted methyl)chloroformate to give an intermediate of the type
  • That intermediate which contains a linking group bearing a reactive
  • the various protecting groups for hydroxyl, carboxyl and amino functions discussed above can be substituted for the hydroxyl, carboxyl and amino functions in the instant compounds or their precursor molecules by methods well-known in the art. Most frequently, the protecting group will first be introduced into the drug molecule by well-known methods and the protected drug will then be subjected to the processes described above for preparation of the instant compounds.
  • amine protecting groups are chemically removed by acidolysis (acid hydrolysis) or hydrogenation, depending on the particular protecting group employed.
  • Hydroxyl and carboxyl protecting groups are typically removed chemically by acid or base hydrolysis.
  • Protecting groups which are incorporated into the pharmaceutical end product must be amenable to hydrolytic or metabolic cleavage in vivo.
  • the starting materials needed for the vanous processes described above are commercially available or can be readily prepared by known methods.
  • the drug containing a reactive hydroxyl or mercapto function is reacted with a phosphorylating agent such as 2-chloromethyl-4-nitrophenylphosphorodichloridate, followed by hydrolysis, followed by reaction with methanol, to afford the intermediate phosphate diester.
  • a phosphorylating agent such as 2-chloromethyl-4-nitrophenylphosphorodichloridate
  • the resultant intermediate is then reacted with cesium fluoride and in an organic solvent such as dimethylformamide to give the desired compound of formula (la) or (lb).
  • the representative drugs depicted below may be derivatized in this manner, first to the phosphate diester intermediate
  • the drug containing a reactive hydroxyl or mercapto function also contains a reactive imide or amide function
  • a reactive imide or amide function in addition to the major product which is depicted above, there may be isolated a minor product in which the hydroxy function is derivatized as shown while the amide or imide function is acyloxyalkylated.
  • the minor product will be produced in a larger amount if excess or analogous reagent is employed in the final step.
  • zidovudine zidovudine
  • Drugs such as tiazofurin, 5-FUDR (floxuridine), ribavirin, 6-azauridine, acyclovir, 3-deazaguanosine, ganciclovir (DHPG), 6-azauridine, idoxuridine, trifluridine, dideoxylnosine (DDI), dideoxydehydrothymidine, BVDU, FIAU, FMAU, FIAC, Ara-T, FEAU, seienazofurin and buciclovir
  • DHBG may be acyloxyalkylated at the amide or imide nitrogen in a similar manner to zidovudine; derivatives of this type are even more lipophilic than the major products depicted hereinabove where the imide or amide group is unreacted.
  • the selected drug contains multiple reactive hydroxyl functions
  • a mixture of intermediates and final products may again be obtained.
  • all hydroxy groups are equally reactive, there is not expected to be a predominant product (unless all would give the same product, e.g. ganciclovir), as each mono-substituted product will be obtained in approximately equal amounts, while a lesser amount of multiply-substituted product will also result.
  • one of the hydroxyl groups will be more susceptible to substitution than the other(s), e.g. a primary hydroxyl will be more reactive than a secondary hydroxyl, an unhindered hydroxyl will be more reactive than a hindered one.
  • the major product will be a mono-substituted one in which the most reactive hydroxyl has been derivatized, while other mono-substituted and multiply-substituted products may be obtained as minor products.
  • control of the amount of or analogous reagent affects the
  • Drugs which may afford other hydroxy-substituted (mono- or multiply-substituted) derivatives in addition to those depicted for METHOD A include pentostatin (2'-deoxycoformycin), vidarabine (Ara-A), 5-FUDR (floxuridine), cytarabine (Ara-C), apomorphine, morphine, nalbuphine, naiorphine, buprenorphine, (S)-9-(2,3-dihydroxy ⁇ ropyl)adenine, ganciclovir (DHPG), idoxuridine, trifluridine, BVDU, FIAU, FMAU, FIAC, Ara-T, FEAU, cyclaradine, buciclovir
  • DHBG ethinyl estradiol, estradiol, ethynodiol, cortisone, hydrocortisone, betamethasone, dexamethasone, flumethasone, fluprednisolone,
  • triamcinolone triamcinolone acetonide, cortodoxone, fludrocortisone, flurandrenolide, paramethasone and the like.
  • the selected drug contains multiple reactive hydroxyl functions which are positioned in such a manner that they may form an undesired cyclic product when subjected to the process of METHOD A
  • a synthetic route other than that of METHOD A may be generally preferred.
  • a product which is derivatized only at the 5'-position i.e. as depicted with METHOD A
  • such product is most advantageously produced by use of a transitory protecting group such as the acetonide group described in METHOD F hereinbelow.
  • Drugs such as dihydro-5-azacytidine, tiazofurin, 6-MMPR, 5-azacytidine, ribavirin, 3-deazaguanosine, 6-azauridine, 5,6-dichoro-1- ⁇ -D-ribofuranosyl-benzimidazole, 5,7-dimethyl-2- ⁇ -D-ribofuranosyl-s-triazole (1,5-a)pyrimidine, 3-deazauridine, 6-azauridine, 3-deazaaristeromycin, neplanocin A, selenazofurin and 3-deazaadenosine thus are preferably subjected to METHOD F to afford the preferred 5'-derivatized products depicted with METHOD A.
  • the drug selected as the starting material contains one primary hydroxyl substituent and one or more secondary hydroxyl substituents.
  • the primary hydroxyl is in the 5'-position, while the secondary hydroxyl(s) is/are in the 2'- and/or 3'-position(s).
  • Drugs of this type are exemplified by, but not limited to, vidarabine, cytarabine, ribavirin, 3-deazaguanosine, idoxuridine, BVDU,
  • the selected nucleoside starting material as described above is reacted with 4,4'-dimethoxytrityl chloride to give the 5'-(4,4'-dimethoxytrityl)ether derivative.
  • the 2'- and/or 3'-hydroxy group is then esterified by reaction with a variety of acid anhydrides such as pivaloyl, benzoyl, isobutyryl or acetyl to give the 2'- and/or 3'-ester groupings.
  • the resultant compound is then treated with acetic acid to regenerate the 5'-hydroxy moiety.
  • a starting material with multiple hydroxyl substituents is selected as described in the first paragraph of METHOD E, except that the selected compound must contain hydroxyls at both the 2'- and 3'-positions as well as the 5'-position, e.g. ribavirin, 3-deazaguanosine or the like.
  • Reaction with acetone gives the 2',3'-O-acetonide.
  • That protected intermediate can then be used as the starting material in the process of any of METHODS A-D, followed by, if desired, removal of the acetonide protecting group with formic acid, to give the same compound of the invention as depicted as the final product of METHOD A.
  • the drug e.g. a valproic acid metabolite such as 5-hydroxy-2-n-propylpentanoic acid, sermatacin or the like
  • a valproic acid metabolite such as 5-hydroxy-2-n-propylpentanoic acid, sermatacin or the like
  • That ester is then used as the starting material and METHOD A, B, C or D is repeated to give the desired compound of the invention.
  • METHOD A The process of METHOD A is modified to produce compounds in which there are two residues of hydroxyl-containing drugs.
  • the first drug containing a reactive hydroxyl function is reacted with
  • the diester intermediate can be obtained in one step by reacting 2 equivalents of drug with 2-chlorophenyl-O,O-bis[1- benzotriazolyl]phosphate (formed in Situ by reaction of 1- hydroxybenzotriazole and anhydrous pyridine) and decomposing the product to remove the 2-chlorophenyl group.
  • the diester intermediate can then be converted to the triester of formula (la) as described hereinabove, e.g., by use of cesium fluoride and or by use of sodium methoxide and
  • intermediates and final products depicted above are not always the only intermediates and final products obtained in significant amounts.
  • drugs used as starting material also contain(s) a reactive imide or amide function
  • minor products in which the hydroxy functions are derivatized as shown while the amide or imide function(s) is/are acyloxyalkylated e.g., as described in conjunction with METHOD A hereinabove.
  • METHOD A when one or both selected drugs contain(s) multiple reactive hydroxyl functions, a mixture of intermediates and final product may again be obtained, with the major product being one in which the most reactive hydroxyl in each starting material is derivatized.
  • antineoplastics may be prone to formation of an undesired by-product and may be more advantageously derivatized by prior formation of acetonide protecting groups and ultimate removal thereof, analogously to METHOD
  • METHOD H may also be modified in analogous fashion to
  • the drug containing a reactive amide or imide functional group is reacted with formaldehyde in the presence of potassium carbonate or other suitable basic catalyst, converting the
  • bridged drug The resultant drug with bridging group appended (hereinafter referred to as the "bridged drug”) is then subjected to the multi-step process as described in METHOD A above.
  • the representative drugs depicted below (“Starting Material”) may be derivatized in this manner, first to the bridged drug (not shown), then to the phosphate diester intermediate (“Intermediate”) and finally to the corresponding compound of formula (Id) or (Ie) ("Final Product").
  • the drug containing a reactive carboxyl functional group is reacted with 1-chloroethyl chlorosulfate to convert the -COOH group to a
  • Z can be, and preferably is, selected to be -CH 2 -, and METHOD K is modified by replacing the 1 -chloroethyl chlorosulfate reactant in the first step with chloromethyl sulfate, and otherwise proceeding as detailed in that method.
  • Drugs such as oxacillin, carbenicillin, benzylpenicillin, hetacillin, nafcillin, cloxacillin, cephalothin and cefoxitin can be derivatized in this manner, first to the corresponding chloromethyl derivative by converting the -COOH group to a -COOCH 2 Cl group, then to the intermediate of the partial structure
  • the drug e.g. GABA, melphalan, tryptophan or the like, is first convened to the corresponding ethyl, t-butyl or similar ester grouping by well-known esterification methods. That ester is then used as the starting material and METHOD M is repeated to give the desired compound of the invention.
  • the phosphorodichloridate was obtained as a pale yellow viscous liquid boiling at 157-162° C. The identity of the product was confirmed by NMR analysis.
  • the mixed diester obtained in EXAMPLE 4 (340 mg, 0.89 mmol) was combined with 0.47 mL of 2N aqueous sodium hydroxide solution and 5 mL of water, with stirring. Insoluble materials were removed by filtration. To the yellow filtrate, a few drops of phenolphthalein solution were added. Dilute nitric acid was then added dropwise until the red color disappeared at pH 8-9. A solution of 151 mg (0.89 mmol) of silver nitrate in 1 mL of water was added in one portion in the dark. The resultant mixture was refrigerated overnight, then concentrated to a volume of 2 mL by evaporation. The residue was cooled and the precipitate was removed by filtration and dried at room temperature under vacuum to afford the silver salt of the formula
  • the silver salt obtained in EXAMPLE 5 was suspended in 1 mL of dry benzene. Into the stirred suspension, was slowly added dropwise a solution of 30 mg (0.12 mmol) of iodomethyl pivalate (prepared as in EXAMPLE 6) in 1 mL of dry benzene at room temperature. The resultant mixture was stirred overnight in the dark under a stream of nitrogen.
  • the mixed diester prepared in EXAMPLE 4 (3.45 g, 9.02 mmol), iodomethyl pivalate (4.37 g, 18 mmol) and cesium fluoride (3.01 g, 19.84 mmol) were combined in 20 mL of dimethylformamide and stirred at room temperature for 4 hours under a stream of nitrogen. Then, 150 mL of ethyl ether were added and the resultant mixture was stirred for 5 minutes. Insoluble materials were removed by filtration and the precipitates were extracted twice with ether. The combined ether extracts were washed, twice with equal volumes of water, then with 5% aqueous sodium thiosulfate solution, and again with water.
  • Hexanoyl chloride (5.5 mL, 37 mmol) and acetaldehyde (4.2 mL, 74 mmol) were combined under a stream of nitrogen and stirred in an ice bath. To that solution was added a catalytic quantity of zinc chloride.
  • reaction mixture was maintained in an ice bath for 30 minutes, then was poured into 100 mL of hexane.
  • the hexane solution was washed successively with saturated aqueous sodium bicarbonate solution (2 ⁇ 50 mL) and saturated aqueous sodium chloride solution (50 mL).
  • the organic layer was separated, dried over magnesium sulfate, filtered and concentrated to give 7.81 g of 1'-chloroethyl hexanoate,
  • the mixed diester prepared in EXAMPLE 4 (2.26 g, 6 mmol), 1'-iodoethyl hexanoate (3.24 g, 12 mmol), cesium fluoride (2.01 g, 13.2 mmol) and dimethylformamide (22 mL) were combined under a stream of nitrogen and stirred at room temperature for 19.5 hours.
  • the reaction mixture was then poured into 300 mL of ether and washed successively with water (100 mL) 5% aqueous sodium thiosulfate solution (100 mL) and again with water (100 mL). Each aqueous layer was extracted with one 100 mL portion of ether.
  • the reaction mixture was then stirred in an oil bath (at 80°C.) for 3 hours under a stream of nitrogen.
  • the resulting suspension was poured into 30 mL of ethyl acetate and washed with 50 mL of water and 30 mL of saturated aqueous sodium bicarbonate solution.
  • the aqueous layer was extracted with 30 mL of ethyl acetate.
  • the organic layers were combined and washed with 40 mL of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated.
  • HMPA hexamethylphosphoramide
  • 12.82 mL (89 mmol) of chloromethyl pivalate were added and stirred for 3 hours in an oil bath (80°C.) under a stream of nitrogen.
  • the resulting suspension was poured into 200 mL of ethyl acetate and washed with 500 mL of water and 60 mL of saturated sodium bicarbonate solution.
  • the aqueous layer was extracted with 200 mL of ethyl acetate.
  • the organic layers were combined and washed with 200 mL of saturated aqueous sodium bicarbonate solution, then dried over magnesium sulfate, filtered and evaporated.
  • the compounds of formula (I) which are provided by this invention are typically administered to mammals by incorporating the selected compound into a pharmaceutical composition comprising the compound or a non-toxic pharmaceutically acceptable salt thereof and a non-toxic pharmaceutically acceptable carrier therefor.
  • the compound or its salt is employed in an effective amount, i.e. an amount sufficient to evoke the desired pharmacological response.
  • the compounds of the invention are designed to elicit the kind of pharmacological response which would be obtained by delivery of the parent drug itself to the desired site of action, especially to the brain.
  • the derivative of formula (I) when the parent drug is an antiviral, the derivative of formula (I) will be administered in an amount sufficient to elicit an antiviral response; when the parent drug is an antineoplastic, the derivative of formula (I) will be employed in an amount sufficient to elicit an antineoplastic, i.e.
  • the derivative of formula (I) when the parent drug is an antibiotic, the derivative of formula (I) will be used in an amount sufficient to evoke an antibiotic response; when the parent drug is a steroid sex hormone, the derivative of formula (I) will be used in an amount sufficient to evoke an androgenic or estrogenic or progestational effect (depending on the identity of the parent drug); when the parent drug is an antiinflammatory agent, the derivative of formula (I) will be administered in an amount sufficient to elicit an antiinflammatory response; and so forth.
  • Suitable non-toxic pharmaceutically acceptable carriers for use with the selected compound of formula (I) will be apparent to those skilled in the art of pharmaceutical formulation. See, for example, Remington's
  • the active ingredient may be formulated into a sustained release carrier system and/or a route of administration may be selected to slowly release the chemical, e.g. subcutaneous implantation or transdermal delivery.
  • Routes of administration contemplated for the compounds of formula (I) and pharmaceutical compositions containing them are any of the routes generally used for treatment of the types of conditions for which the parent drugs are administered. These include parenteral (intravenous, intramuscular, subcutaneous), vaginal, rectal, nasal, oral and buccal routes. Appropriate dosage forms for these routes of administration will be apparent to those skilled in the art.
  • the dosage of the formula (I) compound used will be a quantity sufficient to deliver to the target body area an amount of radioisotope, stable isotope or the like which can be effectively detected by radioimaging or other detection means.
  • the amount of radioisotope, stable isotope or the like present in the dosage form will be within or below the ranges conventionally used for diagnostic purposes.

Abstract

The invention provides compounds of formula (I) and the pharmaceutically acceptable salts thereof, wherein [D] is the residue of a drug having a reactive functional group, said functional group being attached, directly or through a bridging group, via an oxygen-phosphorus bond to the phosphorus atom of the (a) moiety; R1 is C1-C8 alkyl, C6-C10 aryl or C7-C12 aralkyl, with the proviso that when [D] is the residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the (a) moiety via an oxygen-phosphorus bond, then R1, taken together with the adjacent oxygen atom, can also be the residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the (b) moiety via an oxygen-phosphorus bond, -OR1 being the same as or different from [D]; R2 is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl; and R3 is selected from the group consisting of C1-C8 alkyl; C2-C8 alkenyl having one or two double bonds; (C3-C7 cycloalkyl)-CrH2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion; (C6-C10 aryloxy)C1-C8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-CrH2r- wherein r is zero, one, two or three and phenyl is unsubstituted, or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms. The compounds are adapted for targeted drug delivery, especially to the brain.

Description

TARGETED DRUG DELIVERY VIA
MIXED PHOSPHATE DERIVATIVES
FIELD OF THE INVENTION:
The present invention relates to an anionic sequestration type of drug modification designed to enhance delivery of the active drug species to the desired site of action, especially to the brain. More especially, the present invention relates to the discovery that a biologically active compound coupled to a lipophilic carrier moiety of the acyloxyalkyl mixed phosphate type readily penetrates biological membranes such as the blood-brain barrier (BBB) and enters the target organ; cleavage of the mixed phosphate carrier/drug entity in vivo provides a hydrophilic, negatively charged intermediate which is "locked in" the brain or other organ and which provides significant and sustained delivery of the active drug species to the target organ. BACKGROUND OF THE INVENTION:
The delivery of drug species to the brain and other organs is often seriously limited by transport and metabolism factors, including biological membranes; specifically, in the case of the brain, delivery is limited by the functional barrier of the endothelial brain capillary wall, i.e. the blood-brain barrier or BBB. Site-specific and sustained delivery of drugs to the brain or other organs, i.e. targeted drug delivery, is even more difficult.
Many drugs are hydrophilic and are unable to penetrate the brain to any considerable extent. Other drugs which are lipophilic and/or for which particular transport mechanisms exist may be able to cross the BBB and reach the brain, but the very lipophilicity which enables their entry likewise facilitates their exit. It is thus necessary to administer large doses of drugs to achieve adequate brain levels (if, indeed, such is even possible), and this in turn overburdens non-targeted loci and results in significant toxicity.
It is now well-known that numerous drugs exert their biological effects through centrally-mediated mechanisms. Thus, a brain-targeted approach is a desirable means of delivery for a wide diversity of drugs, including neurotransmitters, stimulants, dopaminergic agents, tranquilizers, antidepressants, narcotic analgesics, narcotic antagonists, sedatives, hypnotics, anesthetics, antiepileptics/anticonvulsants, hormones such as the male and female sex hormones, peptides, anti-inflammatory steroids, non-steroidal anti-inflammatory agents/non-narcotic analgesics, memory enhancers, antibacterials/antibiotics, antineoplastics (anticancer/antitumor agents) and antiviral agents.
In recent years, the need for more effective treatment of a number of viral disease states has become increasingly urgent. The generally poor therapeutic accessibility of viral infections can be traced to three major facets including the viral life cycle, the lack of efficacious
pharmacologically-active agents and, finally, the inability to deliver those agents which are available to the central nervous system (CNS) for sustained periods and in significant amounts.
Viruses are submicroscopic pathogens which depend on the cellular nucleic acid and protein synthesizing mechanisms of its host for
propagation. In general, viruses invade cells by first interacting at a recognizable surface protein, penetrating the cell membrane and
subsequently releasing themselves from a protective polypeptide coat to eject the core of the virus. The heart of these pathogens is genetic material, either DNA or RNA, and the type of nucleic acid gives rise to the system'of nomenclature for these entities. The viral DNA and RNA can interact with cellular components to produce daughter genetic material as well as various structural or enzymatic proteins. After assembly and release, the viral progeny may infect other cells, yielding disease or ultimately death.
DNA viruses are subdivided into five families and include the pathogens responsible for labial and genital herpes, herpes encephalitis, human cytomegalovirus infection, chicken pox, shingles and mononucleosis. RNA viruses are present in more numerous forms and are subdivided into ten families. These viruses are unusual in that they reverse the usual DNA→ RNA→ protein sequence which occurs in higher life forms. RNA viruses are unusually dangerous for several reasons, including their lethality and the lack of effective treatments. RNA viral diseases include acquired immune deficiency syndrome, hemorrhagic fevers of various descriptions, Dengue fever, Lassa fever, and numerous encephalitic maladies including Japanese B encephalitis.
Chemotherapeutically, very few antiviral agents have been developed that have high in vitro activity against these viruses. One notable advance in the field was the advent of ribavirin or 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide, synthesized in 1972. Ribavirin has a broad range of activity against both DNA and RNA viruses. This riboside, which contains an unnatural triazole base, significantly suppresses the infectivity and cytopathicity of several viral pathogens by mechanisms which are as of yet unclear. Several interactions have been suggested including inhibition of viral RNA polymerase, the inhibition of inosine monophosphate dehydrogenase by ribavirin anabolites and interference of mRNA cap formation by the 5'-triphosphate of ribavirin.
Ribavirin is active against several influenza viruses and respiratory syncytial virus and as such is used in an aerosol form to treat these diseases. Ribavirin is also used in the treatment of Lassa fever which rages in epidemic proportions in Sierra Leone. Unfortunately, while peripheral viral infections can be successfully treated with ribavirin and other riboside derivatives, encephalitis is immune to the action of these drugs. The inability of antiviral drugs, which are highly potent in vitro, to exert activity in the CNS is attributable to their exclusion from the brain. The basis of this impermeability is the blood-brain barrier (BBB), which effectively separates the systemic circulation from the brain parenchyma. As this barrier is lipoidal in nature, the BBB restricts the entry of materials which do not have high affinity for the phospholipid matrix and
consequently hydrophilic compounds are excluded. Thus, drug molecules must be intrinsically lipophilic if they are to gain access to the CNS. This is the restriction which renders ribavirin, which has a log P of only 2.06, ineffective in treating viral diseases of the brain.
Many antiherpetic agents exhibit poor penetration across biological barriers such as the BBB and the ocular and skin barriers, achieving concentrations well below therapeutic levels. Improved delivery of an antiherpetic agent across these barriers would offer a significant advantage in the treatment of such serious and debilitating diseases as encephalitis, ophthalmic infections caused by herpes simplex such as herpetic uveites, keratitis etc. and cutaneous herpes infections such as genital and orofacial herpes.
Vidarabine (9-β-D-arabinofuranosyladenine, Ara-A, adenine arabinoside) is a purine nucleoside analog with a broad spectrum of antiviral activity against a number of DNA viruses, including HSV-1 and 2, cytomegaiovirus and varicella zoster virus. The drug has been shown useful in the treatment of brain biopsy-proven herpes simplex encephalitis (HSE), resulting in a statistically significant reduction in mortality. Ara-A has demonstrated clinical utility as a topical agent for herpes keratitis of the eye. However, when applied locally to the skin, vidarabine has provided no benefit in genital or orafacial HSV infection. In immunocompromised patients with localized herpes zoster, Ara-A has demonstrated a beneficial effect in accelerating cutaneous healing and decreasing the rate of cutaneous dissemination.
The essential mechanism of inhibition of viral replication by vidarabine, although not precisely defined, appears to be a consequence of the incorporation of the drug into viral DNA. To exert its antiviral action, vidarabine must first be phosphorylated by cellular enzymes to the triphosphate, which competitively inhibits HSV DNA polymerase. Some investigators have found that the viral DNA polymerase activity is more sensitive to inhibition than that of cellular DNA polymerases, an observation that could explain some of the selective toxicity of the drug and its dose-related toxicity. Vidarabine triphosphate is incorporated into both cellular and viral DNA, where it may act as a chain terminator for newly synthesized HSV nucleic acid.
Despite its proven efficacy, Ara-A does suffer from a number of limitations, including low lipophilicity as evidenced by a negative log P (octanol/ water), which results in a failure to be adequately transported across biological membranes.
Herpes simplex virus is a causative factor for encephalitis. Its involvement in the CNS represents the most common cause of nonepidemic fatal encephalitis in the United States. An estimated 1,000 to 5,000 cases occur each year in the U.S., with death in over one half of those who are untreated. Herpes simplex virus type 2 causes encephalitis in patients with thymic dyplasia and other severe immunodeficiency states. Encephalitis also is a common opportunistic infection associated with AIDS.
The acute severe encephalitis due to herpes simplex type 1 in humans may represent a primary infection, a reinfection or an activation of latent infection. The primary mode of viral transport into the CNS has not been clearly established. However, it has been shown that following extraneural inoculation, the virus gained access to the CNS by both hematogenous and neural pathways. The neural pathway of transport in man is supported by the fact that the virus can be isolated from explants of both trigeminal ganglia in the majority of routine autopsies.
Herpes simplex encephalitis is the most common cause of sporadic fatal encephalitis. Both the high mortality rate and the risk of severe sequelae in the survivor have prompted attempts at therapy with antiviral compounds. In order for the antiencephalitic agent to exert its effect, it is necessary for the drug to be present in the CNS where the virus is lodged, at an optimum concentration and for a sufficient period of time.
Maintaining a therapeutic level of the drug over a prolonged period at the site of action is essential in optimal reduction of viral concentrations.
Resistance of virus in the brain after treatment has been reported in almost all of the cases studied so far. Only very rarely has total remission been achieved.
The main reason for the lack of successful treatment is the inefficient method of drug delivery to the brain, the major impediment to drug delivery to the brain being the blood-brain barrier. Antiviral agents such as iododeoxyuridine and vidarabine exhibit little activity and high toxicity in the treatment of encephalitis. This is primarily due to their inability to cross the blood-brain barrier at optimum concentrations. In the case of other antivirals such as acyclovir, drug resistance has been observed. To overcome such problems, a new family of fluorinated nucleoside analogs has been synthesized. This family includes 1-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) derivatives of 5-methyluracil (FMAU), 5-iodocytosine (FIAC) and 5-iodouracil (FIAU). FIAU is a metabolite of FIAC. These compounds have been shown to display significant antiviral activity against herpes viruses in vitro and in some in vivo experiments. The mechanism of antiviral activity depends in part on the phosphorylation of these agents by viral-specified thymidine kinase. These agents are rapidly taken up and phosphorylated only to the 5'-monophosphate in HSV-infected cells; the monophosphates are presumably further phosphorylated by cellular enzymes to the corresponding triphosphates. Phosphorylation of these agents by the virus-coded thymidine kinase is much better than by the cellular enzymes. These antiviral agents are incorporated into termini and internucleoside linkages of viral DNA much more than into the DNA of uninfected cells. Since maximum selectivity would improve the therapeutic potential of any new antiviral drug, relatively low toxicity with normal cells is mandatory. The low cytotoxicity exhibited by these agents with uninfected cells indicate selectivity of action.
Although these nucleoside analogs exhibit high selectivity toward viral ceils, they are quite polar and therefore their ability to penetrate the BBB is greatly minimized. They must be administered in high doses to attain an effective level in the brain, resulting in severely toxic side-effects. For example, FMAU, considered the most potent antiviral agent of its class (therapeutic index greater than 3,000) in treating encephalitis, produces irreversible neurological damage at doses greater than 32 mg; other side effects include diarrhea, nausea and blood count depression. High doses of
FIAU have resulted in cardiac fibrosis, myelosuppression and lymphoid depletion. In the case of FIAC and FMAU, significant reduction in body weight or death has also been noted at higher doses. Further, sustained therapeutic levels have not been achieved, even at these higher doses.
It is known that FIAC is metabolized extensively in vivo and that its metabolites retain their antiviral activity in cell culture. The major metabolites of FIAC include the deaminated species FIAU, the deiodinated species 2'-fluoroarbinosylcytosine (FAC) and 2'-fluoroarabinosyluracil (FAU) and their glucuronides. Two metabolites of FMAU have been isolated from the urine of mice. These include 2'-fluoro-5-hydroxymethylarabinosyluracil (FHMAU) and a glucuronide of FMAU. FMAU, FIAU and FIAC have been found to exhibit more potent antiviral activity than acyclσvir. The metabolites of these compounds, even though potent inhibitors of HSV-2 in cell cultures, are essentially devoid of antiviral activity in vivo in the encephalitis model. This dichotomy between in vitro activity and in vivo activity suggests that these agents do not cross the BBB in sufficient concentration to exert activity.
(E)-5-(2-bromovinyl)deoxyuridine (BVDU) is also a polar antiviral agent effective against encephalitis caused by herpes zoster virus and HSV-1. This agent crosses the BBB in low levels only at very high
concentrations; as a result, it has been shown to induce sister chromatid exchange. Other side-effects include toxicity to liver, bone marrow function and gonads.
Dihydroxypropoxymethylguanine (DHPG) belongs to the same class of antiviral agents as acyclovir. However, DHPG has been shown to be at least 100-fold more effective than acyclovir in the treatment of encephalitis in vitro and in vivo. DHPG is more efficiently phosphorylated in infected cells than is acyclovir. As with acyclovir, herpes virus-specific thymidine kinase phosphorylates DHPG to its monophosphate, which is further phosphorylated to its di- and triphosphate by cellular guanylate kinase and other cellular enzymes, respectively. However, DHPG is transported to the brain only at high doses, which in mm produce high plasma levels of the drug which exert cytotoxic effects on normal human mycloid cells. Studies have shown that acyclovir crosses the BBB poorly, and at higher doses causes problems such as renal blockage.
Human cytomegalovirus (HCMV) is a virus of the herpes group which includes herpes simplex I and II, Epstein-Barr virus, and varicella zoster virus. In common with the other members of its group, infection with HCMV leads to a latent state in which the viral genome becomes incorporated in the host DNA, and in which recurrent infections are common. Viral infection with HCMV is quite widespread, with
approximately 50% of Americans showing seropositivity by age 30. In the majority of cases the virus does not cause an overt disease state, but can be detected through serological and other laboratory procedures in otherwise healthy individuals. In the absence of complicating factors, exposure to the virus can result in a clinical presentation ranging from asymptomatic seroconversion to a disease state resembling infectious mononucleosis.
In contrast to viral infection in normal adults, HCMV in the fetus or neonate can result in severe clinical manifestations. The virus in these cases is acquired congenitally, often from asymptomatic mothers. The virus has been said to be the single most frequent cause of viral infections in newborns. The occurrence of HCMV in neonates is from 0.5 % to 4% of all live births, but only 10% to 20% of these will have clinical manifestations of cytomegalic disease, which mainly involve the CNS and which can result in permanent, debilitating brain damage or auditory degeneration.
When the host immune system is suppressed, HCMV becomes a much more serious infective agent. In this state, a latent HCMV infection may recur, or a primary infection may be unusually severe.
Immunosuppression can occur in several circumstances, for example, during use of immunosuppressive drugs, such as corticosteroids, azathioprine, and thymocyte immune globulin which are given to prevent rejection of a transplanted organ when a patient has undergone organ transplant surgery. Along with other complications, cytomegalic disease is a common and sometimes especially serious problem which can follow successful kidney, bone marrow, and heart transplantation. The manifestations of cytomegalic disease following transplant surgery can include, but are not limited to, retinitis and pneumonias. Another particularly serious complication occurring during immunosuppressive therapy is Kaposi's sarcoma (KS). A strong correlation is known to exist between KS and HCMV, to the extent that it has been postulated that HCMV causes KS, analogously to the relationship between Epstein-Barr virus and Burlritt's lymphoma. However, a causal role for the virus has not been definitively established.
An immunosuppressed state is the hallmark of acquired
immunodeficiency syndrome (AIDS), and HCMV has been shown to have an extraordinary prevalence in this population, approaching 94%. In addition, cytomegalic disease and its complications are among the primary causes of much of the suffering from AIDS as well as a major factor causing death. HCMV is known to result in a suppression of cell-mediated immunity through depression of levels of T-helper cells with an increase in suppressor/ cytotoxic T-cells. Before the discovery of human
immunodeficiency virus (HIV), the list of candidates for the cause of AIDS included HCMV. The consequences of HCMV infection in AIDS are manifold, with neural and especially ocular involvement being
predominant. Ocular involvement is presented as a hemorrhagic retinitis, first evidenced by blurring of vision. This retinitis is so common that it has been proposed that it be the primary diagnostic evidence for the presence of AIDS. Neural involvement resulting in viral encephalitis is also common and presents itself post-mortem in the microglial nodules which are typical of HCMV infection. In AIDS, this neural involvement is concomitant with HIV infection of the CNS, often manifesting as subacute encephalopathy.
An antiviral agent which has shown promise in the treatment of HCMV infections in immunosuppressed states is DHPG. As mentioned above, DHPG is structurally similar to acyclovir (ACV), a safe and efficacious antiherpetic agent. The primary mechanism of DHPG action against CMV is inhibition of the replication of viral DNA by DHPG-triphosphate. This inhibition includes a selective and potent inhibition of the viral DNA polymerase. Since HCMV does not encode a virus-specific thymidine kinase, phosphorylation of DHPG is presumably accomplished by the host-cell enzymes, primarily various nucleoside kinases, which have been shown to be elevated in HCMV-infected cells. The markedly increased activity of DHPG toward CMV compared with ACV appears to be due in part to the efficient intracellular metabolism of DHPG to its mono and triphosphate in CMV-infected cells. The relative in vitro
activities, as measured by the IC50 values of DHPG vs ACV are of the same order against herpes simplex virus (HSV), namely 0.2 to 0.8 μM.
However, against HCMV the IC50 for DHPG is approximately 2.5 μM. Thus, DHPG has significant activity against HCMV in vitro. These promising results have been extended in animal models as well as in clinical trials.
As mentioned above, one of the first clinical signs of AIDS infection is a retinitis which is caused by HCMV. One of the most dramatic recent clinical demonstrations of antiviral activity has been in a study of the effects of intravenous DHPG in AIDS patients who were suffering from progressive blindness caused by cytomegalic infection of the retina. In these patients, not only did viral titers drop to an unobservable level, but clinically observable improvement in sight was achieved. In other studies, significant improvement in other areas of cytomegalic infection was shown. These included improvement in the cytomegalic pneumonias and encephalitis, as well as gastrointestinal infections.
DHPG, obviously, has very high intrinsic activity but, as with most useful drugs, has a number of inherent undesirable properties as well.
Problems with the aqueous solubility of the compound (5.1 mg/mL at 37°C) necessitate the use of the sodium salt for the intravenous
administration of the drug. This induces pain or phlebitis at the infusion site, since the pH of the solution is about 11. In humans, oral
bioavailability of DHPG is only 3-4.6% based on urinary excretion, with
99% of the drug being excreted unchanged by the kidneys. The
pharmacoknetic disposition of intravenous DHPG in humans is similar to that observed in rats and dogs, with the finding of a biphasic elimination with an α-phase half-life of 0.23 hours and a β-phase of 2.53 hours. These values are quite similar to those for acyclovir, and show that repeated dosing is necessary to maintain effective plasma concentration.
Neutropenia is the most frequent dose-dependent toxicity associated with DHPG therapy.
DHPG is a hydroxymethyl analog of acyclovir and consequently is more polar and is expected to pass through the blood brain barrier (BBB) even less readily. In rodent models, it has been shown that acyclovir distributes into most organs, with the highest levels found in renal tissue and the lowest levels found in brain tissue. Pharmacolrinetic studies of DHPG in the rat and dog have demonstrated behavior similar to acyclovir. Human pharmacokinetics of intravenous DHPG indicate cerebrospinal fluid
(CSF) concentrations equivalent to 24% to 67% of plasma concentrations. However, since CSF levels may reflect transport through the choroid plexus, some uncertainty regarding specific brain levels of DHPG exists. Regardless of the efficiency with which DHPG crosses the BBB, however, it is to be expected that it may leave the CNS by the same mechanism with equal facility. In view of the significant role played by CMV in AIDS patients with severe neurologic complications, and the possibility that CMV could create a reservoir of persistent infection of the CNS even if peripheral clearance were realized, there exists a rationale for identifying antiviral drugs that can penetrate the BBB and accumulate in the brain, thereby providing a sustained release of the antiviral to maintain a therapeutically effective concentration.
Acquired immune deficiency syndrome (AIDS) was first described as a distinct clinical entity in 1981. As of October 1989, 110,000 cases of AIDS, as defined by the Center for Disease Control (CDC), have been diagnosed and 65,000 people have died from the disease. This insidious and pernicious malady has a 2-3 year fatality rate of almost 100% and is expected to strike between 135,000 and 270,000 people by 1991 alone. AIDS is now the leading cause of premature mortality in a number of areas and in several subpopulations in the US; by 1991, it is expected to be a major killer. In other areas of the world, a similarly grim picture is developing. In central Africa, where the AIDS pathogen evolved, the disease is endemic and in several locations the increase in incidence of infection exceeds 0.75% of the total population per year. AIDS is caused by a retrovirus related to the lentivirinae family and has been designated human immunodeficiency virus (HIV-1). This pathogen selectively infects lymphocytes bearing a T4 surface antigen. These helper/ inducer T-cells are responsible for containing and eliminating various types of infection including those precipitated by Pneumocystis carinii, Toxoplasma gondii, Cryptococcus neoformans, Candida , Mycobacterium aviumintracellular and others. The destruction of cellular immunity induced by
HIV-1 causes the normally benign infections resulting from the above mentioned pathogens to run more fulminate courses. These opportunistic infections are generally the causes of death in patients with AIDS.
Early in the course of the AIDS epidemic, clinicians noted that patients were depressed and initially this was attributed to a normal psychological response to learning that one had a terminal disease. Later, however, it was realized that cognitive impairment and dementia were associated with AIDS. These CNS-associated symptoms of AIDS are now well-recognized and affect 40% of all AIDS patients at some point in the course of the disease.
In AIDS, the CNS, like the periphery, is susceptible to opportunistic infections and unusual neoplasms. Several of these have been identified, including cerebral toxoplasmosis, cryptococcal infection, candidiasis, cerebral tuberculosis, progressive multifocal leukoencephalopathy, cytomegalovirus encephalitis and primary brain lymphomas. Interestingly, these occur in less than 30% of neurologically-impaired AIDS patients. In addition, symptoms caused by these pathogens are generally focal in nature and are expressed as seizures. In the majority of AIDS patients, neuropsychiatric changes are characterized as an insidious, progressive dementia related to diffuse parenchymal brain dysfunction. Early symptoms of this disease include impaired cognitive, motor and behavior functions, including the inability to concentrate, difficulty in recalling recent events, losing one's train of thought in midsentence and general mental slowing. Motor impairments include leg weakness and problems in proprioception. Behaviorally, victims become apathetic, withdrawn and distraught. Later symptoms include global cognitive dysfunction with psychomotor retardation. Victims are autistic, mute, lethargic and quietly confused. Patients manifest urinary and fecal incontinence and may be afflicted by painful peripheral neuropathies including burning sensations or numbness. Neurohistopathologically, the picture is even worse. While only 40% of AIDS patients are recognized as demonstrating brain dysfunction, 80-95% of the brains from AIDS patients are abnormal at autopsy. Gross changes include decreased brain weight and general cerebral atrophy. Histopathologically, several unique abnormalities are consistently seen in demented AIDS patients. Most of these are white matter changes and include a diffuse pallor, perivascular and parenchymal sites that contain lymphocytic and macrophage infiltrates and vacuolation.
Other changes include the presence of microglial nodules whic infect both gray and white matter and bizarre giant multinucleated cells. The presence and number of these cells which contain HIV-1 virons give excellent correlation with the severity of the dementia. The agent responsible for subacute encephalitis, also known as AIDS encephalopathy, has been shown to be HIV-1. Several direct and indirect lines of evidence support this etiology.
This central infection will have a detrimental impact on possible therapies directed at AIDS. The CNS is protected by the BBB and is not drained by the lymphatic system, making it an excellent location for eluding the immune system. If, therefore, agents are found that
reconstitute the immune system, peripheral manifestation of AIDS, including many opportunistic infections, can be cured but the central infection will persist. The result of this could be a physically healthy but severely demented individual. In addition, host-cell restriction, i.e. partial expression of the viral genome, may cause viral latency in the CNS for many years. Also, once proviral DNA is incorporated, the only hope of containing the disease is by preventing the spread of further cellular infection. This implies, based on active in vitro doses, that for antiviral therapies to be effective, agents must pass the BBB and achieve relatively high sustained levels in neural tissue. The neurotropic nature of HIV-1 and the fact that the brain probably acts as a viral reservoir makes
implementing the preceding statement imperative. Of agents presently available, azidothymidine (also known as zidovudine or AZT) has been clinically shown to be the most useful in mitigating the effects of the AIDS virus. AZT inhibits retroviral transcriptase, the enzyme responsible for initiating viral replication.
AZT has been shown to improve the immunological picture in AIDS patients. In various clinical studies, T-cell lymphocytes (T4+) were shown to increase in number, opportunistic infections spontaneously disappeared, and patients gained weight due to increased appetite. Also, fever subsided and skin hypersensitivity returned. At high doses of AZT, viremia disappeared and T-cell function was restored. The bioavailability is about 60%. The drug is generally well-tolerated, but several untoward side effects occurred, including headache and abdominal discomfort. The most severe side effect was anemia, which proved to be dose-limiting in several cases. AZT has been used in large clinical trials, the results of which are very exciting. In a double blind study, 16 out of 137 died in the placebo group while only one patient out of 145 died in the AZT treatment group (250 mg/4 hrs). T4+ lymphocytes were higher in the treated group and fewer opportunistic infections occurred. As before, a reversible bone marrow depression resulting in granulocytopenia, thrombocytopenia, etc., was observed. Recently, dideoxyinosine has also been shown to be effective in reducing the cytopathicity and infectivity of HIV in vivo. The effect of AZT on the neurological manifestation of AIDS has been reported by Yarchoan et al, Lancet, i, 132 (1987). In a series of four case reports, AZT was shown to improve immunoiogical and neurologic functioning. T4+ cells increased in number, motor symptoms improved, gait became less ataxic and muscle strength returned. Attention span increased in one case and verbal skills improved. Unfortunately, when the drug was stopped in cases of anemia, all improvements disappeared and mental function declined. This initial report indicated that AZT can at least partially reverse neurological dysfunction. The authors noted at the end of the paper that "even modest enhancement of BBB penetration might have very important clinical consequences." These limited improvements in neurological symptomatology are consistent with the similarly limited ability of AZT to pass into the CSF. Unfortunately, CSF levels of a drug may be a poor indication of brain tissue levels. Several studies have shown that the correlation between CSF and parenchyma concentrations are not necessarily significant. In general, polar compounds such as AZT are the most deceptive in this respect. The reason for this is that if a hydrophilic compound is taken up primarily via an unprotected area like the choroid plexus, detectable concentrations may indeed reach the CSF but the compound may not partition into the lipoidal brain parenchyma and as a result may be restricted to the CSF. This would be manifested by apparently adequate AZT levels as measured by CSF sampling but inadequate levels in brain tissue where the drug is needed. This assumption has been borne out in a recent paper by Terasaki et al, J. Inf, Dis., 158, 630 (1988). In it, the BBB penetration of AZT was shown to be very low, close to the uptake of sucrose, a vascular marker.
The high concentrations of AZT found in CSF are presumably due to active transport of AZT at the choroid plexus via the thymidine pump. Again, these CSF levels represent AZT which is not in equilibrium with the brain interstitial fluid and therefore is not accessible to infected sites. It is clear that high levels of AZT are required to provide even marginal improvement in AIDS encephalopathy and that these doses are peripherally toxic.
The previous discussion has indicated that the AIDS virus is neurotropic and that the resulting brain infection by this pathogen is disastrous. Various agents have been identified which inhibit infection and abolish cytopathology in the AIDS virus. In some instances these compounds, like AZT, pass the BBB and achieve quantitative levels in CSF. Clinical results suggest, however, that high sustained drug levels, i.e. those that approach in vitro inhibitory concentrations, are required in the brain. Importantly, CSF levels do not reflect brain tissue concentration of AZT. Unfortunately, simply increasing the dose proportionally to achieve these ends increases blood concentrations and leads to various dose-related toxicities. Anemia has proved to be dose-limiting in many cases with AZT. Increasing brain levels of the nucleoside is possible by administering lipophilic esters of AZT leading to an increase in brain concentration of the nucleoside. These prodrugs are, however, not optimized in terms of pharmacokinetics and tissue distribution. Thus, while it is true that by increasing the lipophilicity of AZT, the drug will more easily pass the BBB and enter the CNS, the increased lipophilicity will increase the distribution of the compound in general, leading to an even greater tissue burden in all locations. This has ramifications in terms of peripheral toxicity such as anemia, i.e. a bad situation is made even worse. The other major drawback of simply increasing the lipophilicity of AZT is that while influx to the CNS is increased, the efflux is also greater, with the result being poor retention in the CNS and a therapeutically insufficient biological half-life. These two objections to simple antiviral prodrugs, namely: 1) increased tissue burden with little tissue specificity, and 2) poor CNS retention, point to the need for a more sophisticated approach, i.e. a chemical delivery system for brain-targeted drug delivery.
A dihydropyridine↔ pyridinium salt redox carrier system has recently been successfully applied to brain-targeted delivery of a variety of drug species. Generally speaking, according to that system, a
dihydropyridine carrier moiety is covalently bonded to a biologically active compound, which derivative can enter the CNS through the blood-brain barrier following its systemic administration. Subsequent oxidation of the dihydropyridine species to the corresponding pyridinium salt leads to delivery of the drug to the brain.
More specifically, the redox carrier system provides for brain-targeted drug delivery by means of carrier-drugs, which in their reduced form, which is the form intended for administration, can be represented by the formula wherein [D] is a centrally acting drug species and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating, lipoidal form of a dihydropyridine↔ pyridinium salt redox carrier. In their oxidized form, which is the form "locked" in the brain from which the active drug is ultimately released, the carrier-drugs can be represented by the formula
[D-QC]+ X- wherein X- is the anion of a non-toxic pharmaceutically acceptable acid, [D] is a centrally acting drug species and [QC]+ is the hydrophilic, positively charged ionic pyridinium salt form of a dihydropyridine↔ pyridinium salt redox carrier.
Various aspects of the redox carrier system have been described in detail in Bodor United States Patent No. 4,479,932, issued October 30, 1984; Bodor United States Patent No. 4,540,564, issued September 10, 1985; Bodor et al United States Patent No. 4,617,298, issued October 14, 1986; UNIVERSITY OF FLORIDA's International Application No.
PCT/US83/00725, published under International Publication No.
WO83/03968 on November 24, 1983; Bodor United States Patent No. 4,727,079, issued February 23, 1988; Bodor United States Patent No. 4,824,850, issued April 25, 1989; Bodor United States Patent No.
4,829,070, issued May 9, 1989; Anderson et al United States Patent No.
4,863,911, issued September 5, 1989; Bodor United States Patent No. 4,880,816, issued November 14, 1989; Bodor United States Patent No. 4,880,921, issued November 14, 1989; Bodor United States Patent No. 4,900,837, issued February 13, 1990; UNIVERSITΥ OF FLORIDA'S European Patent Application No. 88312016.4, published under European
Publication No. 0327766 on August 16, 1989; UNIVERSITY OF
FLORIDA'S European Patent Application No. 89302719.3, published under European Publication No. 0335545 on October 4, 1989; and numerous related publications. Among the redox carrier-drugs provided by the earlier chemical delivery system are dihydropyridine/pyridinium salt derivatives of dopamine, testosterone, phenytoin, GABA, valproic acid, tyrosine, methicillin, oxacϋlin, benzyipemcillin, cioxacillin, dicloxacillin, desipramine, acyclovir, trifluorothymidine, zidovudine, hydroxy-CCNU, chlorambucil, tryptamine, dexamethasone, hydrocortisone, ethinyl estradiol, norethindrone, estradiol. ethisterone, norgestrel, estrone, estradiol 3-methyl ether, estradiol benzoate, norethynodrel, mestranol, indomethacin, naproxen, FENU, HENU, 5-FU and many others.
The dihydropyridine redox carrier system has achieved remarkable success in targeting drugs to the brain in laboratory tests. Unfortunately, the dihydropyridine-containing derivatives suffer from stability problems, since even in the dry state they are very sensitive to oxidation as well as to water addition. Such problems have significantly complicated attempts to commercialize the system. Thus, a different earner approach to brain-targeted drug delivery which would not include the inherently unstable dihydropyridine system would be desirable.
A few mixed phosphate derivatives of antiviral agents have been previously described, but such are structurally distinct from the mixed phosphates to which the present invention relates.
Thus, Farquhar et al, in J.Pharm. Sci. Vol. 72, No. 3, 324-325 (March, 1983), have described bis(acyloxymethyl)phosphotriesters of the type
Figure imgf000021_0001
where R1 is, for example, -CH3 or -C(CH3)3, and R is phenyl (as a model residue). Synthesis of two bis(acyloxymethyl)phosphotriesters of two nucleosides is disclosed, i.e. the compounds of the formula
Figure imgf000022_0001
wherein R is -CH3 or F. In another report on the same work, Srivastava and Farquhar, in Bioorganic Chemistry 12, 118-129 (1984), discuss the synthesis and stability of model acyloxymethyl phosphates, including six bis(acyloxymethyl) esters of phenyl phosphate and benzyl phosphate and three acyloxymethylbenzylphenyl phosphates. The authors present their study as "a guideline in developing a neutral phosphotriester which conceivably could traverse cell membranes by passive diffusion and then revert biologically, possibly intracellularly, by enzymatic cleavage of the protective group to the parent phosphomonoester." Although further studies using 2'-deoxy-5-fluorouridine- 5'-monophosphate were said to be in progress, to the present applicant's knowledge, such have not been reported.
Very recently, Farrow et al, in J. Med. Chem. 33, 1400-1406 (1990), have reported on a series of aryl bis(3'-O-acetylthymidin-5'-yl)phosphates synthesized in an attempt to find an aryl derivative which would hydrolyze under physiological conditions to the bis(nucleosid-5'-yl)phosphate. The compounds synthesized have the formula
Figure imgf000023_0001
where R is a 5'-linked nucleoside and R' is a group designed to possess suitable hydrolytic properties. As model compounds, thymidin-5-yl was selected for R and several substituted phenyl groups as R', i.e. 4-(methylthio)phenyl, 4-chlorophenyl, 2-chlorophenyl, 4-(methylsulfonyl)phenyl, 2,5-dichlorophenyl and 4-nitrophenyl. The following 5'-5'-linked triester derivatives of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and acyclovir (ACV) were then synthesized and studied for their antiviral effects:
Figure imgf000024_0001
where R' is 4-(methylthio)phenyl or 4-(methylsulfonyl)phenyl or 2- chlorophenyl and R" is H or Ac. The data are consistent with a conclusion that the triesters simply act as prodrugs for BVDU and ACV, respectively.
SUMMARY OF THE INVENTION:
The present invention provides novel mixed phosphate derivatives, adapted for targeted drug delivery, which have the formula
Figure imgf000024_0002
wherem [D] is the residue of a drug having a reactive functional group, said functional group being attached, directly or through a bridging group, via an oxygen-phosphorus bond to the phosphorus atom of the ,
Figure imgf000025_0001
moiety; R1 is C1-C8 alkyl, C6-C10 aryl or C7-C12 aralkyl, with the proviso that when [D] is the residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the ,
Figure imgf000025_0002
moiety via an oxygen-phosphorus bond, then R1, taken together with the adjacent oxygen atom, can also be the residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the ,
Figure imgf000025_0003
moiety via an oxygen-phosphorus bond, -OR, being the same as or different from [D]; R2 is hydrogen, C1-C6 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl; and R3 is selected from the group consisting of C,-C, alkyl; Q-C3 alkenyl having one or two double bonds; (C3-C7 cycloalkyl)-C1H2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion; (C6-C10 aryloxy)C1-C8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-C1H2r- wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to
3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms.
The invention further provides a generic method for target-enhanced delivery to the brain and other organs of a wide variety of drug species via the bidirectional transport of the drug species into and out of the organ by anioπic sequestration via novel mixed phosphate derivatives.
DETAILED DESCRIPTION OF THE INVENTION:
In a preferred aspect, the present invention provides novel mixed phosphate derivatives of hydroxy-containing drugs, which derivatives have the formula
Figure imgf000026_0001
wherein D-O- is the residue of a drug having a reactive hydroxyl functional group, the oxygen atom of said functional group being bonded to the phosphorus atom of the
Figure imgf000027_0001
moiety, and wherein R1, R2 and R3 are as defined with formula (I).
In another aspect, the present invention provides novel mixed phosphate derivatives of mercapto-containing drugs, which derivatives have the formula
Figure imgf000027_0002
wherein D-S- is the residue of a drug having a reactive mercapto functional group, the sulfur atom of said functional group being bonded to the phosphorus atom of the
Figure imgf000027_0003
moiety, and wherein R1, R2 and R3 are as defined with formula (I). The present invention further provides novel mixed phosphate derivatives of carboxyl-containing drugs, which derivatives have the formula
Figure imgf000028_0001
wherein
Figure imgf000028_0002
is the residue of a drug having a reactive carboxyl functional group, the carboxyl carbon atom of said functional group being linked, via an -O-Z-O- bridging group, to the phosphorus atom of the
Figure imgf000028_0003
moiety; wherein Z is wherein the alkylene group contains
Figure imgf000028_0004
1 to 3 carbon atoms and R2 is defined as is R2 with formula (I); or wherein
Z is C3-C8 cycloalkylene in which two adjacent ring carbon atoms are each bonded to a different oxygen atom in the -O-Z-O- bridging group; and wherein R1 and R3 are as defined with formula (I).
Still further, the invention provides novel mixed phosphate derivatives of drugs containing imide or amide functional groups, which derivatives have the formulas
Figure imgf000029_0001
and
Figure imgf000029_0002
wherein is the residue of a drug having a reactive
Figure imgf000029_0003
imide functional group, is the residue of a drug having a reactive
Figure imgf000029_0004
amide functional group, the nitrogen atom of the imide or amide functional group being linked, via a
Figure imgf000029_0005
bridging group, to the phosphorus atom of the
Figure imgf000029_0006
rnoiety; R4 is preferably H but may also be C1-C7 alkyl or combined with
Figure imgf000030_0005
to form a cvciic amide; and wherein the R2 groups in formulas (Id) and (Ie), which can be the same of different, are as defined with formula
(I); and R1 and R3 are as defined with formula (I).
The present invention also provides novel mixed phosphate derivatives of amino-containing drugs, which derivatives have the formula
Figure imgf000030_0001
wherein is the residue of a drug having a reactive primary
amino (R4=H) or secondary amino (R4 = other than H, but preferably C1-
C7 alkyl or combined with D-N- to form a cyclic secondary amine) group, the nitrogen atom of the amino functional group being linked, via a bridging group, to the phosphorus atom of the
Figure imgf000030_0002
Figure imgf000030_0003
moiety; wherein R"2 is defined as is R2 with formula (I); and wherein R1 and R3 are as defined with formula (I). The identity of the R4 group (R4 = other than H) in drugs having reactive secondary amino groups, while often C1-C8 lower alkyl, is immaterial to the invention, since R4 is of course part of the drug residue itself and is left unchanged by the conversion to the formula (If) compound. More particularly, in accord with the present invention, the following definitions are applicable:
The term "lipoidal" as used here is intended to mean lipid-soluble or lipophilic.
The term "drug" as used herein means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and conditions in man or animal.
By "centrally acting" drug, drug species, active agent or compound as used herein, there is of course intended any drug species or the like, a significant (usually, principal) pharmacological activity of which is CNS and a result of direct action in the brain. Centrally acting drugs are preferred for derivation in accord with the present invention, brain-targeted drug delivery being the preferred goal of the invention.
The expression "drug having a reactive functional group" as used herein means that the drug possesses at least one functional group which is capable of covalently bonding to the phosphorus atom in the phosphate moiety, either directly or through a bridging group, in such a manner that an active drug species will ultimately be released at the desired site of action, e.g. the brain. Such reactive functional groups include hydroxyl, carboxyl, mercapto, amino, amide and imide functions.
The word "hydroxyl" means an -OH function.
The word "carboxyl" means a -COOH function.
The word "mercapto" means an -SH function.
The word "amino" means a primary or secondary amino function, i.e. -NH2 or -NHR4. The secondary amino function is also represented herein as -NH-, particularly since the exact identity of the R4 portion of -NHR4 is immaterial, R4 being a part of the drug residue itself which is left unchanged by conversion of the drug to the phosphate carrier system.
The word "amide" means a carbamoyl (-CONH2) or substituted carbamoyl (-CONΗR4) or a sulfamoyl (-SO2NH2) or substituted sulfamoyl (-SO2NHR4) functional group. The -CONHR4 and -SO2NHR4 groups may also be represented herein as -CONH- and -SO2NH-, respectively, since the identity of R4 is immaterial, R4 being a pan of the drug residue itself which is left unchanged by conversion of the drug to the phosphate carrier system.
The word "imide" means a functional group having the structure
Figure imgf000032_0001
that is, the structure which characterizes imides (i.e. compounds having a succinimide-type or phthalimide-type structure).
It will be apparent from the known structures of the many drug species exemplified hereinbelow, that in many cases the selected drug will possess more than one reactive functional group, and, in particular, that the drug may contain hydroxyl or carboxyl or amino or other functional groups in addition to the groups to which the mixed phosphate carrier will be linked, and that these additional groups will at times benefit from being protected during synthesis and/or during administration. The nature of such protection is described in more detail hereinafter. Obviously, such protected drug species are encompassed by the definition of "drug" set forth hereinabove.
The expression "a bridging group" as used herein refers to a bivalent group used to attach the mixed phosphate carrier moiety to the drug when the drug does not contain a functional group susceptible to direct bonding to the phosphorus atom to form a linkage which will ultimately cleave to release an active drug species in the target organ. Drugs containing reactive hydroxyl and mercapto groups are capable of direct bonding to the phosphorus atom to form the desired linkage; other reactive functional group require appropriate bridging groups, for example as shown in structures (Ic), (Id), (Ie) and (If) hereinabove.
The term "C1-C8 alkyl" as used herein includes straight and branched-chain lower alkyl radicals having up to eight carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
The term "C6-C10 aryl" includes aromatic radicals having the indicated number of carbon atoms, e.g. phenyl and naphthyl.
The term "C7-C12 aralkyl" designates radicals of the type
-alkylene-aryl wherein the aryl portion is phenyl or naphthyl and the alkylene portion, which can be straight or branched, can contain up to 6 carbon atoms, e.g. methylene, ethylene, propylene, trimethylene, 1,2-butylene, 2,3-butylene, tetramethylene and the like. A typical aralkyl group is benzyl.
The term "C4-C9 heteroaryl" refers to aromatic radicals having the indicated number of carbon atoms and additionally containing 1 or 2 hetero atoms in the ring(s) selected from the group consisting of N, O and S. Illustrative radicals of this type include furyl, pyrrolyl, imidazolyl, pyridyl, indolyl, quinolyl and the like.
The torn "C3-C7 cycloalkyl" designates saturated alicyclic hydrocarbon radicals containing the indicated number of carbon atoms, e.g. cyclopentyl and cyclohexyl.
The term "C3-C7 cycloheteroalkyl" refers to saturated alicyclic hydrocarbon radicals having the indicated number of carbon atoms and additionally containing 1 or 2 hetero atoms in the ring selected from the group consisting of N, O and S. Examples include morpholino, piperazinyl and pyrrolidinyl. The term "C2-C8 alkenyl" designates unsaturated aliphatic hydrocarbon radicals, or olefinic groups, which contain one or two double bonds and the indicated number of carbon atoms, e.g. 1-propen-1-yl, 1,3- pentadien-1-yl and the like.
The term "(C6-C10 aryloxy)C1-C8 alkyl" includes aryloxyalkyl radicals such as phenoxymethyl, i.e. the aryl portion contains 6 to 10 carbon atoms, e.g. phenyl or naphthyl, while the alkyl portion contains 1 to 8 carbon atoms, e.g. methyl or ethyl.
The term "C3-C7 cycloalkyl-CrH2r-" includes cycloalkyl and cycloalkyl-alkylene- radicals containing the indicated number of carbon atoms and bearing 0 to 2 C1-C4 alkyl groups as ring substituents.
Illustrative radicals include cyclopentyl, cyclohexyl, cyclohexylmethyl, 1-methylcyclohex-1-yl, 2,2,3,3-tetramethylcycloprop-1-yl and the like.
The term "phenyl-CrH2r-" includes phenyl and phenyl-alkyleneradicals containing the indicated number of carbon atoms, e.g. benzyl, any of which can bear 0 to 3 substituents as defined above. The substituents can be selected from C1-C4 alkyl, which can be straight or branched, e.g. methyl, ethyl, propyl, isopropyl; C1-C4 alkoxy, which can be straight or branched, e.g. medioxy, ethoxy; halo, which includes bromo, chloro, iodo and fluoro; trifluoromethyl; C2-C8 dialkylamino, e.g. dimethylamino and diethylamino; and C2-C6 alkanoylamino, e.g. acetamido and propionamido. Substituted phenyl-CrH2r- radicals include such radicals p-tolyl, 2,4,6-trimethylphenyl and m-trifluoromethylbenzyl.
The word "alkylene" when used in conjunction with the Z term herein refers to bivalent radicals of the type -(CH2)n- where n is 1, 2 or 3, and the corresponding branched-chain groups. When it is part of the Z term, die alkylene grouping can only be unsubstituted methylene if the drug residue is sufficiently hindered; otherwise, it should be substituted methylene or unsubstituted or substituted C2-C3 alkylene.
The term "C3-C8 cycloalkylene" as used in conjunction with the Z term designates radicals of the type
Figure imgf000035_0001
where m is 1 to 6 and the corresponding branched-chain groups.
The expression "non-toxic pharmaceutically acceptable salts" as used herein generally includes the non-toxic salts of compounds of formula
(I) formed with non-toxic, pharmaceutically acceptable inorganic or organic acids. For example, the salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, giucolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyciic, sulfanilic, fumaric, methanesulfonic, toluenesulfonic and the like.
The expression "hydroxyl protecting group" as used herein is intended to designate a group (Y) which is inserted in place of a hydrogen atom of an OH group or groups in order to protect the OH group(s) during synthesis and/or to improve lipoidal characteristics and prevent premature metabolism of the OH group(s) prior to the compound's reaching the desired site in the body. The expression "protected hydroxy substituent" designates an OY group wherein Y is a "hydroxyl protecting group" as defined above.
Typical hydroxyl protecting groups contemplated by the present invention are acyl groups and carbonates. When the hydroxyl protecting group is acyl (i.e., when it is an organic radical derived from a carboxylic acid by removal of the hydroxyl group), it can be selected from the same group of radicals as those encompassed by the
Figure imgf000035_0002
portion of formula (I) hereinabove. Thus, the hydroxyl protecting group preferably represents an acyl radical selected from the group consisting of alkanoyl having 2 to 8 carbon atoms; alkenoyl having one or two double bonds and 3 to 8 carbon atoms;
Figure imgf000036_0001
wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three; phenoxyacetyl; pyridinecarbonyl; and
Figure imgf000036_0002
wherein r is zero, one, two or tiiree and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, tnfluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms.
When the acyl group is alkanoyl, there are included both
unbranched and branched alkanoyl, for example, acetyl, propionyl butyryl, isobutyryl, valeryl, isovaleryl, 2-methylbutanoyl, pivalyl (pivaloyl), 3-methylpentanoyl, 3,3-dimethylbutanoyl, 2,2-dimethylpentanoyl, hexanoyl and the like. Pivalyl, isobutyryl, isovaleryl and hexanoyl are especially preferred, both
Figure imgf000036_0003
groupings and as hydroxyl protective groups.
When the acyl group is alkenoyl, there are included, for example, crotonyl, 2,5-hexadienoyl and 3,6-octadienoyl.
When the acyl group is
Figure imgf000036_0004
there are included cycloalkanecarbonyl and cycloalkanealkanoyl groups wherein the cycloalkane portion can optionally bear 1 or 2 alkyl groups as substituents, e.g. cyclopropanecarbonyl, 1-methylcyclopropanecarbonyl, cyclopropaneacetyl, α-methylcyclopropaneacetyl, 1-methylcyclopropane acetyl, cyclopropanepropionyl, α-methylcyclopropanepropionyl,
isobutylcyclopropanepropionyl, cyclobutanecarbonyl, 3,3-dimethylcyclobutanecarbonyl, cyclobutaneacetyl, 2,2-dimethyl-3-ethylcyclobutaneacetyl, cyclopentanecarbonyl, cyclohexaneacetyl, cyclohexanecarbonyl, cycloheptanecarbonyl and cycloheptanepropionyl.
When the acyl group is pyridinecarbonyl, there are included picoiinoyl (2-pyridinecarbonyl), nicotinoyl (3-pyridinecarbonyl) and isonicotinoyl (4-pyridinecarbonyl).
When the acyl group is
Figure imgf000037_0001
there are included, for example, benzoyl, phenylacetyl, α-phenylpropionyl,β-phenylpropionyl, p-toluyl, m-toluyl, o-toluyl, o-ethylbenzoyl, p-tert-butylbenzoyl, 3,4-dimethylbenzoyl, 2-methyl-4-ethylbenzoyl, 2,4,6-trimethylbenzoyl, m-methylphenylacetyl, p-isobutylphenylacetyl, β-(p-ethylphenyl)propionyl, p-anisoyl, m-anisoyl, o-anisoyl, m-isopropoxybenzoyl, p-methoxyphenylacetyl, m-isobutoxyphenylacetyl, m-diethylaminobenzoyl, 3-memoxy-4-ethoxybenzoyl, 3,4,5-trimethoxybenzoyl, p-dibutylaminobenzoyl, 3,4-diethoxyphenylacetyl, β-(3,4,5-trimethoxyphenyl)propionyl, o-iodobenzoyl, m-bromobenzoyl, p-chlorobenzoyl, p-fluorobenzoyl, 2-bromo-4-chlorobenzoyl, 2,4,6-trichlorobenzoyl, p-chlorophenylacetyl, α-(m-bromophenyl)propionyl, p-trifiuoromethyl benzoyl, 2,4-di(trifluoromethyl)benzoyl, m-trifluoromethylphenylacetyl, β-(3-methyl-4-chlorophenyl)propionyl, p-dimethylaminobenzoyl, p-(N-methyl-N-ethylamino)benzoyl, o-acetamidobenzoyl, m-propionamidobenzoyl, 3-chloro-4-acetamidophenylacetyl, p-n-butoxybenzoyl, 2,4,6-triethoxybenzoyl, β-(p-trifluoromethylphenyl)propionyl, 2-methyl-4-methoxybenzoyl, p-acetamidophenylpropionyl, and 3-chloro-4-ethoxybenzoyl. When the hydroxyl protecting group is a carbonate grouping, it has the structural formula
Figure imgf000038_0001
i.e., it is an organic radical which can be considered to be derived from a carbonic acid by removal of the hydroxyl group from the COOH portion. Y' preferably represents alkyl having 1 to 7 carbon atoms; alkenyl having one or two double bonds and 2 to 7 carbon atoms; cycloalkyl-CrH2r- wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three; phenoxy; 2-, 3-, or 4-pyridyl; or phenyl-CrH2r- wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, tnfluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms. Most preferably, Y' is C1-C7 alkyl, particularly ethyl or isopropyl.
Similarly, the expression "carboxyl protecting group" as used herein is intended to designate a group (W) which is inserted in place of a hydrogen atom of a COOH group or groups in order to protect the COOH group(s) during synthesis and/or to improve lipoidal characteristics and prevent premature metabolism of said COOH group or groups prior to the compound's reaching the desired site in the body. Typical of such carboxyl protecting groups W are the groups encompassed by Y' above, especially C1-C7 alkyl, particularly ethyl, isopropyl and t-butyl. While such simple alkyl esters and the like are often useful, other carboxyl protectmg groups may be selected, e.g. in order to achieve greater control over the rate of in vivo hydrolysis of the ester back to the acid and thus enhance drug delivery. To that end, carboxyl protecting groups W such as the following may be used in place of the hydrogen of the -COOH group: ,
Figure imgf000039_0003
or
Figure imgf000039_0002
-alk-O-alkyl, wherein alk is C1-C6 straight or branched alkylene and the alkyl radical is straight or branched and contains 1 to 7 carbon atoms (e.g. -
Figure imgf000039_0001
Other carboxyl protecting groups W which can be used in place of the hydrogen of the -COOH group and which are especially useful herein are the following:
C3-C12 cycloalkyl-CpH2p- wherein p is 0, 1 , 2 or 3; C6-C28 polycycloalkyl-CpH2p- wherein p is defined as above:
C6-C28 polycycloalkenyl-CpH2p- wherein p is defined as above;
C3-C12 cycloalkenyl-CpH2p- wherein p is defined as above;
-CH2-Xa-Ra wherein X4 is S, SO or SO2 and Ra is C1-C7 alkyl or C3-C12 cycloalkyl;
Figure imgf000040_0001
wherein Ra is defined as above;
Figure imgf000040_0002
wherein Xa is defined as above, Rb is C1-C7 alkyl and Rc is C1-C7 alkyl or wherein Rb and Rc taken together represent -(CH2)m'- wherein m' is 3 or 4 and -(CH2)m'- is optionally substituted by one to three C1-C7 alkyl;
Figure imgf000040_0003
wherein Rd is hydrogen or C1-C7 alkyl and Rc is unsubstituted or substituted C1-C12 alkyl [e.g.
Figure imgf000041_0001
cycloalkyl -CpH2p-wherein p is defined as above, C3-C12 cycloalkenyl-CpH2p- wherein p is defined as above or C2-C1 alkenyl, the substituents bemg selected from the group consisting of halo, C1-C7 alkoxy, C1-C7 aikylthio, C1-C7 alkylsulfinyl, C1-C7 alkylsulfonyl,
Figure imgf000041_0002
alkyl), or Ra is unsubstituted or substituted phenyl or benzyl, the
substituents being selected from the group consisting of C1-C7 alkyl, C1-C7 alkoxy, halo, carbamoyl, C2-C1 alkoxycarbonyl, C2-C8 alkanoyloxy, C1-C7 haloalkyl, mono(C1-C7 alkyl)amino, di(C1-C7 alkyl)amino, mono(C1-C7 alkyl)carba moyl, di(C1-C7 alkyl)carbamoyl, C1-C7 aikylthio, C1-C7 alkylsulfinyl and C1-C7 alkylsulfonyl, or Ra is C6-C28 polycycloalkyl-CpH2p- or C6-C2g poiycycloalkenyl-CpH2p- wherein p is defined as above;
Figure imgf000041_0003
wherein Rd and Ra are defined as above; and
Figure imgf000041_0004
wherein Rd is defined as above and Rf and Rg, which can be the same or different, are each hydrogen, C1-C7 alkyl, C3-C12 cycloalkyl-CpH2p-, C3-C12 cycloalkenyl-CpH2p-, phenyl or benzyl, or one of Rf and Rb is hydrogen. C1-C7 alkyl, C3-C12 cycloaikyl-CpH2p-, C3-C12 cycloalkenyl-CPH2p-, phenyl or benzyl and the other of Rf and Rb is C6-C28 polycycloalkyl-CPH-2p- or C6- C2g polycycloalkenyl-CpH2p-, or Rf and Rg are combined such that -NR Rg represents the residue of a saturated monocyclic secondary amine. When the carboxyl protecting group is C3-C12 cycloalkyl-CpH2p- or otherwise contains a C3-C12 cycloalkyl group, the cycloalkyl groups contain 3 to 8 ring atoms and may optionally bear one or more, preferably one to four, alkyl substituents. Exemplary such cycloalkyl groups are
cyclopropyl, 2-methylcyclopropyl, 3-ethylcyclopropyl, 2-butylcyclopropyl,
3-pentylcyclopropyl, 2-hexylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 2,3-dimedιylcyclobutyl, 3-butylcyclobutyl, 4-hexylcyclobutyl, 2,3,3- trimethylcyclobutyl, 3,3,4,4-tetramethylcyclobutyl, cyclopentyl, 2- methylcyclopentyl, 3-ethylcyclopentyl, 4-butylcyclopentyl, 5- methylcyclopentyl, 3-pentylcyclopentyl, 4-hexylcyclopentyl, 2,3-dimethylcyclopentyl, 2,2,5,5-tetramethylcyclopentyl, 2,3,4-trimethylcyclopentyl. 2,4-dimethyl-3-ethylcyclopentyl, 2,2,3,4,4-pentamethylcyclopentyl, 2,3-dimedιyl-3-propylcyclopentyl, cyclohexyl, 2,6-dimethylcyclohexyl, 3,3,5,5-tetramethylcyclohexyl, 2-methylcyclohexyl, 2-etiιylcyclohexyl, 4-propylcyclohexyl, 5-butylcyclohexyl, 2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl, 2,3,4-trimethylcyclohexyl, 2,3-dimedιyl-5-ethylcyclohexyl, 2,5-dimethyl-6-propylcyclohexyl, 2,4-dimethyl-3-butylcyclohexyl, 2,2,4,4-tetramethylcyclohexyl, 3,3,6,6-tetramethylcyclohexyl, 3,3,4,5,5-pentamethylcyclohexyl, 3,3,4,5,5,6-hexamethylcyclohexyl, 3,3,5-trimethyl-4-ethylcyclohexyl, 3,4,4-trimethyl-5-propylcyclohexyl, cycloheptyl, 3-methylcycloheptyl, 5-propylcycloheptyl, 6-butylcycloheptyl. 7-medιylcycloheptyl, cyclooctyl, 2-methylcyclooctyl, 3-etiιylcyclooctyl, 3,3,4-trimethylcyclooctyl, 3,3,5,5-tetramethylcyclooctyl and the like.
When the carboxyl protecting group is C3-C12 cycloalkenyl-CpH2p- or otherwise contains a C3-C12 cycloalkenyl group, the corresponding unsaturated radicals such as cyclopentenyl and cyclohexenyl and the like are contemplated.
The polycycloalkyl-CpH2p- radicals which can serve as carboxyl protecting groups, or as portions of carboxyl protecting groups, are bridged or fused saturated alicyclic hydrocarbon systems consisting of two or more rings, optionally bearing one or more alkyl substituents and having a total of 6 to 28 carbon atoms in the ring portion. The corresponding bridged or fused unsaturated alicyclic hydrocarbon systems are intended by the term "C6-C28 polycycloalkenyl-CpH2p-". Such polycycloalkyl and
polycycloalkenyl radicals are exemplified by adamantyl (especially 1- or 2-adamantyl), adamantylmethyl (especially 1-adamantylmethyl),
adamantylethyl (especially 1-adamantylethyl), bomyl, norbonyl, (e.g. exonorbornyl or endo-norbomyl), norbomenyl (e.g. 5-norbornen-2-yl), norbornylmethyl (e.g. 2-norbomylmethyl) and norbornylethyl (e.g. 2-norbornylethyl), and by radicals of the type -CpH2p-(sterol residue) wherein p is defined as above and the steroi residue is the portion of a steroidal alcohol which remains after removal of a hydrogen atom from a hydroxy group therein. The steroi residue is preferably that of a pharmacologically inactive steroid, e.g. cholesterol, a bile acid (cholic acid or related compound) or the like. In the case of polycyclic radicals, p is preferably 0, 1 or 2.
When the carboxyl protecting group is wherein
Figure imgf000043_0001
-NRfRg represents the residue of a saturated monocyclic secondary amine, such monocycles preferably have 5 to 7 ring atoms optionally containing another hetero atom (-O-, -S- or -N-) in addition to the indicated nitrogen atom, and optionally bear one or more substituents such as phenyl, benzyl and methyl. Illustrative of residues of saturated monocyclic secondary amines which are encompassed by the -NRfRg term are morpholino, 1-pyrrolidinyl, 4-benzyl-1-piperazinyl, perhydro-1,2,4-oxathiazin-4-yl, 1- or
4-piperazinyl, 4-methyl-1-piperazinyl, piperidino, hexamethyleneimino, 4-phenylpiperidino, 2-methyl-l-pyrazolidinyl, 1- or 2-pyrazolidinyl, 3-methyl-1-imidazolidinyl, 1- or 3-imidazolidinyl, 4-benzylpiperid_no and 4-phenyl-1-piperazinyl. As yet another alternative, the carboxyl group can be protected by converting it to an amide, i.e. the -COOH group is convened to a
-CONRfRg group wherein Rf and Rg are as defined and exemplified above. Such amide groups are also intended to be encompassed by the expression "carboxyl protecting group" as used herein.
Selection of an appropriate carboxyl protecting group will depend upon the reason for protection and the ultimate use of the protected product. For example, if the protecting group is intended to be present in a pharmaceutically useful end product, it will be selected from those protecting groups described hereinabove which offer low toxicity and the desired degree of lipophilicity and rate of in vivo cleavage. On the other hand, if the protecting group is used solely for protection during synthesis, then only the usual synthetic requirements will generally apply.
The expression "amino protecting group" as used herein is intended to designate a group (T) which is inserted in place of a hydrogen atom of an amino group or groups in order to protect the amino group(s) during synthesis and/or to improve lipoidal characteristics and prevent premature metabolism of said amino group or groups prior to me compound's reaching the desired site in the body.
As with the carboxyl protecting groups, selection of a suitable amino protecting group will depend upon the reason for protection and the ultimate use of the protected product. When the protecting group is used solely for protection during synthesis, then a conventional amino protecting group may be employed. When the amino protecting group is intended to be present in a pharmaceutically useful end product, then it will be selected from among amino protecting groups which offer low toxicity and the desired degree of lipophilicity and rate of in vivo cleavage. Especially suitable for in vivo use as amino protecting groups T are activated carbamates, i.e. the protecting group T has the structure
Figure imgf000045_0001
wherein Rh is hydrogen, C1-C7 alkyl or phenyl and Ri can be selected from the groups indicated as suitable carboxyl protecting groups W hereinabove.
Again, the bulkier groups are preferred for use in vivo, and Ri is preferably a polycycloalkyl or polycycloalkenyl-containing group, such as adamantyl or a steroi residue, especially a cholesterol or bile acid residue.
The drugs which can be derivatized in accord with the present invention must contain at least one functional group capable of bonding to the phosphorus atom in the mixed phosphate carrier moiety, directly or through a bridging group. Drugs which are capable of direct bonding are generally preferred because directly-bonded derivatives are more readily synthesized and their in vivo cleavage to the active drug species is likewise less complex. When a linking or bridging group is required, such must be chosen judiciously so that in vivo cleavage will occur in the desired sequence. The mixed phosphate derivatives of formula (I) are designed to be cleaved in vivo in stages after they have reached the desired site of action. The first cleavage, by esterase, provides a negatively charged "locked-in" intermediate of the type
Figure imgf000045_0002
cleavage of the terminal ester grouping in (I) thus affords an inherently unstable intermediate of the type
Figure imgf000045_0003
which immediately and spontaneously releases R2CHO and the negatively charged "locked in" intermediate depicted above. With time, a second cleavage occurs; this cleavage is catalyzed by means of alkaline phosphatase, releasing the original drug (D-OH in the case of hydroxy-linked drugs, D-SH in the case of mercapto-linked drugs or, in the case of other drug classes, a drug-bridging group entity which will readily release the original drug), along with R1OPO2- 3. In the selected instances in which the drug is of the nucleoside type, such as is the case of zidovudine and numerous other antiretroviral agents, it is known that the drug is activated in vivo by phosphorylation; such activation may occur in the present system by enzymatic conversion of the "locked-in" intermediate with phosphokinase to the active triphosphate and/or by phosphorylation of the drug itself after its release from the "locked-in" intermediate as described above. In either case, the original nucleoside-type drug will be convened. via the derivatives of this invention, to the active phosphorylated species according to the sequence:
Figure imgf000047_0001
It is apparent from the foregoing that, in the case of nucleoside-type drugs which are activated by phosphorylation, the instant invention provides derivatives which need only a two-step in vivo phosphorylation to amve at the active tri-phosphorylated species, while the original drug requires a tiiree-step activation in vivo to the triphosphate.
In the case of drugs having a reactive hydroxyl or mercapto function directly bonded to the phosphorus atom, me cleavage to form the negatively charged "locked-in" intermediates is much faster than the cleavage of the drug itself from me remainder of the negatively charged intermediate, no matter what the identity of the
Figure imgf000048_0001
grouping in formula
(la) or (lb). The same is true for the case of imide-type and amide-type drugs. Thus, R2 in structures (Id) and (Ie), like R2 in structures (la) and
(lb), can be any of the groups defined as R2 values with formula (I) hereinabove. The derivatives of formulas (Id) and (Ie), like those of formulas (la) and (Ib), are thus first cleaved by esterase to give the negatively charged intermediate; subsequent cleavage by alkaline
phosphatase in the case of the amides and imides gives an unstable intermediate which rapidly is transformed into the original drug. On the other hand, in the case of drugs linked via amine or carboxylic acid functions, the identity of the R2 groups must be carefully controlled so that the enzymatic cleavages occur in the proper order. It is apparent from a study of structures (Ic) and (If) hereinabove, that each of these structures contains more than one bond susceptible to cleavage by esterase; if these esterase-cleavable bonds do not cleave in the proper sequence, i.e. if the bond linking
Figure imgf000048_0002
to the rest of the molecule does not cleave before the carboxyl bond linking the drug to the phosphonate moiety, then the negatively charged "locked-in" intermediate will not be formed and targeted drug delivery will not occur. By utilizing an -OCH2- linkage for
Figure imgf000049_0001
in formulas (Ic) and (If), that linkage becomes particularly susceptible to esterase. Nevertheless, judicious selection of the -O-Z- linkage in formula (Ic) and the linkage in formula (If)
Figure imgf000049_0002
is required. For example, when the drug residue is stericaily hindered, -O-Z- can be -OCH2- in formula (Ic), because that bond will be less susceptible to esterase than the bond linking
Figure imgf000049_0003
to the rest of the molecule, due to steric considerations. Likewise, can be -OCH.
Figure imgf000049_0004
in formula (If) when the drug residue is hindered. On the other hand, when structurally simple drugs which are not bulky/sterically hindered are derivatized, it may be required that -O-Z- cannot be -OCH2- in formula (Ic) and -OCH- cannot be in formula (If). In this way,
Figure imgf000049_0005
the compounds are designed so that the bonds will cleave in the proper sequence.
From the foregoing, it will be apparent that many different drugs can be derivatized in accord with the present invention. Numerous such drugs are specifically mentioned hereinbelow. However, it should be understood that the following discussion of drug families and their specific members for derivatization according to this invention is not intended to be exhaustive, but merely illustrative.
Drugs containing a reactive hydroxyl or mercapto function for use herein include, but are not limited to, steroid sex hormones, antivirals, tranquiUzers, anticonvulsants, antineoplastics (anticancer/antitumor agents), hypotensives, antidepressants, narcotic analgesics, narcotic antagonists and agonist/antagonists, CNS anticholinergics, stimulants, anesthetics, antiinflammatory steroids, nonsteroidal antiinflammatory agents/analgesics, antibiotics and CNS prostaglandins. Preferred drugs of this type are antivirals, antineoplastics and steroids.
More specifically, among the steroid sex hormones there are included: male sex hormones/androgens such as testosterone and methyl testosterone; and female sex hormones, including estrogens, both semisynthetic and natural, such as mestranol, quinestrol, ethinyl estradiol, estradiol, estrone, estriol, estradiol 3-methyl ether and estradiol benzoate, as well as progestins, such as norgestrel, norethindrone, ethisterone, dimethisterone, allylestrenol, cingestol, ediynerone, lynestrenol, norgesterone, norvinisterone, ethynodiol, oxogestone, tigestol and norethynodrel. Typically, the mixed phosphate moiety will be bonded to the steroid via a hydroxyl in the 3- or 17-position, with the 17-position being generally preferred.
Among the antivirals, there are included those of the nucleoside type, glycosides, phenyl giucoside derivatives and others. Those of the nucleoside type (i.e. a purine or pyrimidine base-type structure, including analogs of purines and pyrimidines, bearing a singly or multiply hydroxylated substituent, which may be a natural or unnatural sugar, hydroxy-bearing alkyl group or similar substituent) are preferred.
Exemplary nucleoside-type antivirals include zidovudine (AZT;
azidothymidine), ribavirin, (S)-9-(2,3-dihydroxypropyl)adenine, 6-azauridine, acyclovir (ACV), 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole, 5,7-dimethyl-2-β-D-ribofuranosyl-s-trizoole (1,5-a) pyrimidine, 3-deazauridine, 3-deazaguanosine, DHPG (ganciclovir), 6-azauridine, idoxuridine, dideoxycytidine (DDC), trifluridine
(trifluorothymidine), dideoxylnosine, dideoxydehydrodiymidine,
dideoxyadenosine, BVDU, FIAU, FMAU, FIAC, Ara-T, FEAU, cyclaradine, 6-deoxyacyclovir, 3-deazaaristeromycin, neplanocin A, buciclovir (DHBG), selenazofurin, 3-deazaadenosine, cytarabine (cytosine arabinoside; Ara-C), 5-FUDR, vidarabine (Ara-A), tiazofurin, 3'-fluoro- 2',3'-dideoxythymidine (FddThd), 1-(2,3-dideoxy-β-D-glyceropent-2- enofuranosyl)thymine (D4T or d4T), 3'-fluoro-2',3'-dideoxy-5-chlorouridine (FddClUrd), 5-(2-chloroethyl)-2'-deoxyundine (CEDU), 5-edιyl-2'-deoxyuridine (EDU), 5-(1-hydroxy-2-chioroethyl)-2'-deoxyuridine. 5 -(1-methoxy-2-bromoethyl)-2'-deoxyuridine, 5-(1-hydroxy-2-bromo-2-(ethoxycarbonyl)ethyl)-2'-deoxyuridine. 5-(1-hydroxy-2-iodo-2- (edιoxycarbonyl)ethyl)-2'-deoxyuridine, 3'-azido-2',3'-dideoxyuridine (AZU), 3'-azido-2',3'-dideoxy-5-bromouridine, 3'-azido-2',3'-dideoxy-5-iodouridine, 3'-azido-2',3'-dideoxy-5-methylcytidine and 3'-fluoro-2',3'-dideoxyuridine (FddUrd). These and numerous other nucleoside-type antivirals suitable for derivatization in accord with the present invention have been descnbed in the literature. See, for example, Van Aerschot et al, J. Med. Chem. 1989, 32, 1743-1749; Mansuri et al, J. Med. Chem. 1989. 32, 461-466; Kumar et al, J. Med. Chem. 1989. 32, 941-944; Lin et al, J, Med, Chem. 1989, 32, 1891-1895; Kim et al, J. Med. Chem. 1987, 30, 862-866; Lin et al, J. Med. Chem. 1987. 30, 440-444; Herdewijn et al, J, Med, Chem. 1988, 31, 2040-2048; Turk et al, Antimicrobial Agents and Chemotherapy, Apr. 1987, Vol. 31, No. 4, 544-550; Elion, in Topics in Medicinal Chemistry, 4th SCI-RSC Medicinal Chemistry Symposium, ed. P. R. Leeming, Royal Society of Chemistry, London, 1988, pp. 163-171; Roberts et al, in Topics in Medicinal Chemistry, 4th SCI-RSC
Medicinal Chemistry Symposium, ed. P. R. Leeming, Royal Society of Chemistry, London, 1988, pp. 172-188; Kelley, in Topics in Medicinal Chemistry, 4th SCI-RSC Medicinal Chemistry Symposium, ed. P. R.
Leeming, Royal Society of Chemistry, London, 1988, pp. 189-212;
Hamden et al, in Topics in Medicinal Chemistry, 4th SCI-RSC Medicinal Chemistry Symposium, ed. P. R. Leeming, Royal Society of Chemistry, London: 1988, pp. 213-244; Reist et al, in Nucleotide Analogues as Antiviral Agents. ACS Symposium Series 401, ed. John C. Martin, American Chemical Society, Washington, D.C., 1988, Chapter 2, pp. 17-34; DeClercq, in Approaches to Antiviral Agents, ed. Michael. R. Hamden,
VCH, Great Britain, 1985, Chapter 3, pp. 57-99; Holy, in Approaches to Antiviral Agents, ed. Michael R. Hamden, VCH, Great Britain, 1985, Chapter 4, pp. 101-134; and Hovi, in Antiviral Agents: The Development and Assessment of Antiviral Chemotherapy, Volume I, ed. Hugh J. Field, CRC Press, Inc., Boca Raton, Florida, 1988, Chapter 1, pp. 1-21.
Typically, the mixed phosphate moiety will be bonded to the
nucieoside-type antiviral via a primary hydroxyl in the 5'-position or corresponding position when the antiviral does not have a 5'-hydroxyl. Non-nucleoside antivirals for possible derivatization herein include hydroxy-containing giycosides such as 2-deoxy-D-glucose and 2-deoxy-2- fluoro-D-mannose, phenyl glucosides such as phenyl-6-chloro-6-deoxy-β-D-glucopyranoside and benzimidazole analog type antivirals such as the syn and anti isomers of 6[[(hydroxylmino)phenyl]methyl]-1-[(1-methylethyl)sulfonyl]-1H-benzimidazol-2-amine.
Among the tranquilizers for derivatization herein, there can be mentioned hydroxy-containing benzodiazepine tranquilizers, for example oxazepam, lorazepam and temazepam; tranquilizers of the butyrophenone group, such as haloperidol; tranquilizers of the diphenylmethane group, for example hydroxyzine; phenothiazine-type tranquilizers, for example acetophenazine, caxphenazine, fluphenazine, perphenazine and
piperacetazine; and tranquilizer analogs of phenothiazines, e.g.
clopenthixol.
Among the hydroxy-containing anticonvulsants, there can be mentioned, for example, the metabolites of valproic acid, i.e. 5 -hydroxy- 2-n-propylpentanoic acid, 4-hydroxy-2-n-propylpentanoic acid and 3-hydroxy- 2-n-propylpentanoic acid.
Among the antineoplastics, i.e. anticancer and/or antitumor agents, there can be mentioned as illustrative urea derivatives, hormonal
antineoplastics, podophyllotoxins (e.g. teniposide, etoposide), antibiotic-type antibiotics, nitrosourea-type alkylating agents and, especially, purine and pyrimidine antagonists. The punne and pyrimidine antagonist-type antineoplastics include simple purine and pyrimidine base-type structures, e.g. thioguanine and 6-mercaptopurine, as well as those of the nucleoside-type, e.g. Ara-AC, pentostatin, dihydro-5-azacytidine, tiazofurin, sangivamycin, Ara-A (vidarabine), 6-MMPR, 5-FUDR (floxuridine), cytarabine (Ara-C; cytosine arabinoside), 5-azacytidine (azacitidine), uridine, thymidine, idoxuridine, 3-deazauridine, cyclocytidine, dihydro-5-azacytidine, triciribine and fiudrabine. Many nucleoside-type compounds have utility both as antineoplastics and as antiviral agents. Such are typically derivatized as described hereinabove with reference to the nucleoside-type antivirals.
Among the anesthetics, there can be mentioned pentothal
(thiopental).
Among the antibiotics, there can be mentioned lincomycin type antibiotics such as clindamycin and lincomycin.
Among the narcotic analgesics, there can be mentioned those of the meperidine type such as meptazinol, profadol and myfadol; and those which can be considered morphine derivatives. The morphine derivatives include those of the morphine series, such as hydromorphone,
oxymorphone, apomorphine, levorphanol, morphine and metopon; those of the benzomorphan series, such as pentazocine, cyclazocine and
phenazocine; and those of the codeine series, such as codeine, oxycodone, drocode and pholcodine.
The narcotic antagonists and mixed agonist/antagonists include such compounds as nalbuphine, naloxone, nalorphine, buprenorphine, butorphanol, levallorphan, naltrexone, naimefene, alazocine, oxilorphan and nalmexone.
The antiinflammatory steroids include such compounds as cortisone, hydrocortisone, betamethasone, dexamethasone, flumethasone,
fluprednisolone, methyl prednisolone, meprednisone, prednisolone, prednisone, triamcinolone, triamcinolone acetonide, cortodoxone. fludrocortisone, flurandrenolone acetonide (flurandrenolide) and
paramethasone.
Among the nonsteroidal antiinflammatory agents/non-narcotic analgesics, there can be mentioned, for example, clonixeril, sermatacin and naproxol.
It will be apparent from the definition of R, in formula (I), that when drugs containing a reactive hydroxyl function are selected for derivatization in accord with the present invention, both [D] and OR1 is formula (I) can be drug residues. While virtually any of the hydroxyl-containing drugs disclosed above could be used to prepare a compound of formula (I) in which [D] and OR1 are the same or different drug residues, specific utility classes and specific hydroxyl-containing drugs within those classes lend themselves especially to this type of derivatization. Thus, the nucleoside-type drugs, which are especially useful as antivirals and antineoplastics, and are known to be activated in vivo by phosphorylation, are particularly desirable targets for this type of derivatization; the bioavailability of drugs of this type may be enhanced by providing two identical drug residues in the compound of formula (I), in essence providing for faily rapid release of the first drug residue and its conversion to active species, followed by a sustained release of the second drug residue and its activation. Of particular interest are compounds of the invention in which botii [D] and -OR, represent AZT (zidovudine) residues or in which both represent DDI (dideoxylnosine) residues.
Moreover, the possibility of including two different drug residues within a system for targeted drug delivery is of particular interest when it is desired to deliver two drugs to the same target organ, especially when the drugs may have a synergistic, rather than a simply additive, effect when co-administered. Of particular interest in this connection are combinations of two antineoplastics or two antivirals, especially two nucleoside-type antivirals. Nevertheless, even when the combined effect is no more than additive, it may be convenient to incorporate residues of two different drugs in the same molecule, as may be the case for certain antineoplastic-antineoplastic or antiviral-antiviral combinations, antineoplastic-antiviral combinations, antibiotic-antiinflammatory combinations and estrogen-progestin combinations. Still further, when -OR1 represents a drug residue in formula (I), it may be a substance which functions wholly or partially as an enhancer or activator when used in combination with the drug whose residue is represented by [D], or to prevent deactivation thereof, e.g. an enzyme inhibitor for use with an antiviral agent, or it may function as a transport facilitator, in which case it may not be a "drug" residue in its normal sense but simply a protective residue which functions to enhance transport or delivery of the drug whose residue is represented by [D], principally by improving lipophilicity. It must, however, be a group which is enzymatically much less sensitive to cleavage in vivo than the
acyloxyalkyl group -OCH(R2)OCOR3. It is not an acyloxyalkyl group in any event. Preferred protective residues are discussed in more detail hereinbelow.
As particular pairs of non-identical hydroxy-containing drugs to be combined in a single compound of formula (I) as [D] and OR1 residues, an estrogen such as estradiol may be paired with a progestin such as norediindrone, or norgestrel, for contraceptive use or other use known for an estrogen/progestin combination.
Of special interest as pairs of hydroxy-containing drugs whose residues may be combined in a single compound of formula (I) are combinations of antiviral drugs with enzyme inhibitors and combinations of two antiviral agents. The rationale for such combination in a single molecule includes the fact that the antivirals and antivirals/enzyme-inhibitors have themselves been co-administered. See, for example,
Antiviral Agents: The Development and Assessment of Antiviral
Chemotherapy, Volume II, ed. Hugh J. Field, CRC Press, Inc., Boca Raton, Florida , 1988, Chapter 3, pp. 29-84. Adenosine-containing nucleoside antivirals are susceptible to adenosine deaminase metabolism. Deamination appears to substantially decrease activity. Incorporation of an deaminase inhibitor residue into the same molecule as a nucleoside antiviral susceptible to such an inhibitor is thus designed to alleviate inactivation of the antiviral by the widespread
adenosine deaminase enzyme. Antiviral drugs susceptible to such inactivation include vidarabine (adenine arabinoside or Ara-A), 3-deoxyadenosine (3-dA, cordycepin) and 2',3'-dideoxyadenosine.
Adenosine deaminase inhibitors include coformycin, 2'-deoxycoformycin, EHNA [erythro-9-(2-hydroxy-3-nonyl)adenine], acyclo-coformycin, DHPA
[9-(2,3-dihydroxypropyl)adenine] and N6-methyldeoxyadenosine.
Combination of such an antiviral drug and such an enzyme inhibitor in a single molecule of formula (I) may be of particular use in combating DNA viruses such as vaccinia virus, varicella-zoster, HSV-1, HSV-2, adenoviruses, etc.
2'-Deoxycytidine and many cytidine analogs are substrates for cytidine-deoxycytidine deaminase, which is widely occurring. Deamination by cytidine-deoxycytidine deaminase may lead to enhanced cytotoxicity and/or reduced activity. Antiviral nucleosides susceptible to this enzyme include the 5-iodo- and 5-bromo-2'-deoxycytidines, Ara-C and FIAC [1- (2'-deoxy-2'-fluoro-β-D-arabinofuranosyl)-5-iodocytosine], while the enzyme inhibitors includes tetrahydrouridine (THU) and
2'-deoxytetrahydrouridine (2-dTHU). DNA viruses such as HSV-1 and -2, VZV and HCMV may be particularly susceptible to such combination in formula (I).
Thymidine, uridine and many pyrimidine nucleoside analogs are subject to cleavage by phosphorylases. By inhibiting phosphorylysis, it may be possible to increase drug half-life and enhance plasma levels of drug. Antivirals susceptible to cleavage of this sort include idoxuridine (IUdR or 5-iodo-2'-deoxyuridine), 5-ethyl-2'-deoxyuridine (EtUdR), trifluridine (TFT or 5-trifluoromethyl-2'-deoxyuridine), 5-E-(2-bromovinyl)- 2'-deoxyuridine (BVDU) and 5-(2-chloroethyl)-2'-deoxyuridine (CEDU). Thymidine and uridine phosphorylase inhibitors include 5-benzyl acyclouridine, 2'-deoxyglucosyl thymine and 5-methyl acyclouridine. Again, combination of antiviral and inhibitor in a single compound of formula (I) may be of particular interest in treating inflections caused by DNA viruses.
Selection of two different antiviral agents for incorporation of their residues into formula (I) may be made, by way of illustration, from among virus-specific agents which act on or via DNA polymerase, from
combinations of those specific agents with less specific agents, from among less specific agents and from among agents active against RNA viruses.
Thus, two DNA virus-specific agents such as acyclovir (ACV), 5-E- (2-bromovinyl)-2'-deoxyuridine (BVDU), 9-(2-hydroxy-1- (hydroxymethyl)ethoxymethyl)guanine (DHPG), spongothymidine (Ara-T) and 5-ethyl-2'-deoxyuridine (EtUdR) may be selected, e.g. residues of ACV and BVDU, DHPG and BVDU, ACV and DHPG, Ara-T and ACV, and Ara-T and EtUdR combinations as the [D] and OR1 moieties.
Combinations of DNA- specific with less specific nucleosides include, for example, selection of a specific agent such as ACV, EtUdR,
MMUdR (5-methoxymethyl-2'-deoxyuridine), BVDU or Ara-T, together with a less specific agent such as Ara-A, IUdR, TFT, FUdR, FMAU, FIAC or Ara-C. Illustrative of such combinations as [D] and -OR1 are the residues of ACV/Ara-A, ACV/FIAC, ACV/IUdR, ACV/TFT and
ACV/FUdR. Theoretically, such combinations are of interest because of blockade of interdependent or convergent pathways. Combinations utilizing a TFT residue as the less specific agent are of particular interest because TFT itself has proved synergistic with numerous more specific antiviral agents.
Two agents, each with little antiviral specificity (e.g. Ara-A, IUdR,
TFT, FUdR, FMAU, FIAC, Ara-C) can also be selected for derivatization in accord with the present invention. Such combination may lead to lower doses and thus to lower toxicity. Likely combinations of residues include those of Ara-A with IUdR, Ara-A with Ara-C, IUdR with FUdR, Ara-A with FIAC, Ara-A with FMAU, Ara-A with TFT. Moreover, choice of one of these agents for derivatization may be combined with a choice of a selective inhibitor such as 5' -amino-5'-deoxythymidine (5' -AdThd) or with a selective protector such as deoxythymidine (dThd). An objective of selective inhibition may be to inhibit enzymes responsible for undesired activation of the antiviral drug in uninfected cells, while an objective of selective protection may be to provide a competitive substrate for enzymes which are responsible for cellular toxicity.
RNA virus-specific agents whose residues can be combined as [D] and -OR1 in a compound of the present invention include selenazofurin, ribavirin, 3-deazaguanosine, 3-deazauridine, tiazofurin, 2-deoxy-D-glucose, 6-mercapto-9-tetrahydro-2-furylpurine (6-MPTF), zidovudine (AZT), dideoxylnosine (DDI), dideoxyadenosine, DDC, D4T and the like.
Selection of two such agents from the group consisting of ribavirin, selenazofurin and tiazofurin for derivatization herein is of particular interest. Also of particular interest are compounds of formula (I) in which both [D] and -OR1 are selected from the group consisting of residues of
AZT, DDI, D4T, DDC and dideoxyadenosine, especially when one of [D] and -OR1 is an AZT residue.
Other especially interesting compounds of the invention in which both [D] and -OR1 represent different drug residues are those in which one of [D] and -OR1 is a highly active drug residue, e.g. an AZT residue or residue of other nucleoside-type antiviral, and the other of [D] and -OR1 is a relatively innocuous or inactive essentially nontoxic lipophilic alcohol residue such as that of a naturally occurring sterol like cholesterol or hydrocortisone or androstan-17-ol or androstanolone (3-hydroxy-Δ5-17-one), or a long chain aliphatic alcohol (typically a C9-C22 fatty alcohol, such as stearyl alcohol, myristyl alcohol, lauryl alcohol, cetyl alcohol or decyl alcohol) or polycarbocyclic alcohol (e.g., adamantanemethanol) used to enhance delivery of the antiviral agent via improved lipophilicity.
Indeed, the R1 group can be many of the groups defined as carboxyl protecting groups hereinabove, from simple alkyl groups such as ethyl to carbocylic and polycarbocyclic groups (cycloalkyl-CpH2p-, polycycloalkyl- CpH2p- and so forth, especially the polycycloalkyl-CpH2p- groups as defined and exemplified hereinabove), just so long as it is enzymatically much less sensitive to cleavage in vivo man the -OCH(R2)OCOR3 portion of the instant compounds. This is true regardless of the identity of the [D] residue. However, use of a large lipophilic protective residue for -OR1 is of particular interest when the drug is hydrophilic (e.g. a nucleoside); on the other hand, when the drug is lipophilic, R1 can easily be one of the smaller, more simple residues (e.g. methyl) as there is no need to enhance lipophilicity. The final compound of formula (I) will optimally have a log P of between about 1 and 5, preferably between about 2 and 3, and this can be controlled by appropriate selection of -OR1 for a given drug residue [D].
It should be understood that in all of the situations discussed above in which both [D] and -OR1 represent drug residues, such residues may bear appropriate protecting groups at either or both locations, just as the drug residues in the other compounds of the invention may optionally bear protecting groups.
Drugs containing a reactive amide or imide function for
derivatization herein include, but are not limited to, tranquilizers, sedatives, anticonvulsants/antiepileptics, hypnotics, antineoplastics, antivirals, antibiotics/antibacterial agents, barbiturate antagonists, stimulants, antihypertensives and antidepressant/psychotropic drugs.
More specifically, there can be mentioned hydantoin-type
tranquilizers and anticonvulsants/antiepileptics, for example, phenytoin, mephenytoin and ethotoin; barbiturate sedatives/anticonvulsants/
antepileptics, e.g. phenobarbital, amobarbital and butalbital; gultarimide or piperidine derivatives which are sedatives and hypnotics, for example, glutethimide, methyprylon and aminoglutethimide (also an anticonvulsant); benzodiazepine-type tranquilizers, such as nitrazepam, bromazepam, demoxepam, oxazepam; antidepressants/psychotropics, e.g. sulpiride; GABAergic agents/antiepileptics, for example progabide; valproic acid derivative-type anticonvulsants, e.g. valpromide; barbiturate antagonists, for example, bemegride; tetracycline-type antibiotics, such as
demeclocycline, oxytetracycline, chlortetracycline, tetracycline,
methacycline, minocycline and doxycycline; nonsteroidal
antiinflammatory/ analgesic agents, e.g. tesicam; and antineoplastics, for example alkylating agents of the nitrogen mustard-type, e.g. uracil mustard, spiromustine and cydophosphamide, alkylating agents of the nitrosourea type such as PCNU, purine/pyrimidine antagonists, e.g. 5-FU(5-fluorouracil), and various other antineoplastics, such as razoxane and
ICRF-187.
Drugs containing a reactive carboxyl function for derivatization in accord with the present invention include, but are not limited to, anticonvulsants, antineoplastics, antibiotics/antibacterials, diagnostics and nonsteroidal antiinflammatory agents/non-narcotic analgesics.
More specifically, there can be mentioned anticonvulsants, e.g. valproic acid; antineoplastics, for example, nitrogen mustard-type alkylating agents such as chlorambucil and folic acid antagonists such as methotrexate and dichloromethotrexate; penicillin-type antibiotics such as amoxicillin, phenoxymethylpenicillin (penicillin V), benzylpenicillin, dicloxacillin, carbenicillin, oxacillin, cloxacillin, hetacillin, methicillin, nafcillin, ticarcillin and epicillin; cephalosporin-type antibiotics, e.g. cephalothin, cefoxitin, cefazolin and cephapirin; miscellaneous other antibiotics, e.g. oxolinic acid; nonsteroidal antiinflammatories/non-narcotic analgesics, including propionic, acetic, fenamic and biphenylcarboxylic acid
derivatives, for example, ibuprofen, naproxen, flurbiprofen, zomepirac, sulindac, indomediacin, ketoprofen, fenbufen, fenoprofen, indoproxen, fluprofen, bucloxic acid, tolmetin, alclofenac, fenclozic acid, ibufenac, flufenisal, pirprofen, flufenamic acid, mefenamic add, clonixin,
meclofenamic acid, flunixin, diclofenac, carprofen, etodolac, fendosal, prodolic acid, diflunisal and flutiazin; and diagnostics such as diohippuric acid and iothalamic acid.
Drugs containing a reactive amino function for use in accord with the present invention include, but are not limited to, GABAergics/antiepileptics, antineoplastics, cerebral stimulants, appetite suppressants, MAO inhibitors, tricyclic antidepressants, decongestants, narcotic analgesics, antivirals, neurotransmitters, small peptides, dopaminergic agents and antibiotics. Illustrative drugs of this structural type include antiepileptics such as GABA, 7-vinyl GABA and γ-acetylenic GABA; nitrogen mustard-type antineoplastics such as mdphalan; antibiotic-type antineoplastics, e.g. daunorubicin (daunomycin), doxorubicin (adriamycin), dactinomycin and mitomycin C; nitrosourea-type antineoplastics such as alanosine;
miscellaneous other antineoplastics, e.g. bactobolin, DON and acivicin: sympathetic stimulants/appetite suppressants, such as methamphetamine. phentermine, phenmetrazine, dextroamphetamine, levamphetamine, amphetamine, phenethylamine, methyl phenidate, aletamine, cypenamine, fencamfamin and etryptamine; MAO inhibitors, e.g. tranylcypromine; tricyclic antidepressants, e.g. protriptyline, desipramine, nortriptyline, octriptyline and maprotiline; cerebral stimulants, e.g. amedalin, bupropion. cartazolate, daledalin, difluanine and nisoxetine; antivirals such as glucosamine, 6-amino-6-deoxy-D-glucose, amantadine and rimantadine; amino adds/neutrotransmitters, e.g. tryptophan; small peptides, typically containing 2-20 amino acid units, e.g. the enkephalins (leu5-enkephalin, met5-enkephalin), endorphins and LHRH analogs; catecholamine
neurotransmitters, e.g. norepinephrine, epinephrine and dopamine; other neurotransmitters, e.g. serotonin, and related compounds such as tryptamine; penicillin-type antibiotics such as ampicillin; cephalosporin-type antibiotics, e.g. cephalexin; and sympatholytic agents such as guanethidine and debrisoquin.
Also illustrative of the drug species contemplated by this invention are pharmacologically active metabolites of drugs. Such metabolites are typified by hydroxylated metabolites of tricyclic antidepressants, such as the E- and Z-isomers of 10-hydroxynortriptyline, 2-hydroxylmipramine, 2-hydroxydesipramine and 8-hydroxychloripramine; hydroxylated metabolites of phenothiazine tranquilizers, e.g. 7-hydroxychlorpromazine; and desmethyl metabolites of N-methyl benzodiazepine tranquilizers, e.g.
desmethyldiazepam. Other active metabolites for use herein will be apparent to those skilled in the art, e.g. SL 75102, which is an active metabolite of progabide, a GABA agonist, and hydroxy-CCNU, which is an active metabolite of CCNU, an anticancer nitrosourea. Typically, tiiese pharmacologically active metabolites have been identified as such in the sdentific literature but have not been administered as drugs themsdves. In many cases, the active metabolites are believed to be comparable in activity to their parent drugs; frequendy, however, the metabolites have not been administered per se because they are not themselves able to penetrate biological membranes such as the blood-brain barrier. Diagnostic agents, including radiopharmaceuticals. are encompassed by the expression "drug" or the like as used herein. Any diagnostic agent which can be derivatized to afford a mixed phosphate derivative of formula (I) which will penetrate biological membranes, e.g. the BBB, and concentrate in the target organ, e.g. the brain, in its negatively charged form and can be detected therein is encompassed by this invention. The diagnostic may be "cold" and be detected by X-ray (e.g. radiopaque agents) or other means such as mass spectrophotometry, NMR or other non-invasive techniques (e.g. when the compound includes stable isotopes such as C13, N15, O18, S33 and S34). The diagnostic alternatively may be
"hot", i.e. radiolabelled, such as with radioactive iodine (I 123, I 125, I 131) and detected/imaged by radiation detection/imaging means. Typical "cold" diagnostics for derivation herein include o-iodohippuric acid, iothalamic acid, iopydol, iodamide and iopanoic acid. Typical
radiolabelled diagnostics include diohippuric acid (I 125, I 131),
diotyrosine (I 125, I 131), o-iodohippuric acid (I 131), iothalamic acid (I 125, I 131), thyroxine (I 125, I 131), iotyrosine (I 131) and
iodometaraminol (I 123). In the case of diagnostics, unlike the case of drugs which are for the treatment of disease, the "locked-in" negatively charged form will be the form that is imaged or otherwise detected, not the original diagnostic itself. Moreover, any of the drugs disdosed herein which are intended for the treatment or prevention of medical disorders but which can be radiolabelied, e.g. with a radioisotope such as iodine, or labelled with a stable isotope, can thus be converted to a diagnostic for incorporation into the mixed phosphate of formula (I).
When the drug sdected for derivatization according to the present invention is to be linked to the mixed phosphate moiety via a secondary or tertiary hydroxyl, or via a hindered hydroxyl, it may be desirable to use a bridging group
Figure imgf000065_0001
as described above for linking amide and imide groups to the phosphate, rather than a direct bond between the drug's hydroxyl group and the phosphorus atom.
The compounds of formula (I) can be prepared by a variety of synthetic procedures tailored to the structure of the particular drug to be derivatized, particularly to the nature of the reactive functional group to be linked to the mixed phosphate moiety, the identity of the bridging group, if any, and the presence of other functional groups which may benefit from protection. In preferred embodiments of the invention, the drug contains a reactive hydroxyl group susceptible to direct bonding to the phosphorus atom in the mixed phosphate moiety. It is also preferred for simplicity's sake that the selected drug not require protection of other functional groups, although such groups can be protected when necessary. TheILLUSTRATTVE SYNTBETIC METHODS set forth hereinafter describe various methods for the preparation of the compounds of the invention, while the EXAMPLES which follow illustrate these and alternative methods. These methods can be summarized as follows for drugs in each of the major structural categories, wherein the definitions of the structural variables are as set forth above in conjunction with formulas (Ia) to (If):
The compounds of formulas (la) and (lb) can be synthesized by first converting the drug, D-OH or D-SH, respectively, to the corresponding mixed phosphate diester intermediate of the formula
or ,
Figure imgf000065_0002
Figure imgf000065_0003
respectivdy, which can be accomplished by one of variety of methods; then by converting the resultant intermediate depicted above to the
corresponding mixed triester of formula (la) or (lb), which alio can be accomplished by one of a variety of methods. The conversion to the diester is often advantageously effected by reacting the starting alcohol or thiol with a phosphorylating agent such as 2-chlorometiiyl-4- nitrophenylphosphorodichloridate and subsequent hydrolysis to give the corresponding diester of the type
Figure imgf000066_0001
Figure imgf000066_0002
which is then reacted with R1OH to afford the desired intermediate
or
Figure imgf000066_0003
Figure imgf000066_0004
(Alternative routes to that intermediate include reacting the starting alcohol or thiol with POCl3, then subjecting the resultant
or
Figure imgf000066_0005
Figure imgf000066_0006
to reaction with R1OH and subsequent hydrolysis; or reacting the starting alcohol or thiol with
Figure imgf000066_0007
That intermediate can then be treated with aqueous sodium hydroxide and aqueous silver nitrate to afford the corresponding silver salt, or
Figure imgf000067_0001
Figure imgf000067_0002
respectively. Reaction of the silver salt with
Figure imgf000067_0003
, affords the corresponding compound of formula (la) or
Figure imgf000067_0004
(lb), respectively. A preferred alternative to use of a silver salt employs a potassium or cesium salt catalyst, most preferably a cesium salt. In accord with this alternative, the intermediate of the formula
or
Figure imgf000067_0005
O
Figure imgf000067_0006
prepared as described above, is reacted with cesium fluoride (or equivalent cesium salt) and a compound of the formula
Figure imgf000067_0007
in a suitable organic solvent, e.g. dimethylformamide,
Figure imgf000067_0008
acetonitrile, nitromethane, chloroform or dimethylacetamide, to give the corresponding compound of formula (la) or (lb), respectively.
When both D-O- and OR1 in formula (la) represent residues of drugs having reactive hydroxyl functions, an advantageous synthetic method begins with reaction of 2-chlorophenyl phosphorodichloridate with 1- hydroxybenzotriazole to afford 2-chlorophenyl-O,O-bis[1-benzotriazolyl]- phosphate of the formula
Figure imgf000068_0001
according to the method of van der Marel et al, Tetrahedron Letters, 22,
3887-3890 (1981) and Wressmann et al, Nucleic Acid Res. 1 1, 8389-8405 (1983). When D-O- and -OR1 are not identical, there follows a two-step process in which, as the first step, 2-chlorophenyl-O,O-bis[1-benzotriazolyl]-phosphate is reacted with the first drug, D-OH, in the presence of an acid scavenger, e.g. triethylamine or other suitable amine, in an appropriate solvent, for example, tetrahydrofuran/pyridine. In the second step, the intermediate thus obtained is reacted with the second drug, R1OH, under the same conditions as in the first step, to give the desired mixed phosphate diester intermediate of the formula
Figure imgf000068_0002
When D-O- and -OR1 are identical, the two steps can be combined in a single step utilizing two equivalents of D-OH to give the corresponding diester intermediate. In either case, the diester intermediate can then be converted to the compound of formula (I) by one of the methods described in the preceding paragraph, preferably by reaction with cesuim fluoride and a compound of the formula such as
Figure imgf000069_0002
Figure imgf000069_0001
or by reaction with sodium methoxide and a compound of the formula As yet another alternative when D-O- and -OR1 are
Figure imgf000069_0003
identical, a one pot process utilizing 2-chlorophenyl phosphorodichloridate and 1-hydroxybenzotriazole ylelds 2-chlorophenyl-O,O-bis[1-benzotriazolyl]- phosphate as an unisolated predpitate, the reaction suspension then being reacted with two equivalents of D-OH without further addition of solvent to afford the intermediate
Figure imgf000069_0004
That intermediate can be isolated by column chromatography (although the 2-chlorophenyl moiety can be easily hydrolyzed on the column), then subjected to deprotection with pyridine-2-aldoxime and 1,1,3,3- tetramethylguanidine to give the corresponding diester intermediate. The diester intermediate can then be converted to the compound of formula (I) as described immediately above.
The compounds of formula (Ic) can be synthesized by reacting the drug D-COOH with chloromethyl chlorosulfate or similar compound of the type Cl-Z-SO3Cl to give an intermediate of the type
D-COO-Z-Cl, which can be reacted with a silver or cesium salt of
Figure imgf000070_0001
to afford a compound of the type
Figure imgf000070_0002
That intermediate, which contains a linking group bearing a reactive
-OH, can then be reacted with cesium floride or equivalent cesium salt and a compound of the formula
Figure imgf000070_0003
in a suitable organic solvent as discussed in the preceding paragraph, to give the corresponding compound of formula (Ic).
The compounds of formulas (Id) and (Ie) can be synthesized by
reacting the drug, respectively, with an
Figure imgf000070_0004
appropriate aldehyde of the type R2CHO, e.g. formaldehyde, chloral, acetaldehyde, furfural, benzaldehyde or the like, in the presence of a basic catalyst such as potassium carbonate, to give the corresponding
intermediate of the type That
Figure imgf000070_0005
intermediate, which contains a linking group bearing a reactive -OH, can then be reacted, analogously to the compounds of formula (la) and (lb), first to give the intermediate
respectively, then
Figure imgf000071_0001
with cesium floride or equivalent cesium salt and a compound of the formula in a suitable organic solvent, as discussed
Figure imgf000071_0002
hereinabove for the hydroxy-containing drugs, to give the corresponding compound of formula (Id) or (Ie), respectively. Drugs containing reactive primary or secondary sulfonamide functions (D-SO2NH or D-SO2NHR4) can be derivatized similarly to the primary or secondary carboxamide- containing drugs to give analogous compounds of formula (I) and are within the ambit of the present invention. The identity of the R, group in the secondary amides and sulfonamides, like the R4 group in formula (If), is immaterial in that it is of course part of the drug residue itself and is left unchanged by derivatization in accord with this invention.
The compounds of formula (If) can be synthesized by reacting the drug, DNHR4, with a halo(optionally substituted methyl)chloroformate to give an intermediate of the type
Figure imgf000071_0003
SUBSTITUTE SHEET which can then be reacted widi a silver or cesium salt of > to
Figure imgf000072_0001
afford a compound of the type
Figure imgf000072_0002
That intermediate, which contains a linking group bearing a reactive
-OH, can then be reacted with cesium floride or equivalent cesium salt and a compound of the formula in a suitable organic solvent as
Figure imgf000072_0003
discussed hereinabove, to give the corresponding compound of formula (If).
When required, the various protecting groups for hydroxyl, carboxyl and amino functions discussed above can be substituted for the hydroxyl, carboxyl and amino functions in the instant compounds or their precursor molecules by methods well-known in the art. Most frequently, the protecting group will first be introduced into the drug molecule by well-known methods and the protected drug will then be subjected to the processes described above for preparation of the instant compounds.
Methods for chemical removal of the protecting groups (when such are not to be retained in the pharmaceutically useful end product) are likewise well-known to those skilled in the art. Typically, amine protecting groups are chemically removed by acidolysis (acid hydrolysis) or hydrogenation, depending on the particular protecting group employed. Hydroxyl and carboxyl protecting groups are typically removed chemically by acid or base hydrolysis. Protecting groups which are incorporated into the pharmaceutical end product must be amenable to hydrolytic or metabolic cleavage in vivo. The starting materials needed for the vanous processes described above are commercially available or can be readily prepared by known methods.
ILLUSTRATIVE SYNTHETIC METHODS I. Methods for Derivatizing -OH and -SH Functions in Drugs
METHOD A
The drug containing a reactive hydroxyl or mercapto function is reacted with a phosphorylating agent such as 2-chloromethyl-4-nitrophenylphosphorodichloridate, followed by hydrolysis, followed by reaction with methanol, to afford the intermediate phosphate diester. The resultant intermediate is then reacted with cesium fluoride and
Figure imgf000073_0001
in an organic solvent such as dimethylformamide to give the desired compound of formula (la) or (lb). The representative drugs depicted below ("Starting Material") may be derivatized in this manner, first to the phosphate diester intermediate
("Intermediate"), and then to the corresponding compound of formula (la) or (lb) ("Final Product").
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
0
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
In the process of METHOD A described above, the intermediates and final products shown are not always the only intermediates and final products obtained in significant amounts; yet other intermediates and final products of formulas (la) and (lb) may be obtained which are encompassed by the present invention.
Thus, for example, when the drug containing a reactive hydroxyl or mercapto function also contains a reactive imide or amide function, in addition to the major product which is depicted above, there may be isolated a minor product in which the hydroxy function is derivatized as shown while the amide or imide function is acyloxyalkylated. The minor product will be produced in a larger amount if excess
Figure imgf000128_0001
or analogous reagent is employed in the final step. In the case of zidovudine
(AZT), the minor product resulting from METHOD A has the formula
Figure imgf000128_0002
while the major product is that depicted with METHOD A. Drugs such as tiazofurin, 5-FUDR (floxuridine), ribavirin, 6-azauridine, acyclovir, 3-deazaguanosine, ganciclovir (DHPG), 6-azauridine, idoxuridine, trifluridine, dideoxylnosine (DDI), dideoxydehydrothymidine, BVDU, FIAU, FMAU, FIAC, Ara-T, FEAU, seienazofurin and buciclovir
(DHBG) may be acyloxyalkylated at the amide or imide nitrogen in a similar manner to zidovudine; derivatives of this type are even more lipophilic than the major products depicted hereinabove where the imide or amide group is unreacted.
As another example, when the selected drug contains multiple reactive hydroxyl functions, a mixture of intermediates and final products may again be obtained. In the unusual case in which all hydroxy groups are equally reactive, there is not expected to be a predominant product (unless all would give the same product, e.g. ganciclovir), as each mono-substituted product will be obtained in approximately equal amounts, while a lesser amount of multiply-substituted product will also result. Generally speaking, however, one of the hydroxyl groups will be more susceptible to substitution than the other(s), e.g. a primary hydroxyl will be more reactive than a secondary hydroxyl, an unhindered hydroxyl will be more reactive than a hindered one. Consequently, the major product will be a mono-substituted one in which the most reactive hydroxyl has been derivatized, while other mono-substituted and multiply-substituted products may be obtained as minor products. In this instance, too, control of the amount of or analogous reagent affects the
Figure imgf000129_0001
amounts of the various products obtained. Drugs which may afford other hydroxy-substituted (mono- or multiply-substituted) derivatives in addition to those depicted for METHOD A include pentostatin (2'-deoxycoformycin), vidarabine (Ara-A), 5-FUDR (floxuridine), cytarabine (Ara-C), apomorphine, morphine, nalbuphine, naiorphine, buprenorphine, (S)-9-(2,3-dihydroxyρropyl)adenine, ganciclovir (DHPG), idoxuridine, trifluridine, BVDU, FIAU, FMAU, FIAC, Ara-T, FEAU, cyclaradine, buciclovir
(DHBG), ethinyl estradiol, estradiol, ethynodiol, cortisone, hydrocortisone, betamethasone, dexamethasone, flumethasone, fluprednisolone,
methylprednisolone, meprednisone, prednisolone, prednisone,
triamcinolone, triamcinolone acetonide, cortodoxone, fludrocortisone, flurandrenolide, paramethasone and the like.
In the special instance in which the selected drug contains multiple reactive hydroxyl functions which are positioned in such a manner that they may form an undesired cyclic product when subjected to the process of METHOD A, a synthetic route other than that of METHOD A may be generally preferred. Thus, in the case of nucleoside-type antivirals and antineoplastics having hydroxyls at both the 2'- and 3'-positions as well as at the 5'-position, a product which is derivatized only at the 5'-position (i.e. as depicted with METHOD A) is preferred, and such product is most advantageously produced by use of a transitory protecting group such as the acetonide group described in METHOD F hereinbelow. Drugs such as dihydro-5-azacytidine, tiazofurin, 6-MMPR, 5-azacytidine, ribavirin, 3-deazaguanosine, 6-azauridine, 5,6-dichoro-1-β-D-ribofuranosyl-benzimidazole, 5,7-dimethyl-2-β-D-ribofuranosyl-s-triazole (1,5-a)pyrimidine, 3-deazauridine, 6-azauridine, 3-deazaaristeromycin, neplanocin A, selenazofurin and 3-deazaadenosine thus are preferably subjected to METHOD F to afford the preferred 5'-derivatized products depicted with METHOD A.
METHOD B
The process of METHOD A is repeated, except that an equivalent quantity of benzyl alcohol is used in the preparation of the intermediate phosphate diester in place of methanol. When each of the representative starting materials listed with METHOD A is subjected to this process, the intermediate phosphate diester derivative has the partial formula
Figure imgf000131_0001
as depicted in the intermediate column, and the final product of formula (la) or (lb) is as depicted in METHOD A, except that the
Figure imgf000131_0002
portion of the product is replaced with
Figure imgf000131_0003
in each instance.
METHOD C
The process of METHOD A is repeated, except that in the final step the
Figure imgf000131_0004
I reactant is replaced with an equivalent quantity of
Figure imgf000131_0005
When each of the representative starting materials listed with METHOD A is subjected to this process, each of the intermediate phosphate diester derivatives is as depicted in the intermediate column, while the corresponding final product of formula (la) or (lb) differs from that depicted in METHOD A in that the
Figure imgf000132_0001
portion of each product is replaced with
Figure imgf000132_0002
METHOD D
The process of METHOD A is repeated, except that in the final step the
Figure imgf000132_0003
reactant is replaced with an equivalent quantity of
Figure imgf000132_0004
When each of the representative starting materials listed with METHOD A is subjected to this process, each of the intermediate phosphate diester derivatives is as depicted in the intermediate column, while the corresponding final product of formula (la) or (lb) differs from that depicted in METHOD A in that the
Figure imgf000132_0005
portion of each product is replaced with
Figure imgf000133_0001
METHOD E
This is a modification of the basic method described in METHODS A-D for drugs containing multiple hydroxyl substituents, particularly for the nucleoside-type antivirals and antineoplastics. The drug selected as the starting material contains one primary hydroxyl substituent and one or more secondary hydroxyl substituents. When the drug is a nucleoside-type containing a ribofuranosyl grouping, the primary hydroxyl is in the 5'-position, while the secondary hydroxyl(s) is/are in the 2'- and/or 3'-position(s). Drugs of this type are exemplified by, but not limited to, vidarabine, cytarabine, ribavirin, 3-deazaguanosine, idoxuridine, BVDU,
FIAU, FMAU and the like.
The selected nucleoside starting material as described above is reacted with 4,4'-dimethoxytrityl chloride to give the 5'-(4,4'-dimethoxytrityl)ether derivative. The 2'- and/or 3'-hydroxy group is then esterified by reaction with a variety of acid anhydrides such as pivaloyl, benzoyl, isobutyryl or acetyl to give the 2'- and/or 3'-ester groupings. The resultant compound is then treated with acetic acid to regenerate the 5'-hydroxy moiety. The 2'- and/or 3'-protected compound with a free 5'-hydroxy group is thereafter utilized as the starting material in the process of any of METHODS A-D to give the compound of the invention with a mixed phosphate moiety at the 5'-position and protected ester grouping(s) at the 2'- and/or 3'-position(s). METHOD F
A starting material with multiple hydroxyl substituents is selected as described in the first paragraph of METHOD E, except that the selected compound must contain hydroxyls at both the 2'- and 3'-positions as well as the 5'-position, e.g. ribavirin, 3-deazaguanosine or the like. Reaction with acetone gives the 2',3'-O-acetonide. That protected intermediate can then be used as the starting material in the process of any of METHODS A-D, followed by, if desired, removal of the acetonide protecting group with formic acid, to give the same compound of the invention as depicted as the final product of METHOD A.
METHOD G
This is a variation of METHODS A-D used when the drug also contains one or more -COOH function(s) which is/are to be protected.
The drug, e.g. a valproic acid metabolite such as 5-hydroxy-2-n-propylpentanoic acid, sermatacin or the like, is first converted to the corresponding ethyl, t-butyl or similar ester grouping by well-known esterification methods. That ester is then used as the starting material and METHOD A, B, C or D is repeated to give the desired compound of the invention.
METHOD H
The process of METHOD A is modified to produce compounds in which there are two residues of hydroxyl-containing drugs. Thus, the first drug containing a reactive hydroxyl function is reacted with
2-chlorophenyl-O,O-bis[1-benzotriazolyl]phosphate in
tetrahydrofuran/pyridine in the presence of an acid scavenger, then the second drug containing a reactive hydroxyl function is reacted with the resultant intermediate in tetrahydrofuran/pyridine in the presence of an acid scavenger, to afford the desired intermediate phosphate diester. That intermediate is then reacted wtih cesium fluoride and
Figure imgf000135_0001
in an organic solvent such as dimethylformamide as set forth in METHOD A. The representative drugs depicted in the two columns headed "Starting Material #1" and "Starting Material #2" may be converted in this manner, first to the depicted intermediate ("Intermediate") and then to the corresponding compound of formula (la) ("Final Product").
It is understood that when "Starting Material #1" and "Starting Material #2 are identical, then the diester intermediate can be obtained in one step by reacting 2 equivalents of drug with 2-chlorophenyl-O,O-bis[1- benzotriazolyl]phosphate (formed in Situ by reaction of 1- hydroxybenzotriazole and anhydrous pyridine) and decomposing the product to remove the 2-chlorophenyl group. The diester intermediate can then be converted to the triester of formula (la) as described hereinabove, e.g., by use of cesium fluoride and
Figure imgf000135_0002
or by use of sodium methoxide and
Figure imgf000135_0003
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
The intermediates and final products depicted above are not always the only intermediates and final products obtained in significant amounts. When one or both drugs used as starting material also contain(s) a reactive imide or amide function, there may be isolated minor products in which the hydroxy functions are derivatized as shown while the amide or imide function(s) is/are acyloxyalkylated, e.g., as described in conjunction with METHOD A hereinabove. Similarly, as described with METHOD A, when one or both selected drugs contain(s) multiple reactive hydroxyl functions, a mixture of intermediates and final product may again be obtained, with the major product being one in which the most reactive hydroxyl in each starting material is derivatized. Moreover, as mentioned with METHOD A, some of the nucleoside-type antivirals and
antineoplastics may be prone to formation of an undesired by-product and may be more advantageously derivatized by prior formation of acetonide protecting groups and ultimate removal thereof, analogously to METHOD
F hereinabove. Other protecting group variations may also be employed, in analogous fashion to METHOD E or G hereinabove.
METHOD H may also be modified in analogous fashion to
METHOD C or D hereinabove, to give final products of formula (la) in which the
Figure imgf000166_0001
portion of each product is replaced with
as in METHOD C, or
OC
Figure imgf000166_0002
as in METHOD D.
C
Figure imgf000167_0001
II. Methods for Derivatizing Imide or Amide Functions in Drugs
METHOD I
The drug containing a reactive amide or imide functional group is reacted with formaldehyde in the presence of potassium carbonate or other suitable basic catalyst, converting the
or
Figure imgf000167_0003
Figure imgf000167_0002
group in the imide or amide, respectively, to a
or
Figure imgf000167_0005
Figure imgf000167_0004
grouping. The resultant drug with bridging group appended (hereinafter referred to as the "bridged drug") is then subjected to the multi-step process as described in METHOD A above. The representative drugs depicted below ("Starting Material") may be derivatized in this manner, first to the bridged drug (not shown), then to the phosphate diester intermediate ("Intermediate") and finally to the corresponding compound of formula (Id) or (Ie) ("Final Product").
Obviously, the variations of METHOD A described in METHODS B, C and D can be readily applied to the bridged drugs prepared in the first step of METHOD I, affording yet other compounds of formulas (Id) and (Ie).
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
METHOD J
The process of METHOD I is repeated, except that acetaldehyde is used in the first step in place of formaldehyde. The bridged drug of the type
or
Figure imgf000179_0002
Figure imgf000179_0001
is then subjected to the multi-step process described in METHOD A to afford the corresponding compounds of formulas (Id) and (Ie).
This process can be readily modified in the manner described in the final paragraph of METHOD I to give yet other compounds of formula (Id) and (Ie).
III. Methods for Derivatiziny Carboxyl Functions in Drugs
METHOD K
The drug containing a reactive carboxyl functional group is reacted with 1-chloroethyl chlorosulfate to convert the -COOH group to a
substituent, which is then reacted with the mono- or
Figure imgf000179_0003
di-cesium salt of
Figure imgf000179_0004
to afford the corresponding phosphate diester intermediate. That intermediate is then subjected to the final step of the process described in METHOD A, using cesium fluoride and
Figure imgf000180_0001
, to afford the desired compound of formula (Ic). The representative drugs depicted below ("Starting Material") may be derivatized in this manner, first to the chloroethyl derivative (not shown), then to the phosphate diester intermediate ("Intermediate") and finally to the corresponding compound of formula (Ic) ("Final Product").
Obviously, the foregoing procedure can be modified in many ways, e.g. by varying the final step as described in METHOD C, affording yet other compounds of formula (Ic).
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
METHOD L
When the drug containing a reactive carboxyl functional group is sufficiently bulky, it can hinder the -O-Z-O- bridging group. In such a case, Z can be, and preferably is, selected to be -CH2-, and METHOD K is modified by replacing the 1 -chloroethyl chlorosulfate reactant in the first step with chloromethyl sulfate, and otherwise proceeding as detailed in that method. Drugs such as oxacillin, carbenicillin, benzylpenicillin, hetacillin, nafcillin, cloxacillin, cephalothin and cefoxitin can be derivatized in this manner, first to the corresponding chloromethyl derivative by converting the -COOH group to a -COOCH2Cl group, then to the intermediate of the partial structure
Figure imgf000192_0001
and then to the desired compound of formula (Ic) having the partial formula
Figure imgf000192_0002
This method can of course be modified in many ways, e.g. by varying the final step as described in METHOD C. IV. Methods for Derivatizing Amino Functions in Drugs
METHOD M
The drug containing a reactive amino functional group is reacted with 1-chloroethyl chloroformate,
Figure imgf000193_0001
to replace a hydrogen atom of the drug's amino group with a
Figure imgf000193_0002
grouping. Subsequent reaction with the mono- or di-cesium salt of
Figure imgf000193_0003
affords the corresponding phosphonic acid intermediate. That intermediate is then subjected to the final step of the process described in
METHOD A, using cesium fluoride and
Figure imgf000193_0004
to afford the desired compound of formula (If). The representative drugs depicted below ("Starting Material") may be derivatized in this manner, first to the 1- chloroethoxycarbonyl derivative (not shown), then to the phosphate diester intermediate ("Intermediate") and finally to the corresponding compound of formula (If) ("Final Product").
The foregoing procedure can be modified in many ways, for example by varying the final step as described in METHOD C, affording yet other compounds of formula (If). Further, when the drug is sufficiently bulky, the process of METHOD M may be modified by utilizing chloromethyl chloroformate as the reactant in the first step.
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
METHOD N
This is a variation of METHOD M used when the drug also contains one or more -COOH functions which is/are to be protected.
The drug, e.g. GABA, melphalan, tryptophan or the like, is first convened to the corresponding ethyl, t-butyl or similar ester grouping by well-known esterification methods. That ester is then used as the starting material and METHOD M is repeated to give the desired compound of the invention.
In order to further illustrate the compounds of the invention and the methods for their preparation, the following synthetic examples are given, it being understood that same are intended only as illustrative, as many modifications in materials and methods will be apparent to those skilled in the art.
In the examples to follow, all melting points were taken on a Mel-Temp apparatus and are not corrected. Elemental analyses were performed at Atlantic Microlabs, Inc., Atlanta, Georgia.
EXAMPLE 1
To a stirred solution of 1.3 mL (13.9 mmol) of phosphorus oxychloride (POCl3) in 4 mL of absolute ether was added a solution of 1 g (3.47 mmol) of testosterone in 4 mL of pyridine. The addition was carried out at -5° to 0°C. over a period of one hour under a stream of nitrogen. The resultant mixture was then stirred overnight in an ice bath. The white precipitate which formed was removed by filtration and the filtrate was evaporated to give 1.09 g of an oily product. The crude material contained a small amount of pyridine and ether by its NMR spectra; the amount of the phosphorodichloridate of the formula
Figure imgf000207_0001
was calculated from the NMR spectra as 2.14 mmol. The crude material was mixed with 10 mL of tetrahydrofuran and 4 mL of dichloromethane. Into this suspension was dropped a mixture of 0.086 mL (2.1 mmol) of methanol, 0.17 mL (2.1 mmol) of pyridine and 5 mL of tetrahydrofuran over a 30 minute period in an ice bath. The mixture was stirred at room temperature overnight, then was poured slowly into cold water. An insoluble gummy material was separated by decantation and washed with water. The supernatant was evaporated until the organic solvents were removed. The gummy material was dissolved in dichloromethane and the residue was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Thin layer chromatography of the crude material showed the presence of the desired diester of the formula
Figure imgf000208_0001
however, the crude material was too impure to allow easy isolation of the diester. A more successful route to the diester proved to be the process detailed in EXAMPLE 4 hereinbelow.
EXAMPLE 2
A mixture of 2-chloromethyl-4-nitrophenol (5 g, 26.66 mmol) and POCl3 (6.3 mL, 66.65 mmol) was refluxed for 6 hours in the presence of a catalytic amount (270 mg) of potassium chloride until the evolution of hydrogen chloride ceased. Excess POCl3 was removed by evaporation.
The viscous oily residue was distilled under reduced pressure to give 5.06 g (62% yield) of 2-chloromethyl-4-nitrophenylphosphorodichloridate of the formula
Figure imgf000208_0002
The phosphorodichloridate was obtained as a pale yellow viscous liquid boiling at 157-162° C. The identity of the product was confirmed by NMR analysis.
EXAMPLE 3 To a stirred solution of 2-chloromethyl-4-nitrophenylphosphorodichloridate (1.18 g, 3.88 mmol) in 6 mL of anhydrous tetrahydrofuran was added dropwise, at -5° to 0°C. over a one hour period under a nitrogen stream, a mixture of 1 g (3.47 mmol) of testosterone and 0.28 mL (3.47 mmol) of dry pyridine in 8 mL of anhydrous tetrahydrofuran. The resultant mixture was stirred overnight at room temperature, then was poured into 20 mL of cold water, with stirring, at a temperature below 15 °C. The tetrahydrofuran was evaporated and the residue was extracted with three 20 mL portions of dichloromethane. The combined extracts were washed with brine and dried over anhydrous magnesium sulfate. The crude product was purified by column chromatography on silica gel.
Unreacted testosterone was eluted with a mixture of CH2C12 and ethyl acetate (1:1, volume/ volume), then the desired diester of the formula
Figure imgf000209_0001
was eluted with a mixture of CH2Cl2 and methanol (4:1, volume/ volume). The product was obtained as a white amorphous solid (1.7 g, 91 % yield). Its identity was confirmed by NMR analysis.
EXAMPLE 4 A mixture of 8.13 g (15.11 mmol) of the diester produced in
EXAMPLE 3, 1.84 mL (45.33 mmol) of dry methanol and 30 mL of dry pyridine was allowed to stand at room temperature for 2 days. Then, dry methanol (5 mL) was added and the resultant mixture was refluxed at 90- 100° C. for 8.5 hours. The reaction mixture was cooled and the yellow precipitate which formed was removed by filtration and washed with chloroform to give 3.55 g (88%) of 1-(2'-hydroxy-5'-nitro)benzyl pyridinium chloride. The filtrate was purified by column chromatography on silica gel with a mixture of CH2Cl2 and methanol (8:1 and 4: 1, volume/volume) to give 4.67 g (81% yield) of the desired mixed diester of the formula
Figure imgf000210_0001
The identity of the product was confirmed by NMR analysis and by mass spectroscopy. Mass (FAB) m/e = 383 (MH+). EXAMPLE 5
The mixed diester obtained in EXAMPLE 4 (340 mg, 0.89 mmol) was combined with 0.47 mL of 2N aqueous sodium hydroxide solution and 5 mL of water, with stirring. Insoluble materials were removed by filtration. To the yellow filtrate, a few drops of phenolphthalein solution were added. Dilute nitric acid was then added dropwise until the red color disappeared at pH 8-9. A solution of 151 mg (0.89 mmol) of silver nitrate in 1 mL of water was added in one portion in the dark. The resultant mixture was refrigerated overnight, then concentrated to a volume of 2 mL by evaporation. The residue was cooled and the precipitate was removed by filtration and dried at room temperature under vacuum to afford the silver salt of the formula
Figure imgf000211_0001
as a grayish white powder (49 mg, 11 % yield).
EXAMPLE 6 Sodium iodide (24.73 g, 165 mmol) was added to a solution of chloromethyl pivalate (5 g, 33 mmol) in dry acetone (40 mL). The mixture was stirred for 4 hours at room temperature. Insoluble materials were removed by filtration and washed with fresh acetone. The filtrate was evaporated, and hexane and 5% aqueous sodium thiosulfate solution were added to the residue. The mixture was thoroughly shaken, then the organic layer was separated and washed with 5 % aqueous sodium thiosulfate solution. Drying over sodium sulfate, followed by evaporation of the solvent, afforded 7.03 g (88% yield) of yellow liquid. The structure of the product, (CH3)3CCOOCH2I, was confirmed by NMR analysis.
EXAMPLE 7
The silver salt obtained in EXAMPLE 5 was suspended in 1 mL of dry benzene. Into the stirred suspension, was slowly added dropwise a solution of 30 mg (0.12 mmol) of iodomethyl pivalate (prepared as in EXAMPLE 6) in 1 mL of dry benzene at room temperature. The resultant mixture was stirred overnight in the dark under a stream of nitrogen.
Insoluble materials were removed by filtration and washed with benzene. The filtrate was washed, first with 5% aqueous sodium thiosulfate
(Na2S2O3) solution, and then three times with water, then was dried over anhydrous magnesium sulfate. Evaporation of the solvent afforded a residue which was purified by preparative thin layer chromatography (7 cm × 20 cm × 2 mm) with a 3:2 mixture of ethyl acetate and hexane as eluent to give 5 mg (10% yield) of the triester of the formula
Figure imgf000212_0001
as a viscous oil. The identity of the product was confirmed by NMR analysis and by mass spectroscopy. Mass (FAB) m/e = 497 (MH+).
EXAMPLE 8
Potassium fluoride (67 mg, 1.16 mmol) and iodomethyl pivalate (132 mg, 0.53 mmol) were stirred together in 0.55 mL of dry
dimethylformamide at room temperature for one minute. The mixed diester obtained in EXAMPLE 4 (200 mg, 0.53 mmol) was then added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted three times with ether. The ether extracts were combined, washed three times with equal volumes of water to remove dimethylformamide and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 45 mg of crude product, which was purified by preparative thin layer chromatography (7 cm × 20 cm × 2 mm) with a 3:2 mixture of ethyl acetate and hexane. Elution of the collected part of the silica gel with ethyl acetate gave 31 mg (12% yield) of the triester of the formula
Figure imgf000213_0001
NMR values were the same as those for the product of EXAMPLE 7. EXAMPLE 9
The mixed diester prepared in EXAMPLE 4 (3.45 g, 9.02 mmol), iodomethyl pivalate (4.37 g, 18 mmol) and cesium fluoride (3.01 g, 19.84 mmol) were combined in 20 mL of dimethylformamide and stirred at room temperature for 4 hours under a stream of nitrogen. Then, 150 mL of ethyl ether were added and the resultant mixture was stirred for 5 minutes. Insoluble materials were removed by filtration and the precipitates were extracted twice with ether. The combined ether extracts were washed, twice with equal volumes of water, then with 5% aqueous sodium thiosulfate solution, and again with water. Drying over sodium sulfate and evaporation of the extracts gave a crude oily product, which was purified by column chromatography on silica gel (ethyl acetate/hexane, 3:4 to 3:2). The desired triester of the formula
Figure imgf000214_0001
identical to the products of EXAMPLES 7 and 8, was obtained as a slightly viscous yellow oil (2.55 g, 57% yield). Anal. Calcd. for
C26H41O7P: C, 62.88; H, 8.32. Found: C, 62.99; H, 8.38. EXAMPLE 10
To a mixture of hexanoyl chloride (25 g, 0.186 mol) and
paraformaldehyde (5.58 g, 0.186 mol) in an ice bath was added a catalytic quantity (550 mg) of zinc chloride. An exothermic reaction resulted.
After the reaction subsided, the mixture was heated at 90 to 100° C. for 4.5 hours. Purification by reduced distillation gave 22.79 g of the desired compound as a colorless liquid in 75% yield, boiling point 37-40° C./0.55 mm. NMR analysis confirmed the identity of the product as chloromethyl hexanoate, CH3(CH2)4COOCH2Cl. EXAMPLE 11
Chloromethyl hexanoate (205 mg, 1.25 mmol) was stirred with sodium iodide (900 mg, 6.0 mmol) in 3 mL of dry acetone for 4 hours at room temperature. Work-up followed the procedure detailed in
EXAMPLE 6 above for the preparation of iodomethyl pivalate.
Iodomethyl hexanoate, CH3(CH2)4COOCH2I, was obtained as a yellow oil in 78% yield. NMR values were consistent with the assigned structure.
EXAMPLE 12
The procedure of EXAMPLE 9 is repeated, except that an equivalent quantity of iodomethyl hexanoate is substituted for the iodomethyl pivalate there employed. Obtained in this manner is the triester of the formula
Figure imgf000216_0001
EXAMPLE 13
The general procedure detailed in EXAMPLE 3 is repeated, utilizing an equivalent quantity of zidovudine in place of the testosterone there employed. Obtained in this manner is the diester of the formula
Figure imgf000216_0002
EXAMPLE 14
The general procedure detailed in EXAMPLE 4 is repeated.
utilizing an equivalent quantity of the product of EXAMPLE 13 in place of the diester starting material there employed. Obtained in this manner is the mixed diester of the formula
Figure imgf000217_0001
EXAMPLE 15
The general procedure detailed in EXAMPLE 9 is repeated, utilizing an equivalent quantity of the product of EXAMPLE 14 in place of the mixed diester there employed. Obtained in this manner is the desired triester of the formula
Figure imgf000218_0001
EXAMPLE 16
Hexanoyl chloride (5.5 mL, 37 mmol) and acetaldehyde (4.2 mL, 74 mmol) were combined under a stream of nitrogen and stirred in an ice bath. To that solution was added a catalytic quantity of zinc chloride.
Within 30 seconds, an exothermic reaction (-8° C.→ 43° C.) occurred.
The reaction mixture was maintained in an ice bath for 30 minutes, then was poured into 100 mL of hexane. The hexane solution was washed successively with saturated aqueous sodium bicarbonate solution (2 × 50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to give 7.81 g of 1'-chloroethyl hexanoate,
CH3(CH2)4COOCH(CH3)Cl, as a slightly yellow oil. It was used in the procedure detailed in EXAMPLE 17 below without further purification. NMR analysis confirmed the identity of the product. EXAMPLE 17
Sodium iodide (27.9 g, 186 mmol) and acetonitrile (39 mL) were combined under a stream of nitrogen and stirred at a temperature below 10°C. To that solution was added dropwise 1'-chloroethyl hexanoate (7.80 g) in 39 mL of acetonitrile at a temperature below 10° C. The reaction mixture was stirred for 3 days at 0° to 10° C. Insoluble materials were removed by filtration and washed with acetonitrile. The filtrate was evaporated and hexane (100 mL) and water (100 mL) were added to the residue. The mixture was thoroughly shaken, then the organic layer was separated and washed successively with 5% aqueous sodium thiosulfate solution (100 mL × 2) and water (100 mL). Each aqueous layer was extracted with one 50 mL portion of hexane. The hexane layers were combined, dried over magnesium sulfate, filtered and concentrated to give 7.77 g of yellow oil (77.5% yield). The crude 1'-iodoethyl hexanoate, CH3(CH2)4COOCH(CH3)I, was used in the procedure of EXAMPLE 18 without further purification. NMR analysis confirmed the identity of the product.
EXAMPLE 18
The mixed diester prepared in EXAMPLE 4 (2.26 g, 6 mmol), 1'-iodoethyl hexanoate (3.24 g, 12 mmol), cesium fluoride (2.01 g, 13.2 mmol) and dimethylformamide (22 mL) were combined under a stream of nitrogen and stirred at room temperature for 19.5 hours. The reaction mixture was then poured into 300 mL of ether and washed successively with water (100 mL) 5% aqueous sodium thiosulfate solution (100 mL) and again with water (100 mL). Each aqueous layer was extracted with one 100 mL portion of ether. The ether layers were combined, dried over magnesium sulfate, filtered and concentrated to give a residual oil. The crude material was purified by column chromatography on silica gel using hexane-ethyl acetate (1 to ~0:1, gradation) as eluent to give a yellow oil in 19.4% yield. The product, whose structure was confirmed by NMR, elemental analysis and mass spectroscopy, had the foπnula
Figure imgf000220_0001
Mass (FAB): m/e = 525 (MH+). Anal. Calcd. for C28H45O7P: C, 64.10; H, 8.65. Found: C, 63.97; H, 8.71.
EXAMPLE 19
To a solution of dry 1-hydroxybenzotriazole (3.24 g, 24 mmol), anhydrous pyridine (6.47 mL, 80 mmol) and dry tetrahydrofuran (50 mL), a solution of 2-chlorophenyl phosphorodichloridate (1.98 mL, 12 mmol) in dry tetrahydrofuran (20 mL) was added dropwise, under a stream of nitrogen, while maintaining the reaction mixture at room temperature in a water bath. Stirring was continued for approximately 1 hour, then 5.34 g (20 mmol) of 3'-azido-3'-deoxythymidine (zidovudine) were added in one portion and the mixture was stirred at room temperature for approximately 18 hours under a stream of nitrogen. The resulting suspension was poured into 500 mL of methylene chloride and washed twice with 250 mL portions of (C2H5)3NH+CO2 buffer (prepared by passing a stream of CO2 gas through a cooled 1M solution of triethylamine in deionized water until a neutral solution was obtained). The organic layer was dried over magnesium sulfate, filtered and evaporated to give 11.7 g of crude oil. The crude materials were purified by column chromatography on Florisil® (magnesium silicate, 60 g), using ethyl acetate as eluent. Column chromatography was repeated as before, affording 5.24 g of bis[5'-(3'-azido-3'-deoxythymidyl)]-2-chlorophenyl phosphate as a white amorphous powder in 74.8% yield having the formula
Figure imgf000221_0001
The identity of the product was confirmed by mass spectroscopy and NMR analysis.
Bis[5'-(3'-azido-3'-deoxythymidyl)]-2-chlorophenyl phosphate (0.87 g, 1.2 mmol), pyridine-2-aldoxime (0.90 g, 7.4 mmol), dioxane (8.7 mL), water (8.7 mL) and 1,1,3,3-tetramethylguanidine (0.75 mL, 6 mmol) were combined and the mixture was stirred for approximately 1 hour at room temperature. The resultant solution was added to 30 mL of Amberiite®ion-exchange resin IR-120 (73 meq., H+ form by HCl aq.) and stirred for 1 minute. The ion-exchange resin was removed by filtration and the filtrate was evaporated. The residual syrup was dropped into 200 mL of vigorously stirred ether. The precipitate which formed was collected by filtration and dried in vacuo. There was thus obtained 0.66 g (90.4% yield) of bis[5'-(3'-azido-3'-deoxythymidyl)]phosphate as a white amorphous powder. The structure of the product.
Figure imgf000222_0001
was confirmed by NMR analysis.
EXAMPLE 20
Repetition of EXAMPLE 9, using an equivalent quantity of bis [5'-(3'-azido-3'-deoxythymidyl)]phosphate in place of the mixed testosterone diester there employed, affords the triester of the formula
Figure imgf000223_0001
EXAMPLE 21
To a stirred solution of bis[5'-(3'-azido-3'-deoxythymidyl)]phosphate (0.60 g, 1 mmol) in 6 mL of dry methanol, sodium methoxide (0.23 mL, 25% by weight in methanol, 1 mmol) was added and the mixture was stirred for 5 minutes at room temperature under a stream of nitrogen. The resulting solution was evaporated and dried in vacuo for a minimum of 30 minutes. To the amorphous residue, hexamethylphosphoramide (6 mL) and chloromethylpivalate (1.51 g, 10 mmol) were added. The reaction mixture was then stirred in an oil bath (at 80°C.) for 3 hours under a stream of nitrogen. The resulting suspension was poured into 30 mL of ethyl acetate and washed with 50 mL of water and 30 mL of saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with 30 mL of ethyl acetate. The organic layers were combined and washed with 40 mL of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residual crude oil was purified by column chromatography over silica gel, using a mixture of ethyl acetate and hexane (5: ½→ 10:0, gradient) as an eluent. Two products were isolated and their structure confirmed by NMR and mass spectroscopic data. The major product, recovered in 16.9% yield (0.12 g) was the triester of the formula
Figure imgf000224_0001
The other significant product, recovered in 11.0% yield (0.09 g), was another compound of the invention containing two zidovudine residues, one of which contained an additional pivalyloxymethyl residue. That product was assumed to have the structural formula
Figure imgf000225_0001
Figure imgf000225_0002
EXAMPLE 22
To a stirred solution of bis[5'-(3'-azido-3'-deoxythymidyl)]phosphate (5.30 g, 8.9 mmol) in 53 mL of dry methanol, sodium methoxide (2.03 mL, 25% by weight in methanol, 8.9 mmol) was added and the mixture was stirred for 5 minutes at room temperature under a stream of nitrogen. The resulting solution was evaporated and dried in vacuo for 30 minutes. To the amorphous residue, 53 mL of
hexamethylphosphoramide (HMPA) and 12.82 mL (89 mmol) of chloromethyl pivalate were added and stirred for 3 hours in an oil bath (80°C.) under a stream of nitrogen. The resulting suspension was poured into 200 mL of ethyl acetate and washed with 500 mL of water and 60 mL of saturated sodium bicarbonate solution. The aqueous layer was extracted with 200 mL of ethyl acetate. The organic layers were combined and washed with 200 mL of saturated aqueous sodium bicarbonate solution, then dried over magnesium sulfate, filtered and evaporated. The residual crude oil was purified by column chromatography over silica gel, using a mixture of ethyl acetate and hexane (5:5→10:0, gradient) as eluent. The major product, recovered in 37.1% yield (2.64 g), was identical to the major product of EXAMPLE 21. NMR (CDCl3) δ 1.23 (9H, s), 1.89 (6H, s), 2.30-2.60 (4H, m), 3.85-4.50 (8H, m), 5.67 (2H, d, J =12 Hz),
5.95-6.20 (2H, m), 7.27 (2H, s), 9.95 (2H, bs). Hemental analysis: Calculated for C26H35N10O12P: C, 43.95; H, 4.96; N, 19.71. Found:
C, 43.98; H, 5.00; N, 19.62. The minor product, identical to the minor product of EXAMPLE 21, was recovered in 3.4% yield (0.28 g). NMR (CDCl3): δ 1.18 (9H, s), 1.22 (9H, s), 1.91 (3H, s), 1.95 (3H, s), 2.30- 2.55 (4H, m), 3.85-4.45 (8H, m), 5.65 (2H, d, J= 12Hz), 5.92 (2H, s), 5.90-6.25 (2H, m), 7.24 (1H, s), 7.30 (1H, s), 9.11 (1H, bs).
Elemental analysis: Calculated for C32H45N10O14P: C, 46.60; H, 5.50; N, 16.98. Found: C, 46.61; H, 5.53; N, 16.96. The compounds of formula (I) which are provided by this invention are typically administered to mammals by incorporating the selected compound into a pharmaceutical composition comprising the compound or a non-toxic pharmaceutically acceptable salt thereof and a non-toxic pharmaceutically acceptable carrier therefor. The compound or its salt is employed in an effective amount, i.e. an amount sufficient to evoke the desired pharmacological response. The compounds of the invention are designed to elicit the kind of pharmacological response which would be obtained by delivery of the parent drug itself to the desired site of action, especially to the brain. Thus, for example, when the parent drug is an antiviral, the derivative of formula (I) will be administered in an amount sufficient to elicit an antiviral response; when the parent drug is an antineoplastic, the derivative of formula (I) will be employed in an amount sufficient to elicit an antineoplastic, i.e. anticancer or antitumor, response; when the parent drug is an antibiotic, the derivative of formula (I) will be used in an amount sufficient to evoke an antibiotic response; when the parent drug is a steroid sex hormone, the derivative of formula (I) will be used in an amount sufficient to evoke an androgenic or estrogenic or progestational effect (depending on the identity of the parent drug); when the parent drug is an antiinflammatory agent, the derivative of formula (I) will be administered in an amount sufficient to elicit an antiinflammatory response; and so forth.
Suitable non-toxic pharmaceutically acceptable carriers for use with the selected compound of formula (I) will be apparent to those skilled in the art of pharmaceutical formulation. See, for example, Remington's
Pharmaceutical Sciences, seventeenth edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, PA (1985). Obviously, the choice of suitable carriers will depend upon the exact nature of the particular dosage form selected, as well as upon the identity of the compound to be administered. The therapeutic dosage range for a compound according to this invention will generally be the same as, or less than, that which would characteristically be used for administration of the parent drug itself.
Naturally, such therapeutic dosage ranges will vary with the particular compound of formula (I) used, the size, species and condition of the subject, the severity of the subject's condition, the particular dosage form employed, the route of administration and the like. And the quantity of given dosage form needed to deliver the desired dose will of course depend upon the concentration of the compound of formula (I) in any given pharmaceutical composition/dosage form thereof. In addition, to further enhance the site-specificity of the compounds of the invention, the active ingredient may be formulated into a sustained release carrier system and/or a route of administration may be selected to slowly release the chemical, e.g. subcutaneous implantation or transdermal delivery.
Routes of administration contemplated for the compounds of formula (I) and pharmaceutical compositions containing them are any of the routes generally used for treatment of the types of conditions for which the parent drugs are administered. These include parenteral (intravenous, intramuscular, subcutaneous), vaginal, rectal, nasal, oral and buccal routes. Appropriate dosage forms for these routes of administration will be apparent to those skilled in the art.
Obviously, in the case of diagnostic agents, the dosage of the formula (I) compound used will be a quantity sufficient to deliver to the target body area an amount of radioisotope, stable isotope or the like which can be effectively detected by radioimaging or other detection means. The amount of radioisotope, stable isotope or the like present in the dosage form will be within or below the ranges conventionally used for diagnostic purposes.
While the invention has been described in terms of various preferred embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims.

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula
Figure imgf000229_0001
or a pharmaceutically acceptable salt thereof, wherein [D] is the residue of a drug having a reactive functional group, said functional group being attached, directly or through a bridging group, via an oxygen-phosphorus bond to the phosphorus atom of the
Figure imgf000229_0002
moiety; R1 is C1-C8 alkyl, C6-C10 aryl or C7-C 12 aralkyl, with the proviso that when [D] is the residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the
Figure imgf000229_0003
moiety via an oxygen-phosphorus bond, then R1, taken together with the adjacent oxygen atom, can also be the residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the
Figure imgf000230_0001
moiety via an oxygen-phosphorus bond, -OR, being the same as or different from [D]; R2 is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl; and
R3 is selected from the group consisting of C1-C8 alkyl; C2-C8 alkenyl having one or two double bonds; (C3-C7 cycloalkyl)-CrH2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion; (C6-C10 aryloxy)C1-C8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-CrH2r- wherein r is zero, one, two or three and phenyl is unsubstituted, or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms.
2. A compound of the formula
or
Figure imgf000230_0002
Figure imgf000230_0003
or a pharmaceutically acceptable salt thereof, wherein D-O- is the residue of a drug having a reactive hydroxyl functional group, the oxygen atom of said functional group being bonded to the phosphorus atom of the
Figure imgf000231_0001
moiety; D-S- is the residue of a drug having a reactive mercapto functional group, the sulfur atom of said functional group being bonded to the phosphorus atom of the
Figure imgf000231_0002
moiety; R1 is C1-C8 alkyl, C6-C10 aryl or C7-C12 aralkyl, with the proviso that R, in formula (la), taken together with the adjacent oxygen atom, can also be the residue of a drug having a reactive hydroxyl functional group, the oxygen atom of said functional group being bonded to the phosphorus atom of the
Figure imgf000231_0003
moiety, -OR1 being the same as or different from D-O-; R2 is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl; and R3 is selected from the group consisting of C1-C8 alkyl; C2-C8 alkenyl having one or two double bonds; (C3-C7 cycloalkyl)-CrH2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion; ( C6-C10 aryloxy) C1-C8, alkyl; 2-, 3- or 4- pyridyl; and phenyl-CrH2r- wherein r is zero, one, two or three and phenyl is unsubstituted. or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms.
3. A compound according to Claim 2, wherein R1 is methyl.
4. A compound according to Claim 2, wherein R2 is hydrogen.
5. A compound according to Claim 2, wherein R3 is C1-C8 alkyl.
6. A compound according to Claim 5, wherein R3 is (CH3)3C- or CH3(CH2)4-.
7. A compound according to Claim 2, having formula (la).
8. A compound according to Claim 7, wherein D-O- is the residue of a drug having a reactive hydroxyl functional group, said drug being selected from the group consisting of steroid sex hormones, antivirals, tranquilizers, anticonvulsants, antineoplastics, hypotensives,
antidepressants, narcotic analgesics, narcotic antagonists and
agonist/antagonists, CNS anticholinergics, stimulants, anesthetics, antiinflammatory steroids, nonsteroidal antiinflammatory agents/analgesics, antibiotics and CNS prostaglandins.
9. A compound according to Claim 8, wherein the drug is an androgenic, estrogenic or progestational steroid sex hormone or an antiinflammatory steroid.
10. A compound according to Claim 9, wherein the drug is testosterone, methyl testosterone, mestranol, quinestrol, ethinyl estradiol, estrone, estradiol, estriol, estradiol 3-methyl ether, estradiol benzoate, norgestrel, norethindrone, ethisterone, dimethisterone, allylestrenol, cingestol, ethynerone, lynestrenol, norgesterone, norvinisterone, ethynodiol, oxogestone, tigestol, norethynodrel, cortisone, hydrocortisone, betamethasone, dexamethasone, flumethasone, fluprednisolone, methyl prednisolone, meprednisone, prednisolone, prednisone, triamcinolone, triamcinolone acetonide, cortodoxone, fludrocortisone, flurandrenolide or paramethasone.
1l. A compound according to Claim 8, wherein the drug is an antiviral or an antineoplastic.
12. A compound according to Claim 11, wherein the antiviral or antineoplastic is of the nucleoside type.
13. A compound according to Claim 12, wherein the drug is zidovudine, ribavirin, (S)-9-(2,3-dihydroxypropyl)adenine, 6-azauridine, acyclovir, 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole, 5,7-dimethyl-2-β-D-ribofuranosyl-s-triazole (1,5-a)pyrimidine, 3-deazauridine, 3-deazaguanosine, ganciclovir, 6-azauridine, idoxuridine, dideoxycytidine, trifluridine, dideoxyinosine, dideoxydehydrothymidine, dideoxyadenosine, BVDU, FIAU, FMAU, FIAC, Ara-T, FEAU, cyclaradine, 6-deoxyacyclovir, 3-deazaaristeromycin, neoplanocin A, buciclovir, selenazofurin, 3-deazaadenosine, cytarabine, 5-FUDR, vidarabine, tiazofurin, 3'-fluoro-2',3'-dideoxythymidine, 1-(2,3-dideoxy-β-D-glycero-pent-2-enofuranosyl)thymine, 3'-fiuoro-2',3'-dideoxy-5-chlorouridine, 5-(2-chloroethyl)-2'-deoxyuridine, 5-ethyl-2'-deoxyuridine, 5-(1-hydroxy-2-chloroethyl)-2'-deoxyuridine, 5-(1-methoxy-2-bromoethyl)-2'-deoxyuridine, 5-(1-hydroxy-2-bromo-2-(ethoxycarbonyl)ethyl)-2'-deoxyuridine, 5-(1-hydroxy-2-iodo-2-(ethoxycarbonyl)ethyl)-2'-deoxyuridine, 3'-azido-2',3'-dideoxy-5-bromouridine, 3'-azido-2',3'-dideoxy-5-iodouridine, 3'-azido-2',3'-dideoxy-5-methyluridine, 3'-fluoro-2',3'-dideoxyuridine, Ara-AC, pentostatin, dihydro-5-azacytidine, sangivamycin, 6-MMPR, azacitidine, uridine, thymidine, cyclocytidine, triciribine or fludrabine.
14. A compound according to Claim 13, wherein the drug is zidovudine.
15. A compound according to Claim 2, having the structural formula
Figure imgf000234_0001
16. A compound according to Claim 2, having the structural formula (la) wherein R1, taken together with the adjacent oxygen atom, is the residue of a drug having a reactive hydroxyl function.
17. A compound according to Claim 16, wherein -OR1 and D-O-are identical drug residues.
18. A compound according to Claim 17, wherein each of -OR1 and D-O-, which are identical, is a residue of an antiviral or antineoplastic of the nucleoside type.
19. A compound according to Claim 18, wherein each of -OR1 and D-O- is a residue of zidovudine.
20. A compound according to Claim 18, wherein each of -OR1 and D-O- is a residue of dideoxyinosine.
21. A compound according to Claim 16, wherein -OR, and D-O-are different drug residues.
22. A compound according to Claim 21, wherein each of -OR1 and D-O-, which are different, is a residue of an antiviral or
antineoplastic.
23. A compound according to Claim 22, wherein each of -OR1 and D-O-, which are different, is a residue of an antiviral.
24. A compound according to Claim 21, wherein one of -OR1 and D-O- is a residue of an estrogen and the other of -OR1 and D-O- is a residue of a progestin.
25. A compound according to Claim 21, wherein one of -OR1 and D-O- is a residue of an antibiotic and the other of -OR1 and D-O- is a residue of an antiinflammatory agent.
26. A compound according to Claim 23, wherein each antiviral is of the nucleoside type.
27. A compound according to Claim 21, wherein one of -OR1 and D-O- is a residue of a nucleoside antiviral and the other of -OR1 and D-O-is a residue of an enzyme inhibitor for preventing deactivation of said antiviral.
28. A compound according to Claim 27, wherein the nucleoside antiviral is susceptible to deamination by adenosine deaminase, and the enzyme inhibitor is an adenosine flraminase inhibitor.
29. A compound according to Claim 27, wherein the nucleoside antiviral is susceptible to deamination by cytidine-deoxycytidine
deaminase, and the enzyme inhibitor is a cytidine-deoxcycytidine deaminase inhibitor.
30. A compound according to Claim 27, wherein the nucleoside antiviral is susceptible to cleavage by thymidine or uridine phosphotylase, and the enzyme inhibitor is a thymidine-uridine phosphorylase inhibitor.
31. A compound according to Claim 23, wherein each of -OR1 and D-O-, which are different, is a residue of an antiviral having activity against DNA viruses.
32. A compound according to Claim 31, wherein each of -OR1 and D-O-, which are different, is a residue of an antiviral selected from the group consisting of ACV, BVDU, DHPG, Ara-T, and EtUdR.
33. A compound according to Claim 31, wherein one of -OR1 and D-O- is a residue of an antiviral selected from the group consisting of
ACV, EtUdR, MMUdR, BVDU and Ara-T, and the other of -OR1 and D-O- is a residue of an antiviral selected from the group consisting of Ara-A, IUdR, TFT, FUdR, FMAU, FIAC and Ara-C.
34. A compound according to Claim 31, wherein each of -OR1 and D-O-, which are different, is a residue of an antiviral selected from the group consisting of Ara-A, IUdR, TFT, FUdR, FMAU, FIAC and
Ara-C.
35. A compound according to Claim 23, wherein each of -OR1 and D-O-, which are different, is a residue of as antiviral having activity against RNA viruses.
36. A compound according to Claim 35, wherein each of -OR1 and D-O-, which are different, is a residue of an antiviral selected from the group consisting of selenazofurin, ribavirin, 3-deazaguanosine, 3-deazauridine, tiazofurin, 2-deoxy-D-glucose, 6-mercapto-9-tetrahydro-2-furylpurine, zidovudine, dideoxyinosine, dideoxyadenosine, DDC and D4T.
37. A compound according to Claim 36, wherein each of -OR1 and D-O, which are different, is a residue of an antiviral selected from the group consisting of ribavirin, selenazofurin and tiazofurin.
38. A compound according to Claim 36, wherein each of -OR1 and D-O, which are different, is a residue of an antiviral selected from the group consisting of zidovudine, dideoxyinosine, D4T, DDC and dideoxyadenosine.
39. A compound according to Claim 38, wherein one of -OR1 and D-O is a residue of zidovudine.
40. A compound according to Claim 21, wherein one of -OR1 and D-O- is a residue of a hydrophilic drug and the other of -OR1 and D-O- is a residue of an essentially inactive and nontoxic lipophilic alcohol.
41. A compound according to Claim 40, wherein the lipophilic alcohol is a steroi, a long chain aliphatic alcohol, a carbocyclic alcohol or a polycarbocyclic alcohol.
42. A compound according to Claim 41, wherein the lipophilic alcohol is a steroi.
43. A compound according to Claim 40, wherein the hydrophilic drug is an antiviral of the nucleoside type.
44. A compound according to Claim 43, wherein the lipophilic alcohol is an innocuous naturally occurring sterol.
45. A compound according to Claim 44, wherein one of -OR1 and D-O- is a residue of zidovudine and the other of -OR1 and D-O- is a residue of cholesterol.
46. A compound of the formula
Figure imgf000238_0001
or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000238_0002
D C is the residue of a drug having a reactive carboxyl functional group, the carboxyl carbon atom of said functional group being linked, via an -O-Z-O- bridging group, to the phosphorus atom of the
Figure imgf000238_0003
moiety; wherein Z is wherein the alkylene group contains
Figure imgf000238_0004
1 to 3 carbon atoms and R'2 is defined below; or Z is C3-C6 cycloalkylene in which two adjacent ring carbon atoms are each bonded to a different oxygen atom in the -O-Z-O- bridging group; R1 is C1-C8 alkyl, C6-C10 aryl or C7-C12 aralkyl; R'2 is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl; and R3 is selected from the group consisting of C1-C8 alkyl; C2-C8 alkenyl having one or two double bonds; ( C3-C7 cycloalkyl)- CrH2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion; ( C6-C10 aryloxy)C1-C8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-CrH2r- wherein r is zero, one, two or three and phenyl is unsubstituted, or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms.
47. A compound according to Claim 46, wherein R1 is methyl.
48. A compound according to Claim 46, wherein Z is -CH2-or
Figure imgf000239_0001
49. A compound according to Claim 46, wherein R3 is C1-C8 alkyl.
50. A compound according to Claim 49, wherein R3 is (CH3)3C-or CH3(CH2)4-.
51. A compound according to Claim 46, wherein
Figure imgf000239_0002
is the residue of a drug having a reactive carboxyl functional group, said drug being selected from the group consisting of anticonvulsants,
antineoplastics, antibiotics, diagnostics and nonsteroidal antiinflammatory agents.
52. A compound according to Claim 51 , wherein the drug is an antibiotic.
53. A compound according to Claim 52, wherein the antibiotic is of the penicillin type.
54. A compound according to Claim 53, wherein the drug is amoxicillin, phenoxymethylpenicillin, benzylpenidillin, dicloxacillin, carbenicillin, oxacillin, cloxacillin, hetacillin, methicillin, nafcillin, ticarcillin or epicillin.
55. A compound of the formula
Figure imgf000240_0001
or
Figure imgf000240_0002
or a pharmaceutically acceptable salt thereof, wherein is
Figure imgf000240_0003
the residue of a drug having a reactive imide functional group and is the residue of a drug having a reactive amide functional group,
Figure imgf000240_0004
the nitrogen atom of the imide or amide functional group being linked, via a bridging group, to the
Figure imgf000240_0005
phosphorus atom of the
Figure imgf000241_0001
moiety; R1 is C1-C8 alkyl, C6-C10 aryl or C7-C12 aralkyl; each of the R2 groups, which can be the same or different, is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl; and R3 is selected from the group consisting of C1-C8 alkyl; C2-C8 alkenyl having one or two double bonds; (C3-C7 cycloalkyl)-CrH2r-wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion; ( C6-C10 aryloxy)C1-C8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-CrH2r- wherein r is zero, one, two or three and phenyl is unsubstituted, or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms.
56.. A compound according to Claim 55, wherein R1 is methyl.
57. A compound according to Claim 55 , wherein R2 is hydrogen at each occurrence.
58. A compound according to Claim 55, wherein R, is C1-C8 alkyl.
59. A compound according to Claim 58 , wherein R3 is (CH3)3C-or CH3(CH2)4-.
60. A compound according to Claim 55 , wherein
Figure imgf000241_0002
or is the residue of a drug having a reactive imide or amide functional group, said drug being selected from the group consisting of tranquilizers, sedatives, anticonvulsants, hypnotics, antineoplastics, antivirals, antibiotics, barbiturate antagonists, stimulants, antihypenensives and antidepressants.
61. A compound according to Claim 52, wherein the drug is a tranquilizer, anticonvulsant or sedative.
62. A compound according to Claim 61 , wherein the tranquilizer, anticonvulsant or sedative is of the hydantoin-type or the barbimrate type.
63. A compound according to Claim 62, wherein the drug is phenytoin, phenobarbital, amobarbital or butalbital.
64. A compound of the formula
Figure imgf000242_0001
or a pharmaceutically acceptable salt thereof, wherein is the
Figure imgf000242_0002
residue of a drug having a reactive primary amino or secondary amino functional group, the nitrogen atom of the amino functional group being linked, via a bridging group, to
Figure imgf000242_0003
the phosphorus atom of the
Figure imgf000242_0004
moiety; R1 is C1-C8 alkyl, C6-C10 aryl or C7-C12 aralkyl; R"2 is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl; and R3 is selected from the group consisting of C1-C8 alkyl; C2-C8 alkenyl having one or two double bonds: (C3-C7 cycloalkyl)-CrH2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion; ( C6-C10 aryloxy)C1-C8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-CrH2r- therein r is zero, one, two or three and phenyl is imsubstimted, or is substimted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms.
65. A compound according to Claim 64, wherein R1 is methyl.
66. A compound according to Claim 64 , wherein R"2 is hydrogen or methyl.
67. A compound according to Claim 64, wherein R3 is C,-C, alkyl.
68. A compound according to Claim 67, wherein R3 is (CHj^Cor CH3(CH2)4-.
69. A compound according to Claim 64, wherein is the
Figure imgf000243_0001
residue of a drug having a reactive primary amino or secondary amino functional group, said drug being selected from the group consisting of GABAergic agents, antineoplastics, cerebral stimulants, appetite suppressants, MAO inhibitors, tricyclic antidepressants, decongestants, narcotic analgesics, antivirals, neurotransmitters, small peptides of 2 to 20 amino acid units, dopaminergic agents and antibiotics.
70. A compound according to Claim 69, wherein the drug is an antiviral.
71. A compound according to Claim 70, wherein the antiviral is amantadine or rimanfadine.
72. A compound according to Claim 69, wherein the drug is a small peptide.
73. A compound according to Claim 72, wherein the small peptide is an enkephalin or an endorphin.
74. A method for site-specifically and sustainedly delivering a drug species to a target organ, comprising administering to an animal in need of such treatment a quantity of a compound as claimed in Claim 1 sufficient to release a pharmacologically effective amount of said drug species to the target organ.
75. A method for site-specifically and sustainedly delivering a centrally acting drug species to the brain, comprising administering to an animal in need of such treatment a quantity of a compound as claimed in Claim 1 sufficient to release a pharmacologically effective amount of said centrally acting drug species to the brain.
76. A method according to Claim 74, wherein the compound is administered in the form of a pharmaceutically acceptable sustained release composition or wherein the compound is administered via a route of administration capable of slowly releasing the compound into the body.
77. A pharmaceutical composition of matter, in unit dosage form, for use in delivering a pharmacologically effective amount of a drug species to a target organ, said composition comprising:
(i) an amount of a compound as claimed in Claim 1 sufficient to release a pharmacologically effective amount of a drug species to the target organ; and
(ii) a nontoxic pharmaceutically acceptable carrier therefor.
78. A pharmaceutical composition of matter, in unit dosage form, for use in delivering a pharmacologically effective amount of a centrally acting drug species to the brain, said composition comprising:
(i) an amount of a compound as claimed in Claim 1 sufficient to release a pharmacologically effective amount of a centrally acting drug species to the brain; and (ii) a nontoxic pharmaceutically acceptable carrier therefor.
79. A pharmaceutical composition as claimed in Claim 77 , said composition being formulated for sustained release.
80. A process for the preparation of a compound of formula (D as claimed in Claim 1, said process comprising reacting a phosphoric acid derivative of the formula
Figure imgf000245_0001
wherein [D] and R1 are as defined in Claim 1, with cesium fluoride or an equivalent cesium salt and a compound of the formula
Figure imgf000245_0002
wherein R2 and R3 are as defined in Claim 1, in an organic solvent.
81. A process for the preparation of a compound of formula (la) as claimed in Claim 2, said process comprising reacting a phosphoric acid derivative of the formula
Figure imgf000245_0003
wherein D-O and R1 are as defined in Claim 2, with cesium fluoride or an equivalent cesium salt and a compound of the formula
Figure imgf000246_0001
wherein R2 and R3 are as defined in Claim 2, in an organic solvent.
PCT/US1992/002239 1991-03-29 1992-03-27 Targeted drug delivery via mixed phosphate derivatives WO1992017185A1 (en)

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