AU668506B2 - Targeted drug delivery via mixed phosphate derivatives - Google Patents

Targeted drug delivery via mixed phosphate derivatives Download PDF

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AU668506B2
AU668506B2 AU16748/92A AU1674892A AU668506B2 AU 668506 B2 AU668506 B2 AU 668506B2 AU 16748/92 A AU16748/92 A AU 16748/92A AU 1674892 A AU1674892 A AU 1674892A AU 668506 B2 AU668506 B2 AU 668506B2
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drug
alkyl
residue
compound according
carbon atoms
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AU1674892A (en
AU668506C (en
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Nicholas S. Bodor
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University of Florida
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University of Florida
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    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07F9/5537—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom the heteroring containing the structure -C(=O)-N-C(=O)- (both carbon atoms belong to the heteroring)
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    • C07F9/6503—Five-membered rings
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    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
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    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65611—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system (X = CH2, O, S, NH) optionally with an additional double bond and/or substituents, e.g. penicillins and analogs
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    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65613—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system (X = CH2, O, S, NH) optionally with an additional double bond and/or substituents, e.g. cephalosporins and analogs
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    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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    • C07J—STEROIDS
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    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/0026—Oxygen-containing hetero ring cyclic ketals
    • C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17

Description

OPI DATE 02/11/92 p AOJP DATE 10/12/92 APPLN. D1 16748 92 PCT NUMBER PCT/US92/02239 INTERNATk_... .EATY (PCT) (51) International Patent Classification 5 A61K 31/70, C07H 19/073, 19/173 (11) International Publication Number: Al (43) International Publication Date: WO 92/17185 15 October 1992 (15.10.92) (21) International Application Number: (22) International Filing Date: Priority data: 677,304 29 March Parent Application or Grant (63) Related by Continuation
US
Filed on PCT/US92/02239 27 March 1992 (27,03,92) h 1991 (29.03.91) 677,304 (CIP) 29 March 1991 (29.03.91) (74) Agent: BAUMEISTER, Mary, Katherine; Burns, Donne, Swecker Mathis, George Mason Building, Washington and Prince Streets, P.O. Box 1404, Alexandria, VA 22313-1404 (US).
(81) Designated States: AT, AT (European patent), AU, BB, BE (European patent), BF (OAPI patent), BG, BJ (OAPI patent), BR, CA, CF (OAPI patent), CG (OAPI patent), CH, CH (European patent), CI (OAPI patent), CM (OAPI patent), CS, DE, DE (European patent), DK, DK (European patent), ES, ES (European patent), FI, FR (European patent), GA (OAPI patent), GB, GB (European patent), GN (OAPI patent), GR (European patent), HU, IT (European patent), JP, KP, KR, LK, LI, LU (European patent), MC (European patent), MG, ML (OAPI patent), MN, MR (OAPI patent), MW, NL, NL (European patent), NO, PL, RO, RU, SD, SE, SE (European patent), SN (OAPI patent), TD (OAPI patent), TG (OAPI patent), US.
Published With international search report.
(71) Applicant (for all designated States except US): UNIVERSI- TY OF FLORIDA (US/US]; 207 Tigert Hall, Gainesville, FL 32611 (US).
(72) Inventor; and Inventor/Applicant (for US only) BODOR, Nicholas, S.
[US/US]; 6219 S.W. 93rd Avenue, Gainesville, FL 32608
(US).
pt,-S (54) Title: TARGETED DRUG DELIVERY VIA MIXED PHOSPHATE DERIVATIVES
R
2 0 ?zOCHOCRI (I) [Di- P,,
R
2 0 U OH-OCR
OR,
(a) R, 0 I II 0 OC-OCR [Di-P (57) Abstract The invention provides compounds of formula and the pharmaceutically acceptable salts thereof, wherein 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 Cl-C 8 alkyl, C 6 -CIo aryl or C 7
-C
1 2 aralkyl, with the proviso that when is the residue of a drug having a readtive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the moiety via an oxygen-phosphorus bond, then 1 I, 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 moiety via an oxygen-phosphorus bond, -ORi being the same as or different from R 2 is hydrogen, Ci-C 8 alkyl, C 6 -CIO aryl, C 4
-C
9 heteroaryl, C 3
-C
7 cycloalkyl, C 3
-C
7 cycloheteroalkyl or
C
7 -CI2 aralkyl; and R 3 is selected from the group consisting of Ci-C 8 alkyl; C2-Cs alkenyl having one or two double bonds;
(C
3
-C
7 cycloalkyl)-CrH 2 r- 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 -Clo aryloxy)Ci-C 8 alkyl; 3- or 4-pyridyl; and phenyl-CrH 2 r. 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.
WO 92/17185 PCT/US92/0223,9 1 TARGETED DRUG DELIVERY VIA MIXED PHOSPHATE DERIVATIVES FIELD OF THE L ENTION: 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 bloodbrain 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 bloodbrain barrier or BBB. Site-specific and sustained delivery of drugs to the brain or other organ., 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 SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 -2facilitates 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, nonsteroidal and-inflammatory agents/non-narcotic analgesics, memory enhancers, antibacterials/andbiotics, 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 phainmacologilly-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 SUBSTITUTE SHEET WO 92/17185 PCFUS9202239 3 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, S 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 y4t activity against these viruses. One notable advance in the field was the advent of ribavirin or 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. Ribaviin is also used in the ireatment 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 i~n, to exert SUBSTITUTE SHEET WO 92/17185 PC/US92/022.1, 4 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 scce4 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 antiherpedc agent acrols these barriers would offer a significant advantage in the treatment of such serious and debilitating diseases as encephalitis, ophthalmic infections -used by herpes simplex such as herpetic uveites, keratitis etc. and cutaneous herpes infections such as genital and orofacial herpes.
Vidarabine (9-B-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, cytomegalovirus 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 keratidds 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 SUBSTITUTE SHEET PCr/US92/02239 WO 92/17185 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 S 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 ct 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 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 tgeminal 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 SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 -6- .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'-dxy- 2'-fluoro--D-arabinofuranosyl) derivatives of 5-methyluracil (FMAU), 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 itra 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 HSVinfected 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 SUBSTITUTE SHEET WO 92/17185 PC/US92/02239 -7is mandatory. The low cytotoxicity exhibited by these agents with uninfected cells indicate selectivity of action.
Although these nucleoside analogs exhibit high selectivity toward viral cells, they are quite polar and therefore their ability to penetrate the S 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 hydroxymethylarabinosyluracil (FHMAU) and a glucuronide of FMAU.
FMAU, FIAU and FIAC have been found to exhibit more potent antiviral activity than acyclovir. The metabolites of these compounds, even though potent inhibitors of HSV-2 in cell cultures, are essentially devoid of antiviral activity in ivoL in the encephalitis model. This dichotomy between in yit activity and in vivQ 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 SUBSTITUTE SHEET WO 92/17185 PCr/US9210223p a 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 effctive than acyclovir in the treatment of encephalitis in yiTg and in yjiv. 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 turn 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% SUBSTITUTE SHEET WO 92/17185 PCr/US92/02239 -9of 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 HCMVV 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 pneumonitis. Another particularly serious complication occurring during immunosuppressive therapy is Kaposi's sarcoma A strong correlatior 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 Burkitt's lymphoma. However, a causal role for the virus has not been definitively established.
An immunosupprssed state is the hallmark of acquired immunodeficiency syndrome (AIDS), and HCMV has been shown to have an extraodinary prevince 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 SUBSTITUTE SHEET WO 92/17185 !'Cr/US92/02239 10 included HCMV. The consequences of HCMV infection in AIDS are manifold, with neural and especially ocular involvement being predomninant. 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 ai'so cwrmon and presents itself post-mortem in the microglial nodules which are typical of HCMV infection. In AIDS, this neural involvement is concomitant with H{IV infection of the CNS, often manife-sting as subacute encephalopathy.
An antiviiul agent which has shown promise in the treatment of HCMV infections in immunosuppressed statei is DEPG. As mentioned above, DHPG is structurally similar to acyclovir (ACV), a safe and efficacious antiherpetic agent. The primary mechanism of DHI'G action is3 against CMV is inhibition of the replication of viral DNA by DHPGtriphosphate. This inhibition includes a selective and potent inhibition of the Yviral DNA polymerase. Since HCMV does not encode a virus-specific thymidine kinase, phosphorylation of DH1PG 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 DHIPG toward CMV compared with ACV appears to be due in part to the efficient intracellular metabolism of DRPG to its mono and triphosphatt in CM-infect-ed cells. The relAtive in r 0 activities, as measured by the IC 50 values of DHIG vs ACV are of the 2S same order against herpes simplex virus (HSV), namezly 0.2 to 0.8 M M.
However, against 1ICMV the ICS 0 for DI{PG is approximately 2.5 AM.
Thus, DHPG has significant activity against HCMIV in yi= 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 SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 11 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 pneumonitis 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 'nduces 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 pharmacokinetic disposition of intravenous DHPG in humans is similar to that observed in rats and dogs, with the finding of a biphasic elimination with an a-phase half-life of 0.23 hours and a P-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. Pharmacokinetic studies of DHPG in the rat and dog have demonstrated behavior similar to acyclovir.
Human pharmacokintics of intravenous DHPG indicate cerebrospinal fluid (CSF) concentrations equivalent to 24% to 67% of plasma concentrations.
SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 12 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 incrase in incidence of infection exceeds 0.75% of the total population per year. AIDS is caused by a retrovirus related to tb~ lentivirinae family and has been designated human immunodeficiency 'irus (PtV-i). This pathogen selectively infects lymphocytes bearing a T4 surface antigen. These helpr/inducer T-cells are responsible for containing and eliminating various types of infection including those precipitated by Pneumocvstis ga Txolasma ondii, Crytococcus nmfan9, Candida albican, Mycobactum arimintraclular and otherl. The destruction of cellular immunity induced by HIV-1 causes the normally benign infections resulting from the above- SUBS7TTUTE SHEET WO 92/17185 PCT/US92/02239 -13mentioned 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 di,,traught. 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 SUBSTITUTE
SHEET
WO 92/17185 PCV/US92/02239 -14autopsy. 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 fiTV-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 reconstitut 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 y~i doses, that for antiviral therapies to be effective, agents must pass the BBB and achieve relatively high sustained leveds 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 SUBSTITUTE SHEET PC'f/US92/02239 WO 92/17185 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 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 bicavailability is about 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 ixvQ. The effect of AZT on the neurological manifestation of AIDS has been reported by Yarchoan et at, Lancet, 132 (1987). In a series of four case reports, AZT was shown to improve immunological 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." SUBSTITUTE SHEET WO 92/:17185 P4C/IJS92/02239 -16- 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, L InJL DiiS, 15, 630 (1988). In it, the BBB penetration of AZT was shown 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 nI 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 yit 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 SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 -17dose-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, 9t optimied in terms of pha macgirics and tiss 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 reox carrier system provides for braintargeted 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
[D-DHCI
SUBSTITUTE SHEET WO 92/17185P1'U9fQ2~ PCr/IJS92/022319 18 wherein is a centrlly acting-drug species and CDHC] is the reduced, biooxidizable, blood-brain barrier penetrating, Lipoidal form of a dihydropyridine -pyridiniumn salt redox carrier. In their oxidized form, which is the form "locked" in the brain from which the active drug is 3 ultimately released, the carrier-drugs can be represented by the formula
X*
wherein X* is the anion of a non-toxic pharmaceutically acceptable acid, is a centrally acting drug species and [QCI* is the hydrophilic, positively charged ionic pyridinium salt form of a diliydropyridine pyn'dinium Wat redox carrier.
Various aspects of the r! dox carrier system have been described in detail in flodor United States Patent No. 4,479,932, issued October 1984; flodor United States Patent No. 4,540,564, issued September 1985; Bodor et al United States Patent No. 4,617,298, issued October 14, is 1986; UNIVERSITY OF FLORIDA'S Interntional Application No.
PCr/TJS83/00725, published under International Publication No.
W083/03968 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 !I United States Patent No.
4, 863,911, issue1 September 5, 1989; Bodor United States Patent No.
4,880,816, issued Nov~rnber 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; UNIVERSITY OF FLORIDA's European Patent Application No. 88312016.4, published under European Publication No. 0327766 on August 16, 1989); UNIVERITY 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/pyridiniium salt derivatives of dopamine, testosterone, phenytoin, GABA, vaiproic acid, SUBSTITUTE SHEET PCT/US92/02239 WO 92/17185 19 tyrosine, methicilin, oxacillin, benzvlpenicilin, cloxacifin, dicloxacillin, desipramine, acyclovir, trifluorothytnidine, zidovudine, hydroxy -CCINtJ chiorambucil, tryptarnine, dexamethasone, hydrocortisone, edhinyl estradiol.
,norethindrone, estradiol, ethisterone, norgestrel, estrone, estradiol 3-methyl ether, estradiol. benzoate, norethynodrel, mestranol, indomethacin, naproxen, FENU, HF.NI, 5-FTJ and many others, The dihydropyridine redox carrier system has achieved remarkable success in targeting drugs to the brain in laboratory tests. Unfortunately, the dihydropyridine-onmining 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 carrier approach to braintargeted drug delivery which would not include the inherently unstable dihydropyridine system would be desirable.
is A few mixed phosphate derivatives of antiviral agents have been previously described, but such are structurally distinct from the mixed phosphate.% to which the present invention relates.
Thus, Farquhar et al, in LPliaM..5Sc. Vol. 72, No. 3, 324-325 (March, 1983), have described bis(acyloxymethiyl)phosphotriesters of the type R COCH 2 0~ 0 0 2 where A' is, for example, -CHI or -C(CHI) 3 and R is phenyl (as a model residue). Synthesis of two bis(acyloxymethyl)phosphotriester of two nucleosides is disclosed, iLe. the compounds of the formula SUBSTITUTE SHEET WO 92/17185 rc'rUS92/0239 0 0 (CH 3 3 (GCOCH,0 0 N R* (CH 3) 3 CCCH 20 2 N 0 0
OCOCH
3 wherein R is -CHI or F. In another report on the same work, Srivastava and Farquhar, in Biggi Q~j=U 1l8-iZ) '(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 intraceilularly, 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 Nld Clien, 33, 1400- 1406 (190), have reported on a series of aryl bis(3'-O-acetylthyrnidin-S'is yl)phosphates synthesized in an attempt to find ah aryl derivative which would hydrolyze under physiological conditions to the yl)phosphate. The compounds synthesiized have the formula SUBSTITUTE SHEET 92/17185 PCr/US92/02239 -21-
OR
where R is a 5'-Iinked nucleoside and R' is a group designed to possess suitable hydrolytic properties. As model compounds, thymidii-5-y1 was selected for R and several substituted phenyl groups as i.e. 4- (methylthio)phenyl, 4-chiorophenyl, 2-chlorophenyl, 4- (methylsulfonyl)phenyl, 2,5-dichlorophenyl and 4-nitrophenyl. The following S'-5'-linked triester derivatives of (E)-5-(2-bromovinyl)-2'deoxyuridine (BVDJ) and acyclovir (ACV) were then synthesized and studied for their antiviral effects: SUBSTITUTE SHEET PCT/US92/02239 NNIQ 92/17185 22
OR"
Rk O-P0O \0
OR"
where RI is 4-(Methylthio)phenyl or 4-(methylsulfonyl)phenyl or 2chiorophenyl and R1 'is H or Ac. The data are consistent with a conclusion that dhe tiesters simply act as prodrugs for BVDU and ACV, respectively.
51MMRY E MMIS~{l.
The presort invention provides novel mixed phosphate derivatives, adaptod for targeted drug delivery, which have the formula R0 ?I
II-OR
ORt SUBSTITUTE SHEET 23 or a pharmaceutically acceptable salt thereof, wherein 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
R
2
O
I I jOCH-OCR 3
ORI
moiety; R 1 is C 1
-C
8 alkyl, C 6 -C10 aryl or C 7
-C
12 aralkyl, wit I the proviso that when is the residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the R2 O o II IfOCH-OCR 3
-POR
1 moiety via an oxygen-phosphorus bond, then R 1 taken together with the adjacent oxygen atom, can also be th. residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the
R
2
O
JO(' H-OCR 3
[D]-P
S
0* a'r a.
*5q S Sa a
'S
a.
a Ut, a, a 4* a t.
r' 2.
moiety via an oxygen-phosphorus bond, -OR 1 being the same as or different from 15 R 2 is hydrogen, C 1
-C
8 alkyl; C 6
-C
10 aryl, C 4
-C
9 heteroaryl, C 3
-C
7 cycloalkyl,
C
3
-C
7 eyleheteroalkyl or C 7
-C
12 aralkyl; and R 3 is selected from the group consisting of C 1
-C
8 alkyl; C2-C 8 alkenyl having one or two double bonds; (C 3
-C
7 cycloalkyl)-CrH2r 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)C1-Cg alkyl; 3- or 4-pyridyl; and phenyl-CrH2r Wherein r is zero, one, two or three and phenyl is unsubstituted or is substtauted 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.
There is further provided according to the invention mixed phosphate s2 derivatives of formula as disclosed above wherein cannot be the residue of a phosphate drug which is active per se or which is activated by further phosphorylation of the phosphate in vivo.
tN:LIvVWIo039S:rnk.-T 24 Also provided according to the invention are mixed phosphate derivatives of formula as disclosed above where cannot be the residue of a drug of the nucleoside type.
The invention further provides a generic mthod 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 anionic 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
R
2
O
0 I II 1 O OCH-OCR 3
D-O-P
ORI (la) or a pharmaceutically acceptable salt thereof, wherein D-0- 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
R
2 0 ?OCH-OC
R
OR
1 $t moiety, and wherein R 1
R
2 and R 3 are as defined with formula In another aspect, the present invention provides novel mixed phosphate derivatives of mercapto-containing drugs, which derivatives have the formula
.R
2 0
IIII
I ,OCH-OCR 3
D-S-P
OR1 (Ib) V464 o or a pharmaceutically acceptable salt thereof, 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 \L 00395:rnkTW N:\LIBVVI00395:rnkTCW
R
2
O
0 1
II
II OCH-OCR 3
P
OR1 moiety, and wherein R 1 R2 and R 3 are as defined with formula In yet another aspect of the invention, in the compounds (la) and (Ib) disclosed above, D-0- or D-S- cannot be the residue of a phosphate drug which is active per se or which is activated by further phosphorylation of the phosphate in vivo.
In a further aspect of the invention, in the compounds (la) and (Ib) disclosed above the D-O- or D-S- cannot be the residue of a drug of the nucleoside type.
There is also provided according to the invention a compound of the formula
R
2 0 I II I1'/OCH-OCR 3 D-0-P\ OR1 OR (Ia) o1 or a pharmaceutically acceptable salt thereof, wherein D-0- is the residue of a hydrophilic drug having a reactive hydroxyl functional group, the oxygen atom of said functional group being bonded to the phosphorus atom of the R2 O
SOR
a i moiety; -OR 1 is the residue of an essentially inactive and nontoxic lipophilic alcohol; 15 R 2 is hydrogen, C1-C 8 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 1 -Cg alkyl; C 2
-C
8 alkenyl having one or two double bonds; (C 3
-C
7 cycloalkyl)-CrH2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C 4 alkyl substituents on the ring portion; (C 6
-C
10 20 aryloxy)Ci, C 8 alkyl; 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 invention still further provides a compound of the formula N \V 3 tN;\LIBVV]00395rnk!TCW 26
R
2 0 9OCH--OCR 3
D-O-P
OR a) (la) or a pharmaceutically acceptable salt thereof, wherein D-O- is the residue of a hydrophilic drug having a reactive hydroxyl functional group, the oxygen atom of said functional group being bonded to the phosphorus atom of the
R
2 0 i II iTOCH-OCR 3 P OR 1 moiety; -OR 1 is the residue of an essentially inactive and nontoxic lipophilic alcohol;
R
2 is hydrogen, C 1
-C
8 alkyl, C 6
-C
10 aryl, C 4
-C
9 heteroaryl, C 3
-C
7 cycloalkyl, C 3
C
7 cycloheteroalkyl or C7-C12 aralkyl; and R 3 is selected from the group consisting of C1-C 8 alkyl; C 2 -Cg alkenyl having one or two double bonds; (C 3
-C
7 cycloalkyl)- CrH2r- 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; 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; with the proviso that D-0- cannot be the residue of a phosphate drug which is active per se or which is activated by further phosphorylation of the phosphate in vivo, According to a further embodiment of the invention there is provided a compound of the formula
R
2 0 O I II 1 O: CH-OCR 3
D-O-P
ORI
OR (Ia) or a pharmaceutically acceptable salt thereof, wherein D-O- is the residue of a hydrophilic drug having a reactive hydroxyl functional group, the oxygen atom of said functional group being bonded to the phospborus atom of the [NA:\LIBV}QO395:rnkTCW R 0 0 I Ii [rOCH-OCR 3
POR
1 moiety; -OR 1 is the residue of an essentially inactive and nontoxic lipophilic alcohol;
R
2 is hydrogen, C 1 -Cg alkyl, C6-C 10 aryl, C 4
-C
9 heteroaryl, C 3
-C
7 cycloalkyl,
C
3
-C
7 cycloheteroalkyl or C7-C 1 2 aralkyl; and R3 is selected from the group consisting of C 1
-C
8 alkyl; C 2
-C
8 alkenyl having one or two double bonds; (C 3
-C
7 cycloalkyl)-CrH2r- 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; 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; with the proviso that D-O- cannot be the residue of a drug of the nucleoside type.
The present invention further provides novel mixed phosphate derivatives of carboxyl-containing drugs, which derivatives have the formula 0 O O II II IIOCH 2
-OCR
3 D-C-0-Z-0-P, OR1 (Ic) 0
II
or a pharmaceutically acceptable salt thereof wherein D-C- is the residue of a t* drug having a reactive carboxyl functional group, the carboxyl carbon atom of said a* functional group being linked, via an bridging group, to the phosphorus atom of the S0 11 .OCH2-OCR 3
-P
2" OR1 S 20 moiety; wherein Z is -alkylene- wherein the alkylene group contains 1 to 3 carbon
R,
atoms and R' 2 is defined as is R 2 with formula or wherein Z is C 3
-C
8 [N\LIBVV]00395:rnk:TCW 28 cycloalkylene in which two adjacent ring carbon atoms are each bonded to a different oxygen atom in the bridging group; and wherein R 1 and R 3 are as defined with formula Still further, the invention provides novel mixed phosphate derivatives of drugs containing imide or amide functional groups, which derivatives have the formulas R. 0 o0 2 11 f"C
OCH-OCR
3 D )N-CH-O-P,
C
0 2OR 1 o R 2 (Id) and R 0 0 i ,OCH-OCR 3
D-C-N-CH-O-P
R I
OR
4
R
(le) or pharmaceutically acceptable salts thereof, wherein
O
fC D N- is the residue of a drug having a rac-tive imide functional group, 0
II
D-C-N- is the residue of a drug having a reactive amide functional group, the R4 nitrogen atom of the imide or amide functional group being linked, via a -CH-O- bridging group, to the phosphorus atom of the R2 o 2 0 I OCH-OCR 3 moiety; R 4 is preferably H but may also be C 1
-C
7 alkyl or
OR
1 [N,.\LIBVV]0039S:rnkTCW 0
II
combined with D-C-N- to form a cyclic amide; and wherein the R 2 groups in formulas (Id) and which can be the same or different, are as defined with formula and R 1 and R 3 are as defined with formula The present invention also provides novel mixed phosphate derivatives of amino-containing drugs, which derivatives have the formula 0
II
9
OCH-OCR
II II 3
D-N-C-OCH-O-P,
I I OR
I
R
4
R"
2 (If) wherein D-N- is the residue of a drug having a reactive primary amino (R 4
H)
R
4 or secondary amino (R4 other than H, but preferably C 1
-C
7 alkyl or combined with D-N- to form a cyclic secondary amine) group, the nitrogen atom of the amino 0
I
functional group being linked, via a bridging group, to the
R"
phosphorus atom of the 0 0
II
II OCH2-OCR 3
-P
OR
1 moiety; wherein R" 2 is defined as is R 2 with formula and wherein R 1 and R 3 are as defined with formula The identity of the R 4 group (R 4 other than H) in drugs having reactive secondary amino groups, while often C 1
-C
8 lower alkyl, is immaterial to the invention, since R 4 is of course part of the drug residue itself and is left unchanged by the conversion to the formula (If) compound.
C Also provided according to the invention is a method for site-specifically and sustainedly delivering a drug spteies to a target organ, comprising administering to an animal in need of such treatment a quantity of a compound of the invention sufficient to release a pharmacologically effective amount of said drug species to the target organ.
There is further provided according to the invention a method for sitespecifically 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 003mkTC ^'-[N:\LlBVVJ00395!:mkTCW 28b compound of the invention sufficient to release a pharmacologically effective amount of said centrally acting drug species to the brain.
There is also provided according to the invention 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: an amount of a compound of the invention sufficient to release a pharmacologically effective amount of a drug species to the target organ; and (ii) a nontoxic pharmaceutically acceptable carrier therefor.
There is further provided according to the invention 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: an amount of a compound of the invention sufficient to release a pharmacologically effective amount of a centrally acting drug species to the brain; and (ii) a nontoxic pharmaceutically acceptable carrier therefor.
IC
I
[NALIBVvj003,:rnk:TCW WO 92/17185 PCT/US92/02239 -29- 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 t0 as used herein, there is of courst 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. CenLally acting drugs are preferred for derivation in accord wth the present invention, brain-targeted drug delivery being the preferred goal of the invention.
is The expiesion "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 whydroxyl" means an -OH function.
The word "carboxyl" means a -COOH function.
The word "mercaptO" means an function.
The word 'amino" means a primary or secondary amino function, ie, -NH 2 or -NER,. The secondary amino function is also represented herein as particularly since the exact identity of the R, portion of -NHa 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.
The word "amide" means a carbamoyl (-CON- 2 or substituted carbamnoyl (-CONHI) or a sulfamoyl (-SO 2 NHi) or substituted sulfamoyl SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 (-SONHIR) functional group. The -CONHR, and -SO 2 NHRI groups may also be represented herein as -CONH- and -SO 2 NH-, respectively, since the identity of R4 is immaterial, R, being a part 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 0 _c
NH
C
0 that is, the structure which characterizes imides 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 drg 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/ot 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.
SUBSTITUTE SHEET WVO 92/17185 PCT/ US92/02239 -31- Drugs containing reactive hydroxyl and rnercapto 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 (le) and (If) hereinabove.
The term "C 1 -Cc alkyl" as used herein includes strnaight and branched-chain lower alkyl radicals having up to eight carbon atoms. eg.
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, =r-butyl, penryl, hexyl and the like.
The term "C 6 -Cl 0 aryl" includes aromatic radicals having the indicated number of carbon atoms, e.g. phenyl and naphthyl.
The term "C7-C, 2 aral ,kyl" 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 con'tain up to 6 carbon atoms, e,,g.
is methylene, ethylene, propylene, trimethylene, 1,2-butylene, 2,3-butylene, tetrarnethylene and the likec. A typical aralkyl group is benzyl.
The term "C 4 heteroaryl" refers to aromatic radicals having the indicated number of carbon atoms and additionally containing 1 or 2 hetero atoms in the ring(t) selected from the group consisting of N, 0 and S.
Illustrative radicals of this type include furyl, pyrrolyl, imidazolyl, pyridyl, indolyl, quinolyl and the ie.
The term "C 3
-C
7 cycloalkyl' designates saturated alicyclic hydrocarbon radicals containing the indicated number of carbon atoms. e.g.
cyclopentyl and cyclohexyl.
*The term "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, 0 and S. Examples include morpholino, piperazinyl and pyrrolidinyl.
SUBSTITUTE SHEET WO 92/17!85 P''U9/2~ PCrIUS92102M -32- The term "C, 2 -Cq aikenyl'" designates unsaturated aliphatic hydrocarbon radicals, or olefinic groups, which contain one or two double bonds and the indicated number of carbon atoms, e.g. l-propen-l-vi, 1.3pentadien-1-yl and the like.
The ternm "(C 6 -CIO aryloxy)CI-Cs alkyl" includes atyloxyalkYt radicals such as phenoxyrnethyl, i.e. the aryl portion contains 6 to carbon atoms, e.g. phenyl or naphthyl, while the aikyl portion contains I to 8 carbon atoms, e.g. methyl or ethyl.
The term "C 3 cycloalky-CHI,-" includes cycloalkyl and ;ycloalkyl-alkylene- radicals containing the indicated number of carbon atoms and bearing 0 to 2 CI-CA ailkyl groups as ring substituents.
)lustrative radicals include cyclopentyl, cyclohexyl, cyclohexylmethyl, 1methylcyclohex- l-yl, 2,2,3 ,3-tetramethylcycloprop- l-yl and the like.
Ile term "pheny1-C.Hy". includes phenyl and phenyl-alkyleneis radicals containing the indicated number of carbon atoms, e.g. benzyl, any of which can bcar 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; CI-C 4 alkoxy, which can be straight or branched, e.g. methoxy, ethoxy; halo, which includes brorno, chloro, iodo and fluorot, trifluoromethyl; C2-Cs dialkylamnino, e.g. dimcthylaxnino and diethylamino; and C 2 -Cd alicanoylarnino, e.g, acetamaido and propionamnido.
Substituted phenyl.CH 2 radicals include such radicals P-tolyl, 2,4,6trimethylphenyl and m-trifluoromethylhenzyl.
The word "alikylene" when used in conjunction with the Z term herein refers to bivalent radicals of the type where n is 1, 2 or 3, and the corresponding branched-chain groups. When it is part of the Z term, th~e allkylene 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 -C3 alkcylene, The term "C 3 cycloalkylene' t as used in conjunction with the Z term designates radicals of the type SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 -33- I I CH- CH (CH,)m where m is I 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 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, glucolic, stearic, lactic, malic, tartaric, citric, ascorbic.
pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, fumaric, methanesulfonic, toluenesulfonic and the like.
The expression "hydroxyl protecting group" as used herein is intended to designate a group 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 greup 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 when it is an organic radical derived from a carboxylic acid by removal of the hydroxyl group), it can be selected from th2 same 0
II
group of radicals as those encompassed by the -C-R 3 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; SUeBSTMUTuE WO 92/17185 PCT/1JS92/O22P9 -34- 0 cycloalkyl-CH 2 wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three; phenoxyacetyl; pyridinecarbonyk; and 0 pheny1-Cr.H 2 wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by I to 3 alkyl each having 1 to 4 carbon atoms, aLkoxy having I to 4 carbon atoms, halo, trifluollomethyl, dialkylaxuino having 2 to 8 carbon atoms or alkanoylamnino having 2 to 6 carbon atoms.
When the acyl group is aLka-noyl, there are included both unbranched and branched aikanoyl, for example, acetyl, propionyl, butyryl, isobutyry, valeryl, isovaleryl, 2-methylbutanoyl, pivalyl (pivaloyl), 3methylpentanoyl, 3 ,3-dirnethylbutanoyl, 2 ,2-dimethylpernanoyl, hexanoyl 1s and the 1 ce. Pivalyl, isobutyry, isovalery', and hexanoyl are especially 0 preferred, both as -C-R3 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 0 11 cycioalkyl-Cr-C-, there are included cycloalkanecarbonyl and cycloalkaneaiklanoyl groups wherein the cycloaUkae portion can optionally bear I or 2 alkyl groups as substituents, e.g. cyclopropanecarbonyl, l-methylcyclopropanecarbonyl, cyclopropaneacetyl, a-methylcyclopropaneacetyl, I.-methylcyclopropane- SUBSTITUTE SHEET WO 92/17 185 PCT/US92/02239 acetyl, cyclopropanepropionyl, ca-methylcyclopropanepropionyli, 2isobutylcyclopropanepropionyl, cyclobutanecarbonyl, 3, 3-dimethwlcvck/,bumnntcarnyt, cyclobutaneacetyl, 2 ,2-dimethvl-3-ethylcyclobutaneacetryl, cyclopetanecarbonyl, cyclohexaneaceryl, cyclohexanecycloheptanecarbonyl and cycloheptanepropionyl.
When the acyl group is pyridinecarbonyl, there are inclucled.
picolinoyl (2-pyridinecarbonyiX; nicotinoyl (3-pyridinecarbonyl) and isonicotinoyl (4-pyridinecarbony), When the acyl group is 0 pheny-CH2,-C-, there are included, for example, benzoyl, phenylacetyl, a-phcnylpropionyl, 0-phenylpropionyi, p-toluy1, m-toluyl, o-toly, o-ethylbenzoyl, p-tenbutylbenzoyl, 3,4-dimethylbenzoyt, 2,methyl-4-ethylbenzoyl, 2,4,6is trirnethyibenzoyl, m-methylphenylacetylo p-isobutylphenylacetyl, 1 3 ethylphenyl)propionyi, p-anisoyl, m--nisoyl, o-anisoyl, m-isopropoxybenzoyi, p-methoxyphenylacetyl, n -4sobutoxyphenyLacetyl, m-diethylarninobenzoYl, 3-methoxy-4-ethoxybenzoyl, 3,4,5-trimethoxybenzoyl, pdibutylamninobenzoyl, 3,4-diethoxyphenylacetyl, 0-(3,4,5-trimethoxyphenyl)propionyl, o-iodobenzoyl, m-bromobenzoyl, p-chlorobenzoyl, pfluorobenzoyl, 2-bromo-4-chlorobenzoyl, 2,4,6-trichlorobenzoyl, pchlosmphenylacetyl, at-(m-bronophenyl)propiony),, p-trifluoromethyl tmzoyl, 2,4-di(trifluoromethyl)benzoy), m-trifluoromethylphenylacetyl, 0- (3-methyi-4-orophnyl)propionyl, p-dirnethylamninobenzoyl, p-(N-methyl- N-ethyiamino)benzoyl, o-acetamidoben-myl, rn-propionamidobenzoyl, 3chloro-4-acetamnidophenylacetyl, p-n-butoxybenzoyl, 2,4,6triethoxybenzoyl, 0- -trifluoromethylpheny)propio,. 2-methyl-4methoxybenzoyi, p-acetarnidophenylpropionyl, and 3-chloro-4ethoxybenzoyl.
SUBSTITUTE SHEET WO 92/17185 PC/US92/022?9 -36- When the hydroxyl protecting group is a carbonate grouping, it has the structural formula 0
Y'-O-C-
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; alknyl having oi,, or two double bonds and 2 to 7 carbon atoms; cycloalkyl-CrHawherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three; phenoxy; or 4-pyridyl; or phenyl-CrH 2 twherein r is ero, 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. Most preferably, Y' is alkyl, particularly ethyl or isopropyl.
Similarly, the expression "carboxyl protecting group" as used herein is intended to designate a group 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 CI-C alkyl, particularly ethyl, isopropyl and t-butyl. While such SUBSTITUTE
SHEET
WO 92/17 t 5 PCT/UJS92/02239 -37simple alkyl esters and the like are often useful, other carboxyl protecting 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 endi carboxyl protecting groups W such as the 3 following may be used in place of the hydrogen of the -COOH group: -CI1 2
C-CE
3 I I 0 0
C
11 0 0 -alk-OCO-alkyl or .alk-0-alkyl, wherein alk is C 1
-C
6 straight or branched alkylene and the alkyl radical is straight or branched and contains I to 7 carbon atoms (e.g.
0 -CHO0COCH 2
CH
3 and -CHIIIH),
CE
3 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:
C
3 -C,2 cycloalky1-CAEP" whereid p isO0, 1, 4.or 3, C6-C 2 8 polycycloalkyl-C H 2
P-
SUBSTITUTE 13CTUS92/02239 WO 92/17185 -38wherein p is defined above- Cj-C~s polycycloalkenyt-C~ H, wherein p is defl.,ed ls above;
C
3 -C,7 cycloalkenyt-CPH2,wherein p is defined~ as above; wherein X. is S, SO or SO, and is C 1 -C7 alkyl or C 3 -C12 cycloalkyt;
-CH
2
-S-R,
CH-
3 wherein R. is dAefined as above; Rb wherein X, is defined as above, Rb, is C 1 -C7 aikyl and is C 1
-C
7 alkyl or is wherein 'Rb and 1b taken together represent -(CH 2 wherein in' is 3 or 4 and -(CHa)me- is optionally substituted by one to three C 1 -C7 alkyl; Rd
-CH-OCOR,
wherein Rd is hydrogen or Cl-C, alkyl and P, is unsubstituted or SUBSTITUTE SHEET WO 92/17185 PJ/U9/23 -39- 0 substituted C,.C 13 alkyl -CHiOC-C(CH) 2 1, C 3 cycloalkyl IP~wherein p is, defined as above, C, 3 -C,2 cycloaLkeny1-CH, wherein p is defined as above or alkenyl, the substiruents being selected from the group consisting of halo, CI-C7 alkoxy, CI-C, alkyltliio, CI-C, 0 0 aikylsulfinyl, CI-C7 alkylsulfonyl, -NHC-(C 1 -C7 alkyl) and -C-(CL-CI alkyl), or R, is unsubstituted or substituted phenyl or benzyl, the substiruerits being selected from the group consisting of Ct-C7 alkyl, C,-C, alkoxy, halo, carbarnoyl, CI-C, alkoxycarbonyl, C, -Cj alkanoyloxy, CI-C 7 haloaLkyl, mono(CI-C7 aikyl)amino, di(Ct-C, aikyl)amnino, mono(Ci-C., alkyl)caxbarnoyI, di(Ct-C, aLkyi)carbamaoyl, CI-C7 aiLkylthio, CI-C., a.Uylsulftnyl and CI-C, alkylsulfonyl, or it. is Cd-C 2 1 polycycloalkyl-CH EP or C6-C 2 1 poI~cycloa~kenyI.CH,,. wherein p is defined as above; Rd
-CH-COORI
wheren Rd and are defined as above; and Rd *CII-CONRfRg wherein Ris defined asabove and RfandR,which canibe the same or different, are each hydrogen, Cj-C, aikyl, C)-C 12 CYCIoa~kYI-CP~HP-, C 3 -Ct' cycloakUnyI-CpH2-, phenyl or benzyl, or one of Rtf anid is hydrogen,
C
1 .C7 alky!, Cs-C1 cycloa&kyI-CK2-, C 1
*C,
2 cycjoalIkey1.C 1 phenyl or benzyi and the other of Pj and R, is C6-Cn polycycloakyI-CH:!P or C,polycycloal eyi-C 11 or Rf and R. are combined such that -NRR 1 represets the residue of A~nnured monocyclic secndary amine.
SUBSTITUTE SHEET WO 92/17185 WO 92/71$5rUS92/0223,9 When the carboxyl protecting group is C3-Cl 2 cycloalkyl-CH,,. or otherwise contains a C 3 -Ct7 cycloalkyl group, the cycloalkyl groups contain 3 to 8 ring atoms and may optionally bear one or more, preferably one to four, alkcyl substituents. Exemplary such cycloalkyl groups are cyclopropyl, 2-methylcyclopropyl, 3-etylcyclopropyl, 2 -butylcyciopropyl, 3 .pentylcyclopropyl, Z-hexylcyclopropyl, cyclobutyl, 2 -methylcyciobutyl, 2,3 -dimethylcyclobutyi, 3 -butylcyclobutyl, 4-hexylcycioburyl, 2,3,3trimethylcyclobutyl, 3,3,4 ,4-tetramethylcyclobutyl, cyciopentyl, 2methylcyclopentyL, 3-ethylcyclopencyl, 4-butyicyclopenty'L, metitylcyciopentyl, 3-penrylcyclopentyl, 4-hexylcyclopenryl, 2 ,3-dirnethylcyclopenryl, 2,2.5 ,5-tetramethylcyclopentyl, 2,3, 4-trimethylcyclopentyl.
2, 4-dimethyl-3-ethylcyclopenryl, 2 ,2,3,4 ,4-pentamethylcyclopenryl, 2,3di niethyl-3-propylcyclopenryl, cyclohexyl, 2, 6-dimethyicyclohexyl, 3,3,5.5 tearnaethylcyclohexyl, 2-methylcyclohexyl, 2 -ethylcyclohexyl, 4-propylis cyclohexyl, 5-butylcyclohexyl, 2,3-dimethylcyclohexyl, 2, 4-dimethylcyclohexyl, 2 ,5-dirnethylcyclohexyl, 2,3 ,4-trimethylcyclohexyi, 2 ethylcyclohexyl, 2 ,5-dimethyi-6-propylcyclohexyl, 2 ,4-dimethyl-3butylcyciohexyl, 2,2 ,4,4-tetramethylcyclohexyl, 3,3,6 ,6-tetramethylcyclohexyl, 3,3 ,4,5,S-pernaniehylcyclohexyl, 3,3,4,5,5 ,6-hexamethylcyclohexyl, 3,3 ,5-trimethyl-4-ethycyclohexyl, 3,4 cycloheptyl, 3-methylcycloheptyl, S -provylcycloheptyl, 6-burylcyclaheptyl, 7-methylcycloheptyl, cyclooctyl, 2-methylcyclooctyl, 3-ethiylcyclooctyl, 3,3 ,4-trimnethylcyclooctyl, 3,3,5,5 -tetramethylcyclooctyi and the lie.
When the carboxyl protecting group is C3-C1 2 cycloalkeny-CPH,,- 23 or otherwise contains a C,-C,2 cycloalkenyl group, the corresponding unsaturated radicals such cyciopentenyl and cyclohexenyl and the Like are contemplated.
The polycycloalkyl-C H, 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 SUBST1TUTE SHEET WO 92/17185 PCI'/US92/02239 -41of 6 to 28 carbon atoms in the ring partion. The corresponding bridged or fused unsaturated alicyclic hydrocarbon systems are intended by the term "Cj-C7, polycycloa~kenyi-CH.p-". Such polycycloalkyl and polycycloalkenyl radicals are exemplified by adainantyl (especially I- or 2adaxnantyl), adaxnantyimethyl (especially 1-adainantylmethyl), adamantylethyl (especially I -adarnantylethyl), bornyl, norbonyl, M.
norbomnyl or Mnk-norbornyl), norbornenyl 5-norbornen-2-yl), norbornylmethyl 2-norbornylmethyl) and norbornylethyl 2norbornylethyl), and by radicals of the type -CH,,-(steroI residue) wherein p is defined as above and the sterol residue is the pordion of a steroidal alcohol which remains after removal of a hydrogen atom from a hydroxy group therein. The sterol 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 -CH.ICQNRfR, wherein -NP.fR, represents the residue of a saturated monocyclic secondary amine, such monocycles preferably have 5 to 7 ring atoms optionally containing another hetero atom or in addition to the indicated nitrogen atom, and optionally bear one or more substituents such as phenyl, benzyl and methyl. flustrative of residues of saturated monocyclic secondary amines which are encompassed by the -NRfR 3 term are morpholino, 1pyrrolidinyl, 4-benzyl-l-piperazinyl, perhydro.-1,2,4-oxathiazin-4-yl, 1- or 4-piperazinyl, 4-methyl- 1-piperazinyl, piperidino, hexatnethyleneirnino, 4phenylpiperidino, 2-methyl-1-pyrazolidinyl, I- or 2-pyrazolidinyl, 3-methyl- 1-imidazolidinyl, 1- or 3-irnidazolidinyl, 4-benzylpiperidino and 4-phenyl-lpiperazinyl.
SUBS11TUTE SHEET WO 982/17185 RC/US92/0239 -42- As yet another alternative, the carboxyl group can be protected by converting it to an amide, i.e. the -COOH group is converted to a -CONRfR group wherein R, 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 viv 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 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 the 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 SUBSTITUTE SHEET WO 92/17185 PCITUS92/02239 -43- Rh -COCH-OCRi II II O 0 wherein Rh is hydrogen, CI-C, alkyl or phenyl and R can be selected from the groups indicated ao suitable carboxyl protecting groups W hereinabove.
Again, the bulkier groups are preferred for use in vivo, and R, is preferably a polycycloalkyl or polycycioalkenyl-containing group, such as adamantyl or a sterol 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 vi~v 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 yiva cleavage will occur in the desired sequence. The mixed phosphate derivatives of formula 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
O
[Dr)-P-O
I
OR,
cleavage of the terminal ester grouping in thus affords an inherently unstabl4s intermediate of the type
(D]-P-O-CHOH
OR,
SUBSTITUTE SHEET WO 92/1785 PCr/US92/02239 -44which immediately and spontaneously releases RCHO 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 hydroxylinked 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 RIOPCO;, 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 vivq 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: SUBSTITUTE SHEET PC-T/tS92/02239 WVO 92/17185
D.O-H
onginal nucleosiderype drug chernical derivation
R
2 0 0 OCH-OCR 1
D-O-P
OR, (1a) form adinistered in viva estersecatalyzed hydrolysis in dv phosphorylation negatively charged "locked-in" intermediate
D-O-P-O-P-.O-P-OFH
I I I OR, OH OH1 active phosphorylated species /invivo phosphorylation itq dix alkalne phosphataso.
catalyzed hydrolysis SUBSTITUTE SHEET Wo 92/1$5 PCT/US92/0223, -46- 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 armve at the active tri-phosphorylated species, while the original drug requires a three-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, the cleavage to form the negatively charged "locked-in" intermediates is much faster than the cleavage of the drug itself from the remainder of the negatively charged
R,
intermediate, no matter what the identity of the -OCH- grouping in formula (la) or The same is true for the case of imide-type and amide-type drugs. Thus, R 2 in structures (Id) and like R 2 in structures (la) and can be any of the groups defined as R 2 values with formula (I) hereinabove. The derivatives of formulas (Id) and like those of formulas (la) and 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 R 2 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 0 sequence, ie, if the bond linking RJC- 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 SUBSTITUTE SHEET WO 92/17 185 PCT/US92/02239 -47- *OCH,- linkage for -OCH- in formulas (Ic) and that linkage becomes particularly susceptible to esterase. Nevertheless, judicious selection of the linkage in formula (1c0 and the -OCH- linkage in formula (ITo is required. For example, when the drug residue is sterically hindered, can be -OCH 2 in formula because that bond will be less 0 susceptible to esterase than the bond linking R 3 to the rest of the molecule, due to steric considerations. Likewise, -OCH- can be -OCH-l 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 cannot be -OCH 2 in formula 1s (Ic) and -OCH- cannot be wOCHI- in formula In this way, 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, tranquilizers, anticonvulsants, antineoplastics (anticancer/antitumor agents), hypotensives, antidepressants, narcotic analgesics, narcotic antagonists and agonist/antagonists, CNS anticholinergics, stimulants, anesthetids, antiinflarmatory steroids, nonsteroidal antinflarnmatory agentsanalgesics.
SUBSTITUTE SH-EE:T WO092/17185 ~/U9/2~ FIC17US92/022,19 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 hormoneslandrogens such as testosterone and methyl ,estosterone; and female sex hormones, including estrogens, both semisynthetic and natural, such as mestranol, quinestrol, ethinyl estradiol, estradiol, estrane, estriol, estxadiol 3-methyl ether and estrmdiol benzoate, as well as progestins, such as norgestrel, norethindrone, ethisterone, dimethisterone, allylestrenol, cingestol, ethynerone, 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 glucoside derivatives and others. Those of the nucleoside type 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, ,3-dihydroxypropyl)adenine, 6azauridine, acyclovir (ACV), 5,6-dichloro-1-4-Dribofuranosylbenzimidazole, 5 ,7-dimethyl-2-f3-D-ribofuranosyl-s-triazole pyrimidine, 3-deazuridine, 3-deazaguanosine, DHPG (ganciclovir), 6-azauridine, idoxuridine, dideoxycytidine (DDC), trifluridine (trifluorothymidine), dideoxyinosine, dideoxydehydrothymiddine, dideoxyadenosine, BVDU, FIAU, FMAU* FIAC, Ara-T, FEAI), cyclaradine, 6-deoxyacyclovir, 3-deazaaristeromycin, neplanocin A, buciclovir (DHBG), selenazofurin, 3-deazaadenosine, cytarabine (cytosine arabinoside; Am-C), 5-FUDR, vidarabine (Ara-A), tiazofurin, 3'-fluoro- 2',3 -dideoxythyrnidine (FddThd), 1 -(2,3-dideoxy-o-D-glyceropent-2- SUBSTITUTE SHEET PCr/US92/02239 WO 92/17185 -49enofuranosyl)thrnine (D4T or d4T), 3'-fluoro-2',3'-dideoxy-5chiorouridine (FddCltrd), 5-(2-chloroethyl)-2' -deoxyuridine (CEDU), ethyl-2 -deoxvuridine (EDU), 5-(1 -hydroxy-2-chloroethyl)-2 '-deoxuridine.
5-(1 -methoxy-2-bromoethyi)-2'-deoxyuridine, 5 -hydroxy-2-bromo-2- (ethoxycarbonyl)ethyl)-2' -deoxvuridine. 5-(l-hydroxy-2-iodo-2- (ethoxycarbonyl)ehyl)-2'-deoxyuridine, '-azido-2,3 '-dideoxyuridine (AZT), 3'-azido-2' ,3'-didery-5-bromouridine, 3'-azido-2' iodouridine, 3'-azido-2',3'-dideoxy-5-methylcytidine and 3'-fluoro-2 dideoxyuridine (Fddlrd). These and numerous other nucleorde-type antivirals suitable for derivatization in accord with the present invention have been described in the Literature. See, for example, Van Aerschot et al, L Med.Chm. iML2, 32, 1743-1749; Mansuri et al, M1i. d Che;tZ.
iM, 32, 461-466; Kumar et at, L CM, Chm. IM, 32, 941-944; Lin et al, 1 Med.Chem. IM 32, 1891-1895; Kim et at, JL Mr-LChm. 142L7 30, 862-866; Lin et al, J. Mdcihem,. IM 30, 440-444, Herdewijn et al, 1. c4 Chem, IM, 31, 2040-2048; Turk et al, Antimicrobial Agents andCemothcimy, Apr. 1987, Vol. 31, No. 4, 544-550; Elion, in Toics in Medicinal Chemistry, 4th SCi-RSC Medicinal 'hemisty SI mpsium, ed. P. R. Leening, Royal Society of Chemistry, London, 1988, pp. 163- 171; Roberts et al, in Topics in M 'icinl Chemisty, kUSCI Medicinal Chemistr Symsium, ed. P. R. Leeming, Royal Society of Chemistry, London, 1988, pp. 172-188; Kelley, in TPics in Medicinal CJemila Ath SCI-RSC Medicinal Chemistry Sympos=i, ed. P. R.
Leerning, Royal Society of Chemistry, London, 1988, pp. 189-212; Harnden et al, in Ilicsin Medcinal Chemistry, 4th SCI-RSC Medicinal Che S tuim, ed. P. R. Leeming, Royal Society of Chemistry, London: 1988, pp, 213-244; Reist et al, in Nuclewotide -Anaoues as Anivral An=s, ACS Symposium Series 401, ed. John C. Martin, American Chemical Society, Washington. 1988, Chapter 2, pp. 17- 34; DeClercq, in Appmnahc IQ AntvWL Agnts, ed. Michael.R. Harnden, VCH, Great Britain, 1985, Chapter 3, pp. 57-99- Holy, in Appaches IQ SUBSTITUTE SHEET WO 92/17185 WO 92/7185 c'r/US92/02239 -sontAMAgns ed. Michael R. Hamnden, VCH, Great Britain, 1985, Chapter 4, pp. 101-134; and Hovi, in Antiia L cats The Queelopment and'Assessment of Andj~ral 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 tiucleoside-type antiviral via a primary hydroxyl in the 5'-position or corresponding position when the antiviral does not have a Non-riucleoside antivirals for possible derivatization herein include hydroxy-containing glycosides such as 2-deoxy-D-glucose and 2-deoxy-2fluoro-D-mannose, phenyl glucosides such as phenyl-E-chloro-6-dexyi3-Dglucopyranoside and benzimidazole analog type antivirals such as the syn and anti isomers of 6O[(hydroxyimino)phenyl] methyl]- methylethyl)sulfo~iy1]- H-beftzimidazol-2-amine.
Is Among the tranquilizers for denivatization herein, there can be mentioned hydroxy-containing benzodiazepine tranquilizers, for example oxazepam, lorazepamn and temazeparn; tnanquilizer of the butyrophenone group, such as haloperidol; tranquilizers of the diphenylmethane group, for examtple hydroxyzinel, phenothiazine-type tranquffizers, for example acatophenazine, carphenazine, fluphenazine, perphenazine and piperacetarine; and tranquilizer analogs of phenothidzines, e.g.
ciopendai~l.
Among the hydroxy-containing anticonvulsants, there can be mentioned, for example, the metabolites of vaiproic acid, i.e. 5-hydroxy-2n-propyipentanoic, acid, 4-hydroxy-2-n-propylpentanoic acid and 3-hydroxy- 2-a-propylpentanoic acid.
Among the antineoplastics, i.e. anticancer and/or antitumnor zgents, theri can be mentioned as illustrative urea derivatives, hormonal antineoplastics, podophyllotoxins teniposide, etoposide), antibiotictype antibiotics, nitrosourea-typ alkylating agents and, especially, purine and pyrirnidine antagonists. The purine and pyrimidine antagonist-typ, SUBSTITUTE SHEET WO 92/171$6 PCT/ US92/02239 antineopiastics include simple purine and pyrimidine base-type structures, e.g. thioguanine and 6-merca.ptqpurine, ao well as those of the nucleosidetype,, e.g. Ara-AC, pentosratin, dihydro-5.azacytidine, tiazofurin, sangivamycin, Ara-A (vidarabine), 6-MMPR, 5-FUTDR (floxuridine), cytarabine (Ama-C; cytosine anibinoside), 5-azacytidine (azacitidinc), uridine, thyrnidine, idoxuridine, 3-deazauridine, cyclocytidine, azactidnetriciribine and fludrabine. Many nucleoside-type compounds have utilty 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 clindarnycin and lincomycin.
Among the narcotic analgesics, there can be mentioned those of the ,neperidine type such as meptazirnzl, profadol, and myfadol; and those which can be considered morphine derivativet. 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.
1he narcotic antagonists and mixed agonist/antagonists include such compounds as nalbuphine, naloxone, nalorphine, buprenorphine, butorphanol, levallorphan, naltrexone, naimefene, aLazoine, oxilorphan and nalmexone.
Xhe antiinflammatory steroids include such pompounds as cortisone.
hydrocortisone, betaxnethasone, dexamethasone, flumethasone, fluprednisolone, methyl prednisolone, meprednisone, prednisolone.
prednisone, triamcinolone, triamcinolone acetonide, cortodoxone.
SUBSTITUTE
SHEET
WO 92/17185 PCT/US92/02239 -52afudrocortisone, 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 that when drugs containing a reactive hydroxyl function are selected for derivatization in accord with the present invention, both ID] and OR, is formula can be drug residues. While virtually any of the hydroxylcontaining drugs disclosed above could be used to prepare a compound of formula in which and ORt 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 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 both and -OR, represent AZT (zidovudine) residues or in which both represent DDI (dideoxyinosine) 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 anuvirals. Nevertheless, even when the combined effect is no more than additive, it may be convenient to incorporate residues of two different SUBSTITUTE
SHEET
WO 92/17185 PCI/U$92/0223() .53drugs in the same molecule, as may be the case for certain antineoplasticantineoplastic or antiviral-antiviral combinations, antineoplastic-antiviral combinations, antibiotic-antinflammatory combinations and estrogenprogestin combinations. Still further, when -OR i represents a drug residue in formula 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 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 sen. but simply a protective residue which functions to enhance transport or delivery of the drug whose residue is represented by principally by improving lipophilicity. It must, however, be a group which is enzymatically much less sensitive to cleavage in ivvo than the acyloxyalkyl group -OCH(R)OCOR 3 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 as ID] and OR 1 residues, an estrogen such as estradiol may be paired with a progestin such as norethindrone, 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 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/enzymeinhibitors have themselves been co-administered. See, for example, Antiviral Agents: The Development and Assessment of Antiviral hmotherapy, Volume II, ed. Hugh J. Field, CRC Press, Inc., Boca Raton, Florida, 1988, Chapter 3, pp. 29-84.
SUBSTITUTE SHEET WO 92/17185 C/J9/23 PC'X'/US92/02239 54 Adenosine-containing nucleoside antivirais are susceptible to adenosine deamninase metabolism, Deamination appears to substantially decrease activity, Incorporation of an dearninase 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 SUJBSTITUTE SHEET WO 9211185PCT/UJS92/O2239 adenosine deaminase enzyme. Antiviral drugs susceptible to such inactivation include vidarabine (adenine arabinoside or Ara-A), 3deoxyadenosine (3-dA, cordycepin) and 2',3'-dideoxvadenosine.
Adenosine deaminase inhibitors include coforrnycin, 2'-deoxycoformycin, ERNA (erythro-9-(2-hydroxy-3-nonyladenine1, acyclo-coforrnycin, DHPA [9-(2,3-dihydroxypropyl)adenine] and Nl-methyideoxyadenosine.
Combination of such an antiviral drug and such an enzyme inhibitor in a single molecule of formula may be of particular use in combating DNA viruses such as vaccinia virus, varicella-zoster, HSV-l, HSV-2, adenoviruses, etc.
2'-Deoxycytidine and many cytidine analogs are substrates for cytidine-deoxycytidine deaminase, which is widely occurring. Deaxnination by cytidine-deoxycytidine dearninase may h ito enhanced cytotoxicity and/or reduced activity. Antivirat nucleosides susceptible to this enzyme is include the 5-iodo- and 5-bromo-2'-deoxycytidines, Ara-C and FIAC (I- -deoxy-2'-fluoro-B-D-arabinofuranosyl)-5-iodocytosine], while the enzyme inhibitors includes tetrahydrouridine (THU and 2'-deoxytetrahydrouridine (2-THU). DNA viruses such as HSV-lI and -2, VZV and RCMV may be particularly susceptible to such combination in formula Thymidine, uridine and many pyrimidine nucleoside analogs are subject to cleavage by phosphorylases. By inhibiting phospharylysis, 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-21-deoxyuridine), S-ethyI.2#.deoxyuridine (EM~R), trifluridine CMF or 5-trifluoromethyl-2' -deoxyuridine), 5-E-(2bromovinyl)- 2'-deoxyuridine (BVDU) and 5-(2-chloroethyl)-2 deoxyuridine (CEDtJ). Thymidine and uridine phosphorylase inhibitors include 5-benzyl acyclouridine, 2'-deoxyglucosyl thymine and acyclouridine. Again, combination of antiviral and inhibitor in a single SUJBS1TITUTE
SHEET
PCr/US92/02239 WO 92/17185 -56compound of formula 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 may be made, by way of illustration, from among virus-specific agents which act on or via DNA polymerase, from cormiinations 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), (2-bromovinyl)-2'-deoxyuridine (BVDU), 9-(2-hydroxy- 1- (hydroxymethyi)ethoxymethyl)guanine (DHPG), spongothymidine (Ara-T) and 5-athyl-2'-deoxyuridine (EtUdR) may be selected, e.g. residues of ACV and BVDU, DHPG, and BVDU, ACV and DI{PG, Ara-T and ACV, and Ara-T and EtUdR combinations as the and OR, moieties.
Combinations tcf I)NA- specific with less specific nucleosides include, for example, seleetion of a specific agent such as ACV, EtUdR, MMUdR (5-methoxymethyl-2'-deoxyuridiLne), BVDU or Ara-T, together with a less specific agent such as Ama-A, It~dR, TFT, M~R, FMAU, FIAC or Ara-C. Ilustrative of such combinations as and -OR, are the residues of ACV/Am-A, ACV/FJAC, ACV/1UdR, ACV=TF 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 Ara-A, It~dR, T~r, Mt~R, FMAU, FIAC, Ama-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 Ama-A with IUdR, Ama-A with Ara-C, It~dR with Mt~R, Ma-A with FLAG, Ama-A with FMATJ, Ama-A with TMT Moreover,,choice of one of these agents for derivatization may be combined with a choice of a SUBSTITUTE SHIEET WO 92/17185 I'Cr/US92/022393S 57 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), dideoxyinosine (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 in which both and -OR, are selected from the group consisting of residues of AZT, DDI, D4T, DDC and dideoxyadenosine, especially when one of [D] and -OR 1 is an AZT residue.
Other especially interesting compounds of the invention in which both and -OR, represent different drug residues are those in which one of and -OR, is a highly active drug residue, e.g. an AZT residue or residue of other nucieoside-type antiviral, and the other of and -OR 1 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-As-17one), or a long chain, aliphatic alcohol (typically a C 9
-C
22 fatty alcohol, such as stearyl alcohol, myristyl alcohol, lauryl alcohol, cetyl alcohol or decyl alcohol) or po'ycarbocyclic alcohol adamantanemethanol) used to enhance delivery of the antiviral agent via improved lipophilicity.
Indeed, the R, 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-CpH 2 polycycloalkyl- SUBSTITUTE SHEET WO 92/17185 PCT/IJS92/02239 58 C HZ, "and so forth, especially the polycycloalkyl-CHP- groups as defined and exemplified hereinabove), just so long as it is enzymatically much less sensitive to cleavage in yjvy than the -OCH(R 1
)OCOR
3 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 -OR 1 is of particular interest when the drug is hydrophilic a nucleoside); on the other hand, when the drug is lipophilic, R 1 can easily be one of the smaller, more simple residues methyl) as there is no need to enhance lipophilicity. The final compound of formula 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 It should be understood that in all of the situations discussed above ,n which both and -OR 1 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 sedativesanticonvulsants/ 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; SUBSTITUTE SHEET WO 9J2/17 185 Pc'r/ US92/02239 -59 GAflAergic agents/antiepileptics, for example progabide; vaiproic acid derivative-type anticonvulsants, e.g. vaipromide; barbiturate antagonists, for example, bemnegride; tetracycline-type antibiotics, such as demneclocycline, oxYtetracYclne, chlortetracy-y-ine, tetracycline, methacycline, minocycline and doxycycline; nonsteroidal andinflammatory/analgesic agents, e.g. tesicam; and antineoplastics, for example alkylating agents of the nitrogen mustard-type, e.g. uracil mustard, spiromustine and cyclophosphamide, alkylating agents of the nitrosourea type such as PCNU, purine/pyrimidine antagonists, e.g. 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/antibacteials, diagnostics and nonsteroidal antiinflammatory agents/non-narcotc analgesics.
SUBSTITUTE SHEET WVO 92/17185 PCT/ US92/02239 More specifically, there can be mentioned anticonvulsants, e~g.
vaiproic acid; antineoplastics, for example, nitrogen mustard-type alkylating agents such as chiorambucil and folic acid antagonists such as methorexate and dichloromethotrexate;, penicilin-Mvp antibiotics such as amnoxicillin, phenoxymethylpenicillin (penicillin benzylpeniciiln, dicloxacillin, carbenicillin, oxacillin, cloxacillin, hetacilln, rnethiciflin, nafcillin, ticarcillin, and epicillin; cephalosporin-typ antibiotics, e.g, cephalothin, cefoxitin, cefazolin and cephapirin; miscellaneous other antibiotics, e.g.
oxolinic acid; nonsteroidal andinflammatories/non-naxcotic analgesics, including propionic, acetic, fenanie and biphenylcarboxylic acid derivatives, for example, ibuprofen, naproxen, flurbiprofen, zomepirac, sulindac, indomnethacin, ketoprofen, fenbufen, fenoprofen, indoproxen, fluprofen, bucloxic acid, tolmetin, aiclofenac, fenclozic acid, ibufenac, flufenisal, pirprofen, flufenamic acid, mefenamic acid, cloni'xin, meclofenamic acid, flunixin, diclofenac, carprofen, etodolac, fendosal, prodollc acid, difiunisal and flutiazin; and diagnostics such as diohippuric acid and iothalamnic acid.
Drugs containing a reactive amino function for use in accord with the present invention include, but are not limited to, GAflAergics/antiepileptics, antineoplastics, cerebral stimulants, appetite suppressants. MAO inhibitors, tricyclic antidepressants, decongestants, narcotic analgesics, antivirals, neurotrasmitters, small peptides, dopamninergic agents and antibiotics. Mlustrative drugs of this structural type include antiepileptics such as GABA, -y-vi- yl GABA and 'y-acetylenic GABA; nitrogen mustardtype antineoplsacs such as meiphalan; antibiotic-type antineoplastics, e.g.
daunorubicin (daunomycin), doxorubicin (adriwmycin), dactinomycin and mitomycin C; nitrosourea-type antineoplastics such as alanosine-, miscellaneous other antineoplastics, e.g. bactobolin, DON and acivicinw.
sympathetic stimulantslappetite suppressants, such as methamnphetamine, phentermine, phenmetrazine, dextroarnphetaxnine, levamphetamnine, amphetamine, phencethylarnine. methyl pherudate, aletaniine, cipenarnine, SUBSTITUTE SHEET WO 01V/17185 PCl'/US92/02239 -61.
fenicamnfamin and etrypranine; MAO inhibitors, e.g. tranylcyprornine; tricyclic antidepressants, e.g, protriptyline, desipramine, nortriptyline, octrptyline and mapratiline; cerebral stimulants, e~g. amedalin, bupropion.
cax-taolate, daledalin, difluanine and nisoxetine; antivirais such as glucosamnine, 6-amino-"-eoxy-D-glucose, a'nantadine and rimantadine-, amino acids/neutrotransmitters, eSg. tryptophan; small peptides, typically containing 2-20 amino acid units, e.g, the enkephalins (leus-enkephalin, mevO-enkephalin), endorphins and LHRH analogs; catecholamine neurotranszniters, e.g. norepinephrine, epinephrine and dopamine; other neurotransmiitters, e.g. serotonin, and related compounds such as tryptamine; penicillin-ype 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 is are pharmacologically active metabolites of drugs. Such metabolites are typified by hydroxylated metabolites of tricyclic antidep.,,sants, such as the E- and Z-isorners of l0-hydroxyniortriptyline, 2-hydroxyitiprarnine, 2hydroxydesipramine and 8-hydroxychioriprarine; hydroxylated mnetabolites of phenothluzine tranquillwsn, e.g, 7-hydroxychiorpromazine; and desrnethyl 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-CCNtI, which is an active metabolite of CCNtJ, an anticancer nitrasourea, Typically, these pharmnacologically active metabolites have been idetitifled as such in the scientific fiterture but have not been administered as drugs themselves, In many ce=, the active metabolites are believed to be comparable in activity to their parent drugs;, frequently, however, the metabolites have not been admini1stered r, because they are not themselves able to penetrate biological membranes such as the blood-brain barrier.
SUSTITUTE SHE ET PCT/US92/02239 WO 92/17185 62 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 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 radiopaque agents) or other means such as mass spectrophotometry, NMR or other noninvasive techniques when the compound includes stable isotopes such as C13, N15, 018, S33 and S34). The diagnostic alternatively may be "hot", i.e. radiolabelled, such as with radioactive iodine (1 123. 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 (1 125, 131), diotyrosine (1125, 1131), o-iodohippuric acid (1131), iothalamic acid (I 125, 1131), thyroxine (1125, 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 disclosed herein which are intended for the treatment or prevention of medical disorders but which can be radiolabelled, 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 When the drug selected 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 SUBSTITUTE
SHEET
WO 92/17185 1PCP/US92/02239 63
R,
bridging group -CH-0- as described above for linking amide and imide groups to the phosphate, rather than a direct bond betwee~ the drug's hydroxyl group and the phosphorus atom.
The compounds of formula can be prepared by a variety of synthetic procedures tailored to the strur*re 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. The ILLUSTRATIVE SYNTHETIC 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 (la) to (If): The compounds of formulas (la) and (Ib) can be synthesized by first converting the drug, D-OH or spectively, to the corresponding mixed phosphate diester intermediate of the formula I I ORI ORi respectively, which can be accomplished by one of variety of methods; then by converting the resultant intermediate depicted above to the corresponing mixed triester of formula (la) or which also can be SUB8STITUTE SHEET WO 92/1718 PCT JS92/02239 64 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-chloromethyl-4nitrophenylphosphorodichloridate and subsequent hydrolysis to give the corresponding diester of the type D-O-P-OH or D-S-P-OH I I 0 NO, 0 NO, CH2CI
CHCI
which is then reacted with R 1 OH to afford the desired intermediate D-O-OH or D-S-P-OH OR,
ORI
(Alternative routes to that intermediate include reacting the starting alcohol or thiol with POC1I, then subjecting the resultant D-O-P-Cl or D-S-P-Cl I I Cl Cl to reaction with ROH and subsequent hydrolysis; or reacting the starting 0
II
alcohol or thiol with RiOPC1 2 That intermediate can then be treated with aqueous sodium hydroxide and aqueous silver nitrate to afford the corresponding silver salt, SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 D-O-P-OAg or D-S-P-QAg I I UR, OR 1 0 11 respectively. Reaction of the silver salt with R 3 C-OCH-1, e.g.
0 11 (CH3) 3
CCOCH
2 I, affords the corresponding compound of formula (Ia) or 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 10D-0 P-OFI or D -S-r-OH ORI OR, prepared as desribed above, is reacted with cesium fluoride (or 0 11 equivalent cesium salt) and a compound of the formula R 3 C-OCH-I, e.g.
III
CHX(H
2 4
COCH
2 I, in a suitable organic 6.Avent, e.g. dimethylforrnamide, acetonitrile, nitromethane, chlorofarm or dimethylacetamide, to give the corresponding compound of formula (1a) or respectively.
When both D-0- and OR, in formula (Ia) represent residues of drugs having reactive hydroxyl functions, an advantageous synthetic method SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 66 begins with reaction of 2-chlorophenyl phosphorodichloridate with 1hydroxybenzotriazole to afford 2-chlorophenyl-O,O-bis([-benzotriazolyl]phosphate of the formula 0 _J-N N CI O according to the method of van der Marel et al, TagtredM n Iti 22, 3887-3890 (1981) and Wressmann et al, Nucleic Acid Res. Jl, 8389-8405 (1983). When D-O- and -OR are not identical, there follows a two-step process in which, as the first step, 2-chlorophenyl-O,O-bis[lbenzotriazolyl]-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, ROH, under the same conditions as in the first step, to give the desired mixed phosphate diester intermediate of the formula 0
D-O--OH
bR 1 When D-O- and -ORI 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 by one of the methods described SUBSTITUTE
SHEET
WO 92/17185 PC/US92/02239 67 in the preceding paragraph, preferably by reaction with cesuim fluoride and 0 0 I; II a compound of the formula R 3 C-OCH-I such as CH 3
(CH
2
)COCHI,
RI
or by reaction with sodiun methoxide and a compound of the formula 0O
I
R
3 C-QCH-CI. As yet another alternative when D-0- and -OR, are RzP identical, a one pot process utilizing 2-chlorophenyl phosphorodichloridate and l-hydroxybenzotriazole yields 2-chlorophenyl-O,0-bis(1-benzoriazolyl]phosphate as an unisolated precipitate, the reazion suspension then being reacted with two equivalents of D-OH without further addition of solvent to afford the intermediate 0 0 op-* OD) 2 C1
CI
That intermediate can be isolated by column chromatography (although the 1is 2-chlorophenyl moiety can be easily hydrolyzed on the column), then subjected to deprotection with pyridine-2-aldoxime and 1,1,3,3tetramethylguanidine 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 D-COO-Z-C1, SUBSTITUTE SHEET PCT/US92/02239 WO 92/17185 68 0
II
which can be reacted with a silver or cesium salt of ROP(OH) to afford a compound of the type O OH
II
D-COO-Z-O-P O
OR,
That intermediate, which contains a linking group bearing a reactive -OH, can then be reacted with cesium floride or equivalent cesium salt 0
II
and a compound of the formula ICH20OCR3 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 //o C 0 If reacting the drug, D NH or t-C-NH, respectively, with an C R 0 appropriate 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 0 C R2 O R 2 I It I intermeiate of the type D N-CH-OH or D-C-N-CH-OH. That Co SUBSTITUTE
SHEET
WO 92/17185 PCI/US92/02239 69 intermediate, which contains a linking group bearing a reactive -OH, can then be reacted, analogously to the compounds of formula (Ia) and (Ib), first to give the intermediate 0 C R OH 0, R, O OH D N-CH-OP or D-C-N-CH-O-P respectively, then C OR, R 4
OR,
0 with cesium floride or equivalent cesium salt and a compound of the 0
II
formula RC-OCH-I in a suitable organic solvent, as discussed
R,
hereinabove for the hydroxy-containing drugs, to give the corresponding compound of formula (Id) or respectively. Drugs containing reactive primary or secondary sulfonamide functions (D-SO 2 NH or D-SO 2
NHR
4 can be derivatized similarly to the primary or secondary carboxamidecontaining drugs to give analogous compounds of formula and are within the ambit of the present invention. The identity of the R group in the secondary amides and sulfonamides, like the R. 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, DNHR 4 with a halo(optionally substituted methyl)chloroformate to give an intermediate of the type D-N-CO- H-halogen, Ra R' SUBSTITUTE SHEET WO 92/ t7185 PCT/US92/02239 70 0 O
II
which can then be reacted with a silver or cesium salt of RIOP(OH), to afford a compound of the type 0 0 OH II II/
D-N-CO-CH-P
R. R2 OR, That intermediate, which contains a linking group bearing a reactive -OH, can then be reacted with cesium floride or equivalent cesium salt
O
!I
and a compound of the formula ICH 2 OCRI in a suitable organic solvent as 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- S1 known metho.- dnd 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 wellknown 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 v..
SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 71 The starting materids needed for the vanous processes described above are commercially available or can be readily prepared by known methods.
LUSTRATIVE SYNECMETHODQ1S 1. Mathods nf Dearivizi l -Functions in D METHOD A The drug containing a reactive hydroxyl or mercapto function is reacted with a phosphorylating agent such as 2-chloromethyl-4nitrophenylphphosphorodichloridate, followed by hydrolysis, followed by reaction with methanol, to afford the intermediate phosphate diester. The resultant intermediate is then 0 I I reacted with cesium fluoride and (CH),CCOCH 2 I in an organiic solvent such as dimethylformamide to give the desired compound of formula (la) or 1iS 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 (Ia) or (Ib) ("Final Product").
SUBSTTUTE SHEET Startingc HateriaI Intermediate IntermdiateFinal Product 0U I oclif
II
testosterone 0 OfI 0 11,.0c1H 0 3 0 0 ii I.OCH OCC( Ci 31 H 3 zidovudine (AZT) WO 92/17185 4 0 4 '-4 0 PCr/US92/02239 73 3 14
OU
0
U
0 0 ou0 0 SUBSTITUTE SHEET starting--Iateria7, Coll Cl Intermediate, Final Product CH 3 Op I .1oi j 1 4 temazepam
C-
hydroxy: ine Ct 0 00 CH -0-C 2I OP11.-onH4
O
H- y-CK 2 JCI 20- 2 H4 p1 Ocif
I
staxrti-ncq MaterMEAl Itrei intermadiate Final Product IcLcct CItiZCJlczC1 I" CfC20 S)JLNJ
CCCK
0 I0 j1 1C--tCcl ICz' I~occoCC(I i Of 2C H 2 C 2 1 H ZC II__
O..
acatopbflaziflb ocil 3f101,1Il .Ci 2 CHI0H CCF 0
CU
2 CHCHHt N -CH 2 CH lpON Oci flt~tenaz1z~e startinl Material Intermediate IntemedateFinal PFrOduct I N Cl 0 III Ic1 2 CH 1-N '4-Ci 2 cli I OPji 2 2 c III ICWWIC1.
2 N H-CH 2 ICH 2
OH
perphflazifle :acI 0 ICH 2-I N-CH I CH 2 OP N j o c i 3 CH cif I1Of 2 N H-CI H ai OH
N
0
ICH
2
H
2 CH Ni Ni -C C O p 2JC2I 2 \CC2C2 [Nj cl carphonazile Startingi Material
NAA
I COd] CH11 2 f 2 No CUi ICH 2 0111 piperacetazine Intermediate I aLOH
CH
2
CH
2 ~CHN\-C 3 00 II0..%II -CI .11C CH fH 2 CH 2Oil ?inal Product COCH 1 0 Ioul CCIClIC It CH I'No i ClI OP 2
I
0 11 0 1 CCOCH 2 cxjI A) II 1 C0 "'o-lf2CII L 110- CffHiClly-, z ClI11CA I "C11 OH -hydroxy-2 -npropylpentanoic acid Starting MaterialIteit ia r~~ Intermediate Final Produvt sit It N
N
I
0 Il OHf 0Ch N 3 NE
H
tbioguanine sit H 0 If 00 (CH I CCOCEif 1f 3 C co 6-mercaptopurilB _tartincr mat-erial oil intermegiate IntermdiateFinal Product Cia Oil 0 11I,.,H OP N% o t
N
0 0 1j op-oi IOCC(CiI OP 2 pentostatin (2 '-deoxycoformycin) mu 2011 N c i 3 oNi Startingr Material Jtreit ia rdc Interm2diate Final Produc.
0
NH
NOcif li1_-ucII occicil I 2l I I 3 OH OH 0H off OH Oil tiazofurin Ni
NH
MHoll 0 CH2OP Ok
OH
OH
ti 2 N0 0 0j 2 oe 2 11 3) 0" vidarabine (Ara-A)
WI
(n -i tr±4ncTKaterl
N
24 H l It0 Oil intermediate CH
N-
Ho OH N> 0 KH 3 o 0 l! o-o~it 2
I'
Ito off IntermdiateFinal Product 6-MMPR 0 0 0 11 OCH 3 (floxuridins) 0 \~0 starting Material Intgrmediate Final Product O 00 NJilN~ 2 Ni
N
0 f 011 6 01-1 0 0 if OH
O
cy"t.rabine (Ara-C; 6ytosins arabinoside) Nit N H N~ Ni 0(0 0 Q-CCH 0cll I 0 Cif CHOff0oe 11"'OH Of OP 1 13 3 2 CH P %0d 3 I NJOddt It0 Off Ho OH cn -azacytidine startinct Material Itreit ia rdc intermediate Final Product cci f 2 fICi i 1 I cl Ito CH 2 CH 2 CH 2 N (CHl 3 1 ci I O2c li2II 0 c I If co IllP H 3c 7 -hydroxychiorpromazile OfI2i 2 Of2 1(li312 2 -hydroxyimipramine 0 Ii..OH 2I CH 2CH 2N(CH 31 0 0 1 CIIALT CI II II 2 2212 startingr Material Itreit intermediate FinaL Product 0 0 1 OP 2 C C1 3 Ocli
IC
cH 2 cil il2N H )I -ci 2 2 i3)l I -ci CH 2 CH 2 CH 2 N(CH 3 1 2 8 -hydroxychlorimipramine zcifI 0 i-o -j 0 (Clij ]ccocli I .%jI lii c
IP
hydromorphone Starting Material Intermediate Final Product II o 00 11 H ICo.
oxymorphons H jC flo oil apomorpbine 0
OH
It 3 C0 11 3 C 0 11 0 vi 3 co Starting MaterialItrdatFilPrdt Intermediate Final Product
~PO
Ht ICO (CHI 3) levorphanol /H3 CH 3 0 l.op OP*.
H
0 0 1 OP 2 OcIli morphine startina Material Itreit ia rdc Intermediate Finil Product OfII
I
OfI If 3 CO 'lP CH 3 0 (C1i 1 3 CCOCH 2 O..jI t' 3CO pentazoeile ,CH
I
1H.
3 c0 Hf CO 1 0 0 N1-C HOCC(Cli Of. If 11 3CO codeine startinct Material Itreit ia rdc Inte edi ate Final Product H 1CO 0 0j IIIf 1-OpI C, 2 CC11 I,
OP
ocil 11 CO if 3 C0
OC
oxcycodoflO Ci oil CH o 0 N% 0 oc 3 l~i OdE 3 nalbuphine Startincy Material
H-
1 I4CH 2CH H 110 0 intermediate, N-C" H
=C
2
H~
HO 0 II 3O a Final Product 0
ICH]
3 )f3CCOCHOII 11 3 C00 naloxofle Of CH-CII2 0 00 '01--o ifOCCgCIg op N C
I
OCH 3 nalorphine startingT Material itreit ia rdc Intermediate Final Product -CH2
I
C(CH 3 (ICII 313 Ic,3 N, IC CIl buprenorphine Cif 2 0 11 0 (LiI 33 ,CCOCH o0jI d
PO
i3 Co 0* .Io'ji
APO
If 3CO butorphanol Stairting~ Material intermediate FialProduct 'CHl4 /ci2-
PO
i3c 0 (Cif J1 3 ccocilI o...j llolPO It Co naltrexofle CHf.J If 3 o" PO
CH
2 /cif 2 ~1 0 If c I) 3 cc c I 2 o1-I 1-11PO If 3CO nalmefene Final Product Startingi Material CONH 2
N
IN-I
CONH
N 2 2 OHtNk 0 IL"o-OH 1 OP
C
CONH
2 00 WN 0If ll'-ocu 2 0Cocuo I 0 C P23 j OCliI ribavirin
N
2 110 0ff NH 2 03 NitJ
N
N
0 If Co dihydroxypropyl) adenine Startingr Material 0
IIN
ci.o ji f O
H
Interrv!.Aiate HNi N 0 0 'octi H6 OH Final Product 0 o0 0; 11op-ct 2 occ(CHI1 3 CH7O Iocil' l10 oil 6-azauridifle 0
N
CH2O 142 H op N 2 O CC f( ij Of jocif I cif 2 off 0 O1gt 3 acyclovir Startingr Material rtrdieFnlPodt intermediate Final-PK2duct yC 20H, 0 l.OH lo C11 c I a L1"OCH OCC(CII 0 cli 2O 3 t1 OOIl Ho$ 0111 ribofuranoisylbenz imidazole 'CliI 0 j H IOP OCCIj ONi It0 Oil 7-dimethyl-2-pO-Dribofuranosyl-s-triazoie pyrimidine Ito OH1 110 Oil Starting Material Intermedijate 0 0 0 OCH 3 O" OH Final Product CiI 21OH 00 CH 2 OP I OcIIJ OH Olt 3-deazauridine 0 0 1 11 ocki ocC OP 2 C(a 3 3 OCli Cii OH0 ItI N H 2N 0 II ,OH CH 2OP N oi OH OH 3-deazaguanosine OH OH startingy material Itreit ia rdc Intermediate Final Product I2 Cl HC 2 Of I ILOH CH 2
O.
1 HCH 2 OP 111 CI 2 0Hf 0 '0 11 I 11OCHCH Qp~O 2 CC(Cti I ci 2ocici2 O 23I CII)I i gancielovir (DHPG) 0 0
H
0 -Oclf OCCICHJ 3j 13 Off Oil OH oil OH Oil 6-azauridifle Btaltilc material Itreit ia rdc intermediate Final Product 0 C H l 2 c l 11 0 0 1 c 1 1 2 oOctHOCC(Ci I~ OfI OP 2 N j Oclij C112i l idoxuridine
NH
l"-OCH OCCIH CII CfH2P 2 3 2 Of 2 N
OCH
dideoxycytidine (DDC) Btartinct Material Itre~t ia rdc Intermediate Final-kroduct CF 3
,CF
3 0
IL.-OH
0 CH 2 0P, -0CH 3 0 II,,-octI occi cl CHI OP 11 I ]i trifluridine (trifluorothymidiz8) 0 dideoxyinosine (DDI) 0 -1 0 0 0 OCHO1CCC op 0 N o Startingr Hater.-al Itreit Intermediate Final-Product
~OCH
3 oci d ideoxydehydrothymidine Nit 1 N
H
2 0" dideoxyadenosine Nil 2
N"H
0 0 1 II.1 .ocil I I .OP 2 0c~01 OCH
I
Startingr Material itreit intermqdiate Fial Product ,CII~cHBr Cil Oil 0 11,OH
OP%
OCH
BVDU
0 0 0 CH 2 O1P% A4ct i- Ci 2011 OCH
I
FIAil Ovia f II)JJD II 0 0 Not I0ll I :4 11011.1 Hy
IMO
f (Ej 1 JJ~ do tlJ 0 0 do 0 IN
I
0 Toflpo.d t 1[:A:T Startilct Material Itreit ia rdc intermediate Final Product 'CliI cu 1
,O"
2Ara-T 0 0 11 2I OP 0 0 1 11-0Ci 2 OCCoIC3]
OP~OII
CH 2CH I C Hi CI O
FEAU
Starting- Material Intermediate Final Product
H
2 Nil F IfI OH 0 II,0H ]P P
OCH
3 0 0 1j C" J!ocil 3ciai cyclaraditi, 6-deoxyacyclovir CH 2 OCH I CH 2 OPN
OCH
3 fi N iN N 0
OC:II~
Starting~ Material intermediate Final Product til2 0 C 1 2 O P O C t-!
NH
2 N 0 101--OCfH OccicIL- j oci3 3 Ito oil
U)
w
(I)
U
-I
U)
ni fri 3-deazaarizzteromycin N H 2 14 NW Cii OHi 02 NH 2 0
II"OOH
CHIOP N OCH 3
J
0 0 11 110U OC 2 OCC occI C1, CH 2 OP 11oi 1 Gd 1 1;O OH neplanocin A IO
O
Ito Oki Starting Material Itreit intermediate' Final Product CH HON H 2
NCOP.'
1 7 0
HCH
0 0 1 II, cl OC II CifIOP j 0c11 3 110 OH selenazofurin NH 2 Ito off 3-deazaadenosine
N"
2 2
OCH
0 )C I II INociif cici NO aH [to off statin Mterial treit ia rdc intermediate Final Product 0 1 2 )uciclovir
(DREG)
0 2)7 0 1C 1j1~IZP "ool 2 oc~ci I I Ott H 2 I0 CH 21 HCH IOP~ %%oct all 3 Cif Cif 2lci 3 Hz i 11- 0 CH 2 c" 0 Itj )~cliCH 2 CH 2 Cli O-Psl)(' "I Co
N
I3 Clf 2 cit 1 U CtOI~iC1,) 3cc-IO, thiopental (pentotbal-) Startling Material Intermediate Final Product 0
OP
I Noci 0 oclil L -C I -cff
I
methyl testosterone 0 11OH OP N
OCH
CICH
0 0 1 II-ocil 2 c~I i mestranol startinr Matterial Intermediate IntermdiateFinal Product o<OCHJ Liquinestrol 0 0 1 U...-OCII OCC(Cot 3
OP
03 00 I0cI U 2l-O l OCCICII1jI cIfJ ccCI
I
C-=Cl
-C=-CH
ethinyl estradiol Starting~ Material Itreit ia rdc Intermediate Final Product 0 11 a 'Cf1 3 ccc 2 0j it
~PO
H 3CO, estrone 0 0 Il-OH I
OCH
3 0 0 1 1 1 oct OCCjCjt I OP 2 3 H 3 c 1 N-oci estradiol BtartinlciMaterial Intermediate iaPrut Final Product 0 11-OH It-- 2g:aI, 0 II 0 c I o c ci i OP 2LCIj oci -C=-Cii -C =CH norgestrel off II Cl 0 fl.'OH OP
H
t- NoC-= "l-0cOCL Ccij 2
OP
norethindrofle Starting Material Intermediate Final Product 0 1 3O H 0 0 1 H1--ocitOCCICII
I
OP
It 10011f ethisterofle 0
IIO~H
O P
C
1 0 0 1 2IOl OCC(C11 1 j OP 23 -oc: 1i Of C=-C-Ctf
I
OfII dimethisterone Startingi Material Itreit ia rdc Intermediate Final Product 0 LCCH 2CH=CH 2 Of ZCIfzCH2 0 0 II~11 OP C 2 Occcif f 0- 013 2 f-(I allylestrenol 0 li-OH
OP~
I N-'l 00 OP N cil 2
"OCC'ILII
3 3 -I C0 C l f I EJ cingestol stam-tina Material Intermediate Intermdiate ial Product 0 If-Oln
OP
0 0 1 L1"cif2 c~lj1 ethynarone 0 1 c mc 00 I Oct, 3 -CE=Cil lynestrenol 0 No Final Product
U
startincr Material Intermediate -Cfi=CtH 0 I I 0 0 1 II-OCI, 2 OCCICH ~I
OP
oNi norgesterons CH=CH 2 I=CH 2 0 0 OP 2 CCICiII3 oci Oi C~z.9 norvinisterone 0 Final Product t 8tartina Material intermediate 0 0 Op11jCi1 op 3) Ocif ethyriodiol Ii-C Oil 1I 11 0 c O H %o i Of 0 0.1 1 oxogestofle startina material Intermediate IntermdiateFinal Product 0 0 1 OP 2 oi~ CC(Cly 1
J
tociliCf tigestoi 0 IL-oHi OP
C
03CJC 0 0 OP 2 C11t oCWC -CinCH norethynodrel startingr material Oft 2 0OH Co j
OH
cortisone Co intermediate 0 CH 2 01OH Co Final Product 00 CI20 N 2 Co 0
CH
2 Op IOCji 3 co 0 0
I
II-IOCCH 1-oi~c itiJ 1Ho 2 OP ii No
OH
T III '0 0 hydrocortisOflo '0 Starting Material lntermed-ats Final Product Cli 20 t 1
I
0 II1"o.f O P 1
C
00 oi0p 2~OCI ocl CI) 3 1 -3 co3 botamothasone Of1 2 01 Of 2P N% 0 0 off Cli
I
t H i ft ICI (3i dOxamtbasons starting-Raterial Intermediate IntermdiateFinal Product CII .OH I Cif 2 0P N 2
ICIJ
Co MiI Otl Of flumethasone 0
II.,OH
OPN
locHJ 0 0 11 2
OCRI
fluprednisolole tartina MaterI-al intermediate IntermdiateFinal Product 0 lIf G j -OCIIf, Co Oil1
C"
3 Cli mothylprdlisolole 0 I 1 1,OCIiI~ t11 Co 0
:I
meprednisolo Final Product Itreit Starting Material Intermediate Of I O0H 0 II ,-OH CH 2 0P Co
OC
EfoN 0 11.,OH N OCHI 0 0 1 2 0pOCI 2CC(CII 3
J
Cf 2 N11oi
ICI
Co prednisolofle Co 0 11 CH20P11OCH OCC(Cit i1 1 ~OCif prednisofla Intermediate IntermdiateFinal Product startin material
H
to
-ON
C o"IOCHJ Co HO
OH
H 0H
OH
OH
triamololnfe Co 0-_C 3 0 CH2PIOCHJ 1C3 0 0 jj I ocii 3 Co
HO,
HX.
triamcinoloie acetonide gtArtifng ateia Intermediate intermdiateFinal Product CH 2OH
I
0 CO -o cortodoxofle
IIO
CO
0 11 13CH2OC3 1 oclH
OCH
3 fludrocortisone Startini Material Intermediate IntermdiateFinal Product CH 2 0OH
IO
0
II.-'OH
opi 0 co k CC 312 0-CCH 3 1I 0- 3 flurandrenolide (flurandrenolone acetonide) CH 2 0OH
IO
0
CH
2 0P
COH
00 0l~Ct11 paramethasone startina material flocK 2 coo" Intermediate N; NCH 3 C "3c) CH CCONII KJCO K, Final Product I CI H CH I 11 01 ICH I3) 3CCO C H 2 0, 11 1 o11POCH 2- -COOl! 3 2 sermietacifl
I
Of 2
OK
OCH 3 CHCIOP 2 Lci -OHOC(1 2 naproxol WO 92/17185 PCT/US92/02239 126 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 (Ii) and (Ib) 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 waide or imide function is acyloxyalkylated. The minor
O
II
product will be produced in a larger amount if excess (CH,),CCOCHI 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 o
O
tCH) CCOc 2 -N
CH
oc 0 11 0 II ,OCH OCC(CH C0 H2P 2 3 S OCH 3
N
3 while the major product is that depicted with METHOD A. Drugs such as tiazofurin, 5-FUDR (floxuridine), ribavirin, 6-azauridine, acyclovir, SUBSTITUTE SHEET PCT/US92/022$9 WO 92/17185 1 27- 3-deazaguanosine, ganciclovir (DHPG), 6-azauridine, idoxuridine, trifluridine, dideoxyinosine (DDID, dideoxvdehydrothyrnidine, BVDU, FIAU, FMAL, FIAC, Ara-T, FEAU, selenazofurin and buciclovir (DHBG) may be acyloxyalkylated at the amide or imide nitrogen in a similar manner to zidovudi~ne; derivatives of this type are even more lipophilic than the major products depicted hereinabove where the imide or amide group is unreacted.
As az,,ther 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 monosubstituted 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), eg. a primarmy hydroxyl will be more reactive than a secondary hydroxyl, an unhindered hydroxyl will be more reactive than a hindered one. Consequently, the major product win be a monosubstituted 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 instsoce, too, 0 control of the amount of (CH,1_1) 3 CC0C;OC 2 T or analogous reagent affects the amounts of the v arious products obtained. Drugs which may afford other hydroxy-substituted (mono- or multiply-substituted) derivatives in addition to those depicted for METEQI) A include pentostatin (2'-deoxycoformycin), vidarabine (Ara-A), 5-FUDR (floxuridine), cytarabine (Ara-C), apomorphine, morphine, nalbuphine, nalorphine, buprenorphine, dihydroxypropyl)adenine, ganciclovir (DI{PG), idoxuridine, trifluridine, BVDU, EIAU, FMAU, FIAC, Ara-T, FEAU, cyclaradine, buciclovir (DHBG), ethinyl estradiol, estradiol, ethynodiol, cortisone, hydrocortisone, SUBSTITUTE
SHEET
WO 92/17185 C/U$V23 15MUS92/02239 -128 betamethasane, dexamethasone, flumethasone, fluprednisolone, methyiprednisolone, meprednisone, prednisolone, prednisorie, triamcinolone, triamcinolone acetonide, cortodoxone, fludrocoruisone, flur-andrenolide, paramethasone and the lie.
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 pro~duct when subjected to the process of NMTHOD A, a synthetic route other than that of METHOD A may be generally preferred. Thus, in the case of nucleoside-type antivirals and antineorplastics having hydroxyls at both the and 3'-positions as well as at the S'-position, a product which is derivatized only at the as depicted with NMTHOD A) is preferred, and such product is most advantageously produced by use of a transitory protecting group such as the acetonide group desc-ribed in MIETHOD F hereinbelow. Drugs such as dihydro-5-azarytidine, tiazofurin, 6-MMPR, 5-azacytidine, ribavirin, 3deazaguanosine, 6-azauridine, 5 ,6-dichoro- 1-fl-D-ribofuranosylbenzimidazole, 5 ,7-dimethyl-2-0-D-ribofuranosyl-s-triazole a)pyrimridine, 3-deazauridine, 6-azauridine, 3-deazaaristeromycin, neplanocin A, selenazofurin and 3-deazaadenosine thus are preferably subjerted to MOETHOD F to afford the preferred 5'-derivatized products depicted with N=TOD A.
The process of MTHOD A is repeated, except that an equivalent quantity of benzyl alcohol is used in the preparation of the intermediate phosphase diester in place of methanol, When each of the representative starting materials listed with METIOD A is subjected to this process, the intermediate phosphate diester dtrivative has the partial formula SUBSTITUTE SHEET WO 92/17185 PC/US92/02239 129 0 OH O ,OH .P instead of -P OCH, OCHz as depicted in the intermediate column, and the final product of formula (la) or (Ib) is as depicted in METHOD A. except that the 0 O OCH20CC(CH) 3 -p
OCH,
portion of the product is replaced with 0 O OCH 2
OCC(CH),
-P
OCH
2 in each instance, The process of METHOD A is repeated, except that in the final 0 11 step the (CH 3 3
CCOCH
2 1 reactant is replaced with an equivalent quantity 0
II
of CH 3
(<H
2 4 COCH21. 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 (Ib) differs from that depicted in METHOD A in that the SUBSTITUTE 3HEET WO 92/17185 PC/ US92/02239 130
O
1I o OCHOCC(CH3)3 1i/
-P
OCH,
portion of each product is replaced with
O
II
O 0CH 2 0C(CH')4CH, I
-P
OCH
3
METHQODQ
The process of METHOD A is repeated, except that in the final 0
II
step the (CH),CCOCH 2 I reactant is replaced with an equivalent quantity 0 CHI of CH,(CH z 4 COCHL 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 (Ib) differs from that depicted in METHOD A in that the 0
II
o OCH 2 OCC(CH)j
I-P
-P
SUBSTITUTE SHEET WO 92/17185 PTU9/23 PCIAIS92/02239 -131 portion of each product is replaced with
CHI
o QCHOC(CH 2 4
CH
3 11 11 -P 0 0CH3
MEIRQDE
T'his is a modification of the basic method described in MESTHODS A-D for drugs containing multiple hydroxyl substituents, particularly for the nucleoside-type antivirals and antineoplaskis. 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 position, while the secondary hydroxyl(s) is/are in the 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 t; give the dimethoxytriryl)ether derivative. The 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 and/or 3'-ester groupings. The resultant compound is then treated with acetic acid to regenerate the hydroxy.moiety. The and/or 3'-protected compound with a free 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 andlor 3'-position(s).
SUBSTTTUTE SHEET WO 92/17185 PCT/US92/02239 132 METHOD F A starting material with multiple hydroxyl subsituents is selected as described in thn first paragraph of METHOD E, except that the selected compound must contain hydroxyls at both the and 3'-positions as well as the 5'-posidon, e.g. ribavirin, 3-deazaguanosine or the like. Reaction with acetone gives the 2',3'-O-acetoride. 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.
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-npropylpentanoic acid, sermatacin or the like, is first converted to the corresponding ethyl, 1-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.
QMETHOD
The process of METHOD A is modified to produce compounds in which there are two residues of hydroxyl-containing drugs. Thus, the first drug coptaining a reactive hydroxyl function is reacted with 2-chlorophenyl-O,O-bis[l-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 SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 -133 scavenger, to afford the desired intermediate phosphate diester. That intermediate is then reacted wtih cesium fluoride and 0
(CH
3 3 CCOCHI in an organic solvent such as dimethylforraxnide as set forth in METHOD A. The representative drugs depicted in the two colj.t;nns headed "Starting Material #1N and "Starting Material may be converted in this manner, first to tho depicted !,nterrnediate ("Intermediate") and then to the corresponding compound of formula (ka) ("Final Product").
It is understood that when "Starting Material and "Starting Material #2 are identical, then the diester intermediate can be obtained in one- step by reacting 2 equivalents of drug with 2-chloropheny1-O,O-bis(lbenzotriazolyllphosphate (formed in SiMu by reaction of 1hydroxybenzotriazol and anhydrous pyr~ene) and decomposing the product to remove the 2-chiorophenyl group. The diester intermediate can 1,1 then be converted to the triester of formula (1a) as described hereinabove, 0 by use of cesium fluoride and (CH 3 3
CCOCH
2 I or by use of sodium 0 methoxid6 and (CH 3 3
CCOCUH
2
CI.
SUBSTITUTE SHEET WO 92/17185 PCE/US92/02239 134 Startin2 -Mat~al #1 Starting Materal #2
SH
2
OH
zidovudine (AZT) zidovudilne (AZT) N20-4--oH 01 HN I 0 0 0 0 P-CH.,OCC(CH) SUB3STITUTE SHEET PICT/US92/071419 WO 192/17f185 135 Siarniny-Matraa #1 0
HNN
HN
K I Srar ngMateriaJ #2 0 HN'
N
HN
:HOH
dideoxyinosine (DDI) dideoxyinosine (DDI) 0 HN
N
'N N 0 11 -P-01- 0 HN LN
N
-P-OCH
2 OCC(CH 3 3 SUBSTITUTE SHEET WO 92/17185 PCr/-US92/02239 136 SarnMaeil# Starring Material #2 0
HN
MNN
KN
0 H
OH
dideoxyinosine (DDI) zidovudine
(AZT)
0 0% OCH,OCC(C H 3 0 SUBSTITUTE SHEET WO 192/17185 PCT'/US92/02239 -137- Stardn Mar~a #1 trwiGLMaterial #2 0 HN CH 3 0 ICI
CHH
O C 2 o,
HO
N 3 zidovudine (AZT) D4T(d4T) 0 0 HN" C HN CH 3 O0iN
N
3 Final ProdUct 0 0
CHN
HNI CH 3 O N 00 0 K- o SUBSTITUTE SHEET WO 92/17 185 POT, US92/0223P 138 Sgrz~ng MAterial #1 StAr nL-Material #2
NH,
N
0 mN
:H
2 0H zidovudine (AZT) dideoxycytidine (DDC) Intmediate 0
II
Final Ptxuct
NH
2 SUBSTITUTE SHEET lIC1/US92/02239 WO 92/17185 139 SLUrwn matcriaI #1 S tarting zMatcria #2
N
N C 0 C ,OH zidovudine (AZT) dideoxyadenosine NH2
N
I I 0 SUBSTTUTE SHEET WO 92/17185 PMrUS92/0223.9 14o S!3r1ifl2 M~criaI #1 StitMaterial #2 H3 Hl zidovudine (AZT) cholesterol 0
II
OH
Final, Poduct cmCH 3
CM
0 3
P
~CH.,Oc fCCH)P 1 83 SUBSTITUTE SHEET WO P2/17185 IC/U9/23 PMUS92/02239 141 Srardng MaIwnal #1 Star~inLMatal #2 H .NCO N-,Th C HO H :H ,OH HO OHl ribavirin selenazofurin N ICONH2 N I H 2 N C O CH, Se Final Pwducm SUBSTITUTE SHEET WO 92/17185 PCT/ US9 2/02 239 1.42 CO N H I o. CH Statring Malcxia1#2 0 CH ,OH ribavirin, t Iazo fur; n hnmediaw K0
CH
OH OH 0 H 2N Figal Product I7rCONH 2 N 0 0 cH,- P- ON OH I SUBSTITUTE
SHEET
WO 92/1718$ PICI'/US92/02239 143 S!Arring Material #I
H.NCO
Studtng Matcxia 42 N S H .OH HO OH OH OH t a Zo fUzi n selenazofurin H 2
NCO
OH OH Final Product H 2 NCO )1-7 H 2 N C N ZN So 0 C H 2 O P -O C H 2 H H k 0
OH
OCH OICtCH 3 l SUBS11TUTE SHEET WO 92/17185 PT S20 3 PCT/US92/02239 144 Starrinz.Mati #1
NH.
N
HOHO
OH
vidavabine (Ara-A) Starin Material #2
OH
N
H-N I
N
O H 21 -deoxycoforrnycin (2'-dCF) Ein- rd
NH
2
N
N 0 O0 N OCH %O C(CH 3 13 SUBSTITUTE: SHEET WO 92/17185 prU9/23 PCr/US92/02239 145 starIn malwral #1 StaL~Material #2
N
K
N
:H 2 0OH
HO"VON]
vidarabine (Ara-A) acyclo-coforniyci n 0
OH
N
0 OH OCH 2 0 C(CH 3 3 0 SUBSTITUTE SHEET WO 92/17185 PC'r/US92/02239 1.46 Startig Maagna #1 ig4adl#
H>OH
5-iodo-21 -deoxycytidine ICdR;, ICDR) 2' -deoxytetrahydrou ridine (21 -dTHU) H Final-Product 0 11 p 0- 0
OH
0CH., 9
CCC
3 3 0 SUSSITUTE SHEET WO 92/1,7185 PC/UF')2/02239 1.47 S Luting Material #I Starrin2 Material #2 H XOH OiN) H H 2 0H
FIAC
2'-deox)ytetrahydrouridine (2'-dTHU) H
OH
0 0- P- -1
OHH
OH O 0-
P-O
oH OCH .OCC(C 11 0 SUBSTITUTE SHEET WIO 92/17185 PT S20 3 PCr/US92/02239 1.48 Starting MaNeria #1 Starj ig2 Material #2 CH ,OH cytarabine (Ara-C) NH 2
ON
tetrahydrouridine
(THU)
0
II
OH
OH 6H 0 11 O0- P -0 OCH ,OC C(CH 3 0 SUBSTITUTE SHEET PCr/US92/02239 WO 92/17185 1=49 Stardnf Marenal #1 idoxuridine (IUDR;IUdR) Srrn2 Marerial #2 0 HN 5 -benzyl acyclouridine 0
OHN
0 *0-K0-1 Od- Finol ft~dwc 0 11 -p 0 SUBSITUTE SHEET WO 92/17185 X'/O 9/17185PCT/ US92/02239 15,0 Lm-r t L M w Wil -#I Startn2 Material #2 trifturidine (TFT) 2'-deoxYglucosyl thymine
O
SUBSTITUTE: SHEET WO 92/17185 C/S2023 PCf/LIS92/02239 -151. Suardi Material #1 0 1 CHmCHBr
BVDU
Starrinz Material #2 0 HN C HO-L'o l 5-methyl acyclouridine 0 HN"iCH 3
ANY
0 11 0 HNr
CH
3 0 0 CH 2 0cC (C H 3 3 SUBSTITUTE SHEET wo 92/17185 PC1'/US92/02239 152 sgda-mamw #1 Staring Material #2 0 HN I C H=CH Br
,CHOH
acyclovir (ACV)
BVDU
rCHuCH r ICH1OCH
OH
Fina Product H..N N0 cm OCHCO-P (CH 3 3 CCOCH' .0 0 0 SUBSTITUTE SHEET W0$97/17185 PCr/US92/02239 153 SwIr mas~ba1 #1 0
NN
HNN
CH,.OCHCH ,OH CH 2
OH
Starting Material #2 0 yC H=CHB r 0 CH 2 0H
OH
ganciclovir (DHPG)
BVDU
0 HN 1 CHucHor CH 2 OCHCH2 on 2 0H 0 11 P -OCH
OH
0 ;:'Nl-HmCHBr 2 CHCH 0- P----CH 2 CH 20H 0 0 ON SUBSTtITUTE SHtET PC/US92/0223,9 WO 92/17185 2.54- SM=iz MaIgbAl-f-I StarTiniz Material #2
HN
CH OHH CH OCH.,CH,OH A ra-r acyclovi,- (ACV) :12 0 P -OCH 2 CH2 OCH 2
OH
0 0 HN CH 3
N
HN NH 0 Ho-P -OCH.CH.OCH4,
OHO
OCHOCC(CH
3 OH0 SUBSTITUTE SHEET PCr/US92/02239 WO092/17185 155 Starting MawgrWal Smarinz-Material #2 0
H
H N CH,OCH ,CHOH acyclovir (ACV)
AN
2N' N vidarabine (Ara-A) N H 2 Final Product 0 IOCH.CH.O II
C
3 3 C OHI
HO
OH
SUBSTITUTE SHEET WO 92/17185 PCI'/US92/0223,9 156 S #1 SrartiM -Marcdial 2
CH,OH
CH OH acyclovir (ACV) trifluridine (TF'T; trifluorothymidine) KN CF 3 0 H J~ 0 N C 0 11 .OCH.%CH.0- P -0t.
tCH 3 )3c.cIc40 0 SUBSTITUTE SHEET WO 92/17185 PCr/US92/02239 157 S ]zmac4 #1 StartimgMaterial #l_
CH.,OH
1 *4 ,CH acyclovir (ACV) FUdR (5-FUDR:- floxuridine) InrtMR2njig 0 0
F
Final Parodc 0 0 N
H%.
0
OH
SUBSTITUTE SHEET PCT/ U592/0223,9 WO 92/17185 158 t aL M a Vn #1I
K
N
-N
StartinL~Mateiial #2 N4H, 0~ vidarabine (Ara-A) cytarabine (Ara-C) NH2 Final, ftd~ct 0 H2 0 I
OH
(C H) 3 COCH 0 0 SUBSTITUTE SHEET PC]r/US92/02239 WO 92/17185 C/U9/23 159 Star~n~ Matrial #1, 0
H
0 .C,OH
OH
iUdR (idoxuridine: IUDR) StarTinz MaterWa #2 0 H 11F
N
1 o CH 2 0H FUdR (5-FUDR; floxurldine) 0 0 NH F 0 0 H 2 -dCH2 1 0
OHH
OHH
Final PRoduct CH ,OCC(CH 3 1 3 3 0 SUBSTITUTE SHEET PCT/US92/02239 92/17185 160 Startng~ Matal 4*1 StarrinfMaterial #2 I:H 2 0H vidarabine (Ara-A) FMA U Intermediate NH 2 Na N 0II0
OOH
0 HN ~CH3 Fing- Rrgduct ~oo 0 H 2 O-
OH
(H)CJOCH 0 0 SUBSTITUTE SI-IFrT WO 92/17185 PCT/US92/02239 161 Starting-Ma='ral #1 Strtning-Material #2
N
CHOH
vidarabine (Ara-A) trifluridine (TFT; trifluorothymidine) Intermediate N 1 0 TCF 3 Finl P21uc-t
NH,
N N> N 0 i0i 0 CH 0P -OCH.,
OHON
OH
OH
OCH ,OCC(C H 3 11 0 SUBSTITUTE SHEET WO 92/17185 WO 9217185PCT/US92/0223,9 162 Starrins MaterWa #1 Srarng Material #2 CH ,OH I I idoxuridine (IUDR;IUdR) 51 -amino- Intermediate H 2 N 0 0P.
Final Product 0 0 H 0 SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 163 Startinz Material #1 Srtinnr Material #2 OH OH 3-dea za urid ine 2 -deoxy-D-glucose 0 1 0
OHH
OH OH Hb H Final-rqduCt OH OH SUBSTITUTE SHEET WO 92/17185 PCr/US92/02239 164 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, 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 0
-P-
I
OCH
2
OCC(CH
3 3 portion of each product is replaced with 0 P as in METHOD C, or I 0 OCH 2 0j (CH 2 4
CH
3 0 SUBSTITUTE SHEET PC17US92/02239 WO 92/17185 165 0
II
P
I
OCHOC(CH
2 4
CH
H II
CH
3
O
as in METHOD D.
II. Methods for Derivatizing Imide r Amide Functions in Drus 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
O
-C 0
II-C-NH
-C-NH
R
-C
0 group in the imide or amide, respectively, to a
N-CHOH
-C
0 0 I -C-N-CHOH
R,
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 derivatize, in this manner, SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 166 first to the bridged drug (not shown), then to the phosphate diester intermediate ("Intermediate") and finally to the corresponding compound of formula (Id) or (le) ("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 (le).
SUBSTITUTE SHEET Btartina Material fluorouracil Intermediate
H
F -CH
IOP-OH
OCH 3 Final Product H-gCH 29OCII 0 II3) O$11 2
&C
oci
H
o K CH Z0P-OH
ICH
2 0-0CI 2 01C(Clf 3 3 1 phenytoin 0 Final Product Btartiflg-Material intermediate If
I)--L
C 2 f 0 1 (Cli 3 )CCCH 2 -P0cli 2
II
oC ii 3 o o
CHII
othotoin 2U 3 0 OA-2NI0
I
CH 3 c 2 H (Cif 3 Of I mephenytoin startingr material Itreit Intqmediate Final Product 0 if (Clii ICCOCH O-POCH 3 oci2 1 phenobarbital
II
2l c it 0Ci1 3 00 2f
OICCICII
CH 2Ji-o Ocif CI-CH CI- 1l '2 Ur-r4 1 startincr7 u-terial intermediate IntermdiateFinal Product H 3 C CH3
HO
H* ~CONHCH 2OP-OHf OH 0 OH0O1 CI N H OH- Off
HO
off 0 OHf a OCli chlortetracyclinle o N 0~ glutethimide Cf 2 0P-OH
IC
't"3 1 0 0
C
2
MOCH
2 i Cch 33 -0 Final Product startincr i~ateri&1 IEntermediate CH 2 0F-H 0 OCH -KCH JOCH Ot(C 2 1 2 3 CONH zC tes icam Nt CH CH NIH 2 C2 2KY
CIZ"
fC1I 3 3 dOCH IOPC
OCH
3 Cif N ,l f2c 2 2 Ci H2c i2H CH 2 CH 2
C
2 %CH 2
CH
2
CI
spiromus fine 0 Final Product startingi Material Intermediate ClU OP-OH
I
(CH 3 desmethyldiazepam ci 2 J0H 2 CI Il 3)3 0 oxazepam Startin:7, Material Btar~n~ Material IntermediateFiaPrdc Final Product CH 2 CH=CII 2
H
2 COUCH 3 2
H
butalbital 0 HN H 2 CH=CH 2 CH 2OP-OH
ICH
I:
OCR'
3 C 2'
CH
3 C C CH- C C- 3 CHCH ci C11 "CH 3 amobarbital 0 0 H 2 05-OcHl 2 OLICII
J)
101 j Starting Materiai c2 If XAt8rmediate CH ?1oT 051 0 N 0 Cli 200 c 20CL 2 OCII 3) Out 3J tl-_nA-l.PrO.duct methyprylon It 3 ccif 2 cif If 3 cc"I 2C 1
L
If jclf f 1-lclg~utf ZP-I 2 2 1 3 .1 ci 2c 2N,,CS~ii yo i ValPrOmide En 0D Starting Material Itreit Intermediate Final Product C2 If NI 2 O O Clio 2f H If0oa J1ii 1 11 CII 2 0P-OH
GII
aminoglutethimide IIC ,Cp~ Cic, c p
I
CII 1 Cif j33 bemegride Final Product Starting~ Material Intermediate 11 J OCI 2
OL!!CII
3 l 2 o cf2A~l nitrazepam I 0 Br bromazepam
I
Br 0WJ CH2 iOI2 IC lf) WO 92/17185 PCT/US92/02239 177 METHOD I 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 0 C O
IF
D N-CHOH or D-C-N-CHOH I I I C CH 3 R CH, is then subjected to the multi-step process described in ME'HHOD A to afford the corresponding compounds of formulas (Id) and (le).
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 (le).
III. Methods for Derivatizing Carboxvl Functions in Drurs METHOD K The drug containing a reactive carboxyl functional group is reacted with 1-chloroethyl chlorosulfate to convert the -COOH group to a -COOCHC1 substituent, which is then reacted with the mono- or
III
C H, 0 di-cesium salt of CH 3 OP(OH)2 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 susTITUTE SHEET PCT/US92/02239 WO 92/17185 178 0
II
(CH,)
3
CCOCH
2 I, to afford the desired compound of formula 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).
SUBSTITUTE SHEET Startingi Material ketoprof en Intermediate fH] .HO_-CH-b jO c( 41 i 1
H
H
3 Final Product 1 l Ocif L il
COO-CHO
C~
-CH 0 3 2 p0CH31 COO CHOP. 2 0'(CI 3
I
I ocii 3 cifiJ oxacillin H H
~~COOOCHOV
I
'-OC
Ci x- q-teA--l sta ting Intermediate IntermdiateFinal Product C&u pci 2 COf 2
CHCOOH
C C11 Cli 2 Cli OfCHI 2
ICHCOO-"J-O
C11I CH 2 CH 2 Clf,3 Cit Of CH ClCOC17 Th-,-OCfl 0CCI 3 Of 2 CH C1 O1CiiOP 2 ~~l 1 3 1i 1
I
2 CI C11. vaiproic acid Hoo Of 3NH-CH 2 C I CH 2 C 2 Cl CH 3 3 Cloc t 2 cbiorambucil3 li 3 CO~ -11C 2 CH2 CH 3 01 Of I 2 11 IC1 Cliij Startinr Material Itreit ia rdc IntermeLlAate Final Product M, CHH-CH Nil
CH
CH~
methotrexate COOH CH 1 0 Cooll I A L I N NH-Cit C11 1 2 1'-OCH OL~(ClII LOOCHOP 2 33 1 N i C11 0h 3
ICH
3 -1-11 3
N
C H
JOOCHO--
I N i oCI'3 carbelicilin cli.
Cl'] OOH
A
1 13 cli 3
/CH
00 *OOCIHop I 2 O4!fl
I
Cli, Starting Material Itreit ia rdc Intermediate Final-Product 2 0
J!.NH-
CHI
C H
I
0
COO"
benzylpenicillin 2 CHIi -r 0 cOOCHOPK 2 I OCit OfI C K 0 -00 2cu ci Or"f hetacillin
I
CI"
CH
3 startinr Material Itreit ia rdc Intermediate Final Product 0 0c 2 t 5
COOH
naf cillin 0 0 CH 3 0C 211 5 1 1 OCif cli 3 O f 3 COOCHOP HOCI 2 0LCII J) 3 1 N OCif 3
COOH
H H Of3 3 'c11 3 cloxracillin Startina Material nemdae ia rdc Intermediate Final Product
CH
<9' CU 2
CONH
caphalotilin
COOH
s Cli 2 CNH IIJjY cy
OCH]
CH 2
COH
H 0 COOCtiOP 2 3 3 I or..
cil i
I
COOCH~0 Cili 1 0 COOCHOP -cil 2 0MC(CH3)3 cefoxitin I. CH i s CH 2 C N 2 II %)CH 2 0CONH 2 0013
CILI
startinl Material intermediate IntemedateFinal _roduct cif 1 3 Cllcool-l
CH
(CH 3 1 2 ClIC" 2
CCOH
I3 1 ZCHf H 2 3 CH 3 ibuprof en Cl 0 -C A tl (CH 3CC1 2 1cl J 4 HCOCH ~O CH 3 c olif Of 3
I
,johI
CIIO
clipO CHC00CHO
OC
CH
3 0= Of 11 naproxen CH 3 0 1OCIJ Of 3 o 0 Final Product Starting 14aterial Inte-rme4iate f lurbiprof en 0 R.OCH22C (Cli 313 F Cif 3 I j OCR 3 CHH 3
CICH
cl -0 C CH 2
COOH
11C 0 C1 3 Cif 3 zomepirac 0 a cl--o-c CHlCOOC HOY
,O
I 'oclit CH 3 00 Final Product
U
gtartincr Haterial Intermediate 0 1, Ci Is 0 11 CH 3 s CH 2
COO"
COOCHV
O
I O0CH3 cif 3 sUlindac: If 3 c Ncif 2
COON
II
indomethacin II CoCH COCHJc 3
-O
CHJ
C-o0 cl H Co CH COOCHOP(( C 2 O CCI1 rat C=0 ~tartincT Material Intermediate IntermdiateFinal Product 11OOC fi ct-j NH-P 1 POCHOOC H, C CH If 3 Co' 1 Cli.
(CH 3 3 C&lCcfxjv9
N
H O"POCHOOC It 3 C Cif H 1 Of' I 3 If
I
mefenamic~ acid Cl
CI
C'
17 0 Nl CIIC 3J
CI~
diclofenac startino cia Intermediate Final Product.
f lunixin z F I 4 1 $11
I
0 2 04!C(CJif Cif 3 OCI']3 WO092/17185 PCT/US92/02239 -2.90- When the drug containing a reactive carboxyl functional group is sufficiently bulky, it. can hinder the bridging group. In such a case, Z can. be, and preferably is, selected to be -CH 2 and METHOD K is modified by replacing the 1-chioroethyl chiorosulfate reactant in the first step with chioromethyl sulfate, and otherwise proceeding As detailed in that method. Drugs such as oxacillin, carbenicillin, benzylpeniciilin, hetacillin, naficillin, cloxacillin, cephalothin and cefoxitin can be derivatized in this manner, first to the corresponding chioromethyl derivative by converting the -COOH group to a -COQCHCl group, then to the intermediate of the partial structure and then to the desired compound of formula aIc) having the partial formula 0 11 0 OCH2OCC(CHI)l
-COO-CH
2 -OP
OH
This method can of course be modified in many ways, e.g. by varying the final step as described in NMTE{OD C.
SUBSTITUTE
SHEET
WO 92/17185 PCIYUS92/02239 -191. IV. Methods for DrILVAti=-2 AmIWO Functions in Drums The drug containing a reactive amino functional group is reacted with 1-chiorftthyl chioroformate, 0 11 Cl-CO-CH-Cl,
U,
0 CH 3 to replace a hydrogen atom of the drug's amino group with a -COCH-Cl grouping. Subsequent reaction with the mono- or di-cesium salt of 0 CH3OP(OH) 2 affords the corresponding phosphonic acid intermediate. That intermediate is then subjected to the final step of the process desrribed in 0 MJETHOD A, using cesium fluoride and (CH 3 3
CCOCH
2 I, to afford the desired compound of formula The representative drugs depicted below ("Starting Material") may be derivatized in this manner, first to the 1chloroethoxycarbonyl derivative (not shown), then to the phosphate diester intermediate ("Intermnediate") and finally to the corresponding compound of formula (If) ("Final Product").
The foregoing procedure can be modified in many ways, for ex ,.nple by varying the final step as described in METHOD C, affording yet other compounds of formula Further, when the drug is sufficiently bulky, &h process of METHOD M may be modified by utilizing chioromethyl chioroforinate as the reactant in the first step.
SUBSITUTE SHEET FnlProduct 0 JUl Startingy Material Intermediate Nli NH -Cc IHOP*
OCH
zo CH 3 0 0 CII
H
Ni- Jclo amantadime Of, CH~ ii 1 11 -C fcjH O H f- il c I i p
C
il 0.
clii rimantadine start na Matqriel NH 2
-CII
2 C11 Cl% 2
COOH
intermediate .POCHOC -NH-CI[ 2
CH
2 C 2
CO
CH~
Final Product 0 1 1131 j Ac&CuI.. O- 0 If 3 lit N il C ii C I l LOO ll Cil 3
GALBA
H 1 C 0!N NCH ~Cui 2 C1
H
.,CH
2 CH z2CI INCH 2 Of 2 c a~i~ 3 C0C 2 0aJ 0 11 3 c0 I I /t 0I If If HOOC CICH 7
~N~
melphalan Btartifla Material Itreit Intermediate Final Product C CH 3 'oi OdE] 0FO Of 3z 0"
OHOH
0 0
CH-
CH 0
CH
C ofi 3 dll f il If0 OCCII Sii-CdOHp 2.
I oci i~~1 CCo -CII 2 OCC(Oli Ci 2 CHN IN, Of 3 31oi daunomycin (daunorubicin) 13 methamphetamine Starting Material Intermediate Final Product Ocii 3 OH 0 C-CH Olf
~Q(OH
Oil 00 NH-COCHOP O CH 3 O1i c ii Io O Cu0 Nit 2 doxorubicin (adriamycin) Ij %At C NH 2 Cl. 0 0 CH C-NHi-COCttOP,.
I 2 OCH 3 Cli CH 3 I If C11 -OIOCIC 1 2 j ocif cull 3 phentarmine startingo Haterial
CH
CH-ELI-NH
O -CI 2 CH I Intermediato CHI 0 ."CH H-N -COCHO iV C I 1 OCH 3 kAJOC H 2 CH 3 Final Product I I I(N !tI]NH CofIO -ci (3IJCc 2CI2 phenmetrazifle O
CH
2 HCH 3 NH 2 e\tCH 2 1 HCH, -O0 11 1 'OCH 0 CH 3 3 2 fji CHJ 0( 11-ciIJoccic JiJ NH -COCHOP I If I ocu 3 0 Cif 1 _4-isomer d-isomer deitroamphotamifle -4.-isomer Startinla Material Itreit ia rdc Intermediate Final Product F\j"?-CH CHCHJ NH 2 j-isomer levamphetamine O CI 2 CH 2 NH H 2 F\-CH ICHCH 3 0 NH -C OCHO10 III 1 OCH 3 0 CH 3 1-isomer CH 2 C 2NHJ~tO HOP I- C CH
OCHJ
F\ CH C1CII 1 2 I!4H~OCIIO -OCI 2 OCCICI31 If I OCH 0
I
1-isomer 0 0 CI OCH 3 phenylethylamine (phenethylamine) Starting- Material Ni'? Intermediate
(~CHCHCH
3 0 NH- COCHOI 1
.OH
0 C11 3 Final Product II-O~~ ll-OCII 2 OCCICII Ii Ni-,C O 2 jC 0 C11 amphetamine "9l~ool
Y
Poclioc
H
3 C0 I\ C11 JII)~CIic0OCiIJ H 3 C0 methylphenidate tranylcypromiiie intermediate 00
HOPOCH
Final Product 0) 00 V ICH HNOoCo c CH 3 If2
C
O~f 2 CH 2 CH 2
N%,C
CII CI CH 3 2H 2 CH2- NCHif CH i desipramine Coc a If 3-(jU.-L1 I IIl CH 2 CH ICH 2 'N L.cfI ci1 Starting Material If Intermediate C-H2-CH-COOH kZ N, C I I H-~COCHOVtZ-Of 11 1 -OCH 3 0
CIA
3 Final Product NC II NH-cocioF' -~0I~CII 1 H oct.
3 cl tryptopbafl Off ISO"O c IHNII norepinephrine C 0 0OC
J
1 0 ~~~JCH 3 C OHl 0( 11 _ii i02 i 110ysN HCH NH-C0CsI0P I Ocf fluCiI starina ateral Itreit intermg-diate Final Product off
HOH
0 0 Of II,,~OH oil
COCHOP".
iO CH 2N
OCHJ
HOJ:I1 rH
C"
0 C I z I DOI Io 9~ fCIHZN Of I1 epinephrine It0 CtII 2 Nil* 2 \0 0 If II ,OH 'to 2 CH 2 NH-COCHOP I
OCH
dopamine 110 Of OfI 2 Nil-COCIOP 2 2 1 Oci ItAftina Mteia IntermediAte Intermdiateinal Product 1 O f0 i 0 0 If I cif 0 2
N"-COCROP
I o~ serotonif 110 CH II t" C I C II VfF. (2lJII O -il 1 H I oI cii 2 2 co0C11 3 KIIUI~ CijC1I 2 NIl IN. N 2
NH-CCO
C R 2 2 N H -C 1C HCl 3 CH 3 cpuanethidine 14CI 2 If .Vi 0CIf~ I Oi Intermediate Startilc7 Material IntermdiateFinal Product io u~iiiii Nil2I 0 0 ou I
OCH
0 0 NH-COC~f N. OCIIjC 1I o uCu 3 cypenamine It~ii~i1 CI 2 1 N Of
CH
tryptamine I o i PCT/US92/02239 WO 92/17185 204 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 converted to the corresponding ethyl, 1-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.
SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 205 EX AMPLE 1 To a stirred solution of 1.3 mL (13.9 mmol) of phosphorus oxychloride (POCI,) in 4 mL of absolute ether was added a solution of I g (3,47 mmol) of testosterone in 4 mL of pyridine. The addition was carried out at 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 0
II
O-P-CI
H 3 3C
I
H 3C 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 1S 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 ma"'ti4 was dissolved in dichloromethane and the residue was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution ind dried SUBSTITUTE SHEET WO 92/17185 PCr/US92/02239 206 over anhydrous magnesium sulfate. Thin layer chromatography of the crude material showed the presence of the desired diester of the formula 0
O-P-OH
H3 CH33
H
3 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
POCI
3 (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 POC1 3 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
O-PC!
2 P CH 2
CI
NO
2 2^w SUBSTITUTE
SHEET
WO 92171$5PCT/US92,O22319 -207- The phosphorodichioridate was obtained as a pale yellow viscous liquid boiling at 157-162' C. The identity of the product was confirmed. by NMR analysis, To a stirred solution of 2-chloromethyl-4-nitrophenylphosphorodichioridate 18 g, 3.88 mmol) in 6 tuL of anhydrous tetrahydrofuran was added dropwise, at to 0 0 C, over a one hour period under a nitrogen stream, a mixture of I g (3.47 mmol) of testosterone and 0.28 mL Q3.47 mmol) of dry pyridine in 8 rnL of anhydrous tetrahydrofuran. The resultant mixture was stirred overnight at room timperature, then was poured into 20 mL of cold water, with stirring, at a temperature below 0 C. The tetrahydrofuran was evaporated and the residue was extracted with three 20 mL portions of dichiorornethane. The combined extracts were washed with brine and dried over anhydrous magnesium sulfate. The 1s crude product was purified by column chromatography on silica gel.
Unreacted testosterone was eluted with a mixture of CHIC1 2 and ethyl acetate volume/volume), then the desired diester of the formula
-NO
2 H 3C CH 2 C1 SUBSTITUTE SHEET WO 92/17185 PC'/US92/02239 208 was eluted with a mixture of CH 2 Cl 2 and methanol 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 th 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 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 of l-(2'-hydroxy-S'-nitro)benzyl pyridinium chloride. The filtrate was purified by column chromatography on silica gel with a mixture of CH 2 C1 2 and methanol (8:1 and 4:1, volume/volume) to give 4.67 g (81% yield) of the desired mixed diester of the formula 0
II
0O-P-OCH H3C1
~OH
H
3 The identity of the product was confirmed by NMR analysis and by mass spectroscopy. Mass (FAB) m/e 383 SUBSTITUTE SHEET WO 92/1185 PCT/US92/02239 209 EXAMPLE 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 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
O-P-OCH
3 H 3C Ag H 3C as a grayish white powder (49 mg, 11% yield).
EXAMPLE 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 SUBSTITUTE SHEET WO 92/17185 PC/1US92/02239 2130 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, (CH 3 3
CCOOCHI
2 .Il, was confirmed by NMR analysis.
The silver salt obtained in EXAMPLE 5 was suspended in I 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 thiosulfatc (Na 2
S
2 0) 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 x 20 cm x 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 G 0 It II
O-P-OCH
2 OCC(CH 3 3 H!iC 8CH 3 SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 211 as a viscous oil. The identitry of the product was confirmed by NMR analysis and by mass spectroscopy. Mass (FAB) m/e 497 (MH 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 rmmol) 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 x 20 cm x 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 0 O0
O-P-OCH
2
OCC(CH
3 3 HwC a OCHe NMR values were the same as those for the product of EXAMPLE 7.
SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 212 EXAMPLE9 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 sulfte 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 O-P-OCH OCC(CH H3C OCH3 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 C7 6 HOP: C, 62.88; H, 8.32. Found: C, 62.99; H, 8.38.
SUBSTITUTE 3HEET WO 92/17185 IP'/US92/02239 213 EXAMPLE 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 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, CH 3 (CHz) 4
COOCH
2 C1.
EXAMPLEi 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(CH 2
COOCH
2 1, was obtained as a yellow oil in 78% yield. NMR values were consistent with the assigned structure.
SUBSTITUTE SHEET W0 92/17185 r/S2/23 PCr/US92/02239 214 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 0 O- -OCH 2 OC (CH 2 4 CH 3 EXAN=13f The general procedure detailed in EXANME 3 is repeated, utilizing anequivalent quantity of zidovudine in place of the testosterone there employed. Obtained in this manner is the diester of the formula
H
I c 2
-NO
2 SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 -215- EX MM1L14 The general procedure detailed in EXAMPLE 4 is repeated, utilizing an equivalent quantity of the product of EXAMPLE 13 in place of the diester sta-eting material there employed. Obtained in this manner is the mixed diester of the formula 0 0.
11
CH
2
O-P-OCH
3 SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 216 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 0 H yCH 3 o K:
OCH
N
3 EXAMPLE 16 Hexanoyl chloride (5.5 mL, 37 mmol) and acetaldehyde (4.2 mL, 74 mmol) were combined under a stream of nitrogen Aid stirred in an ice bath. To that solution was added a catalytic quantity of zinc chloride.
Within 30 seconds, an exothermic reaction C. 430 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 x mL) and saturated aqueous sodium chloride solution (50 mL). The organic layer was separated, dried over magnesium sulfate, filtered and SUBSTITUTE SHEET WO 92/1718$5 PCT/US92/02239 -217concentrated to give 7.81 g of I'-chloroethyli hexanoate,
CH
3
(CH
2 4
COOCH-(CH
3 )C1, as a 5,lightly yellow oil. It was used in the procedure detailed in EXAWILE ,t7 below without further purification.
NMR analysis confirmed the i/dentity of the product.
E~XbLLL1 Sodium iodide (27.9 g, 186 mmol) and acetonitrile (39 mL) were combined under a stream of nitrogen and stirred at a temperature below To thzt 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 100 C. Insoluble materials were removed by filtration and washed with acetonitrile. The filtrate w6 s 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 is. solution (100 mL x 2) and water (100 niL). Each aqueous layer was extracted with one 50 mL portion of hexane. The hexane layers were combined, dried over magnesium sulfate, flIted and concentrated to give 7.77 g of yellow oil (77.5 yield). The crude 1'-iodoethyl hexaoate,
CH,(CI{O
4
COOCH(CH
3 was used in the procedure of EXANMLE 18 without further purification. NUR analysis confirmed the identity of the product.
The mixed diester prepared in EXANMLE 4 (2.26 g, 6 nimol), 1'iodoethyl hexanoate (3.24 g, 12 nimol), cesium fluoride (2.01 g, 13.2 rnmol) and dimethylformnamide (22 mL) were combined under a streamr of nitrogen and stirred at room tempetature for 19.5 hours. The reaction mixture was then poured into 300 mL of ether and washed successively SUBSTITUTE SHEET WO 92/17185 PcriUS9","239 21.8with water (100 mL) 5% aqueous sodium thiosulfate solution (100 rnL) 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 (I 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 formula -OCH-OC(CH) CH 3 C 3 Mass mle 525 Anal,'Calcd. for C,3L 5
O
7 P: C, 64. H, 8.65. Found: C. 63.97; H, 8.71.
£XAhRLL12 To a solution of dry I-hydroxybenzotriazole (3.24 g, 24 mmol), arnhydrous pyridine (6.47 mL, 80 inmol) and dry tetrahydrofuran (50 mL), a solution of 2-chlorophenyl phosphorodichloridate (1.98 mL, 12 mnmol) in dry tetrahydrofuran (20 mL) was added dropwise, under a stream of nitrogeii, while maintaining the reaction mixture at room temperature in a water bath. Stirring was continued for approximately 1 hour, then 5.34 g mmol) of 3'-azido-3'-deoxythymidine (zidovudine) were added in one portion and the mixture was stirred at reamut temperature for approximately SUBSTTTUTE
SHEET
WO 92/17185 PCT/US92/02239 219 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 (CH 5 3 NH*ICO2 buffer (prepared by passing a stream of CO, 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 Florisi (magnesium silicate, 60 using ethyl acetate as eluent. Column chromatography was repeated as before, affording 5.24 g of bis[5'-(3'l} azido 3'-deoxythymidyl)]-2-chlorophenyl phosphate as a white amrorphous powder in 74.8% yield having the formula 0 HN 3 CHO2 -NP-0
N
0 2 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 Amberlite)ionexchange resin IR-120 (73 meq., H* form by HCI aq.) and stirred for 1 minute. The ion-exchange resin was removed by filtration and the filtrate SUBSTITUTE SHEET WO 92/17186 PICI/US92/02239 -220was evaporated. The residual syrup was dropped into 200 m.L of vigorously stirred ether. The precipitate which formed was collected by filtration and dried m' vacu. There was thus obtained 0.66 g (90.4%17 yield) of bis '-azido-3 '-deoxythymidyl)] phosphate as a white amorphous powder. The structure of the product, 0
PIO
was confirmed by NMR analysis.
SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 221 EXAMPLE 2l Repetition of EXAMPLE 9, using an equivalent quantity of bis (3'-azido-3'-deoxythymidyl)]phosphate in place of the mixed testosterone diester there employed, affords the triester of the formula 0 HN C H 3 HN N 3 0~ 2 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 vacu 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 0 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 SUBSTITUTE SHEET WO 92/17185PC/U9023 PCT/US92/02239 222 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 (5:1/1 10:0, gradient) as an eluent. Two products were isolated and their structure confirmed by NMR and mass spec~ioscopic data. The major product, recovered in 16.9 yield 12 g) was the triester of the formula 0 HN
CH
3 Q CH 2 0 P-OCH 2 0CC(CH 3 3 SUB~STITUTE SHEET WO 92/17185 PCTr/US92/02239 223 The other significant product, recovered in 11.0% yield (0.09 was another compound of the invention containing two zidovudine residues, one of which contaied an additional pivalyloxymethyl retidue. That product was assumed to have the structural formula 0 0
~OCH
2 0CCCH 3) 3 HN 0 H H C 0 O N OCH 2 -P OC (H 3) 00 3 03 0 or i 0 H 3 C 1 C ii ~NCH OCC(IH) SUBSTITUTE SHEET WO 92/17185 PCT/US92/02239 224- 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 evapon~,ed and dried in vaca 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 0 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 gradient) as eluent. The major product, recovered in 37.1% yield (2.64 was identical to the major product of EXAMPLE 21. NMR (CDCI 3 5 1.23 (9H, 1.89 (6H, 2.30-2.60 (4H, 3.85-4.50 (8H, 5.67 (2H, d, J 12 Hz), 5.95-6.20 (2H, 7.27 (2H, 9.95 (2H, bs). Elemental analysis: Calculated for C H, 5 INtoO 12 P: 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 NMR (CDCI3): 5 1.18 (9H, 1.22 (9H, 1.91 (3H, 1.95 (3H, 2.30- 2.55 (4H, 3.85-4.45 (8H, 5.65 (2H, d, J=12Hz), 5.92 (2H, s), 5.90-6.25 (2H, 7.24 (1H, 7.30 (1H, 9.11 (1H, bs).
Elemental analysis: Calculated for CI 2 HsN 0 oO 14 P: C, 46.60; H, 5,50; N, 16.98. Found: C, 46.61; H, 5.53; N, 16.96.
SUBSTITUTE SHEET PCr/IUS92/02239 WO 92/17185 225 The compounds of formula 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 will be administered in an amount sufficient to elicit an antiviral response; when the parent drug is an antineoplastic, the derivative of formula will be employed in an amount sufficient to elicit an antineoplastic, i.e. ticancer or antitumor, response; when the parent drug is an antibiotic, the derivative of formula 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 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 (1) will be administered in an amount sufficient to elicit an andinflammatory response; and so forth.
Suitable non-toxic pharmaceutically acceptable carriers for use with the selected compound of formula will be apparent to those skilled in the art of pharmaceutical formulation. See, for example, £cingnn~a Pharmaceutical Scieices, seventeenth edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, PA (1985). Obviously, the choice of suitabl; 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 SUBSTITUTE
SHEET
WO 92/17185 PC1/US92/02239 226 characteristically be used for administration of the parent drug itself.
Naturally, such therapeutic dosage ranges will vaxy with the particular compound of formula used, the size, species and condition of the subject, the severity of the subje. t'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 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 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 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 radioisotooe, 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 embodiinents, 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.
SUBSTITUTE SHEET

Claims (79)

1. A compound of the formula R 2 0 I II 0 OCH-OCR, DJ- [D P (I) SOR, or a pharmaceutically acceptable salt thereof, wherein 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 R2 0 i II o OCH-OCR, OR, moiety; R, is CI-C 8 alkyl, C 6 -C 10 aryl or C 7 -C1 2 aralkyl, with the proviso that when is the residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the 1~2 ocH4OCR, OR, moiety via an oxygen-phosphorus bond, then R 1 taken together with the adjacent oxygen atom, can also be the residue of a drug having a reactive SUBSTITUTE SHEET 392/02239 .228- n,9 Rec'd PCT/PTO 14 JUN 1993 hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the R, O I II o OCH-OCR, II/ (D4- P moiety via an oxygen-phosphorus bond, -OR, being the same as or different from R 2 is hydrogen, C 1 -C 8 alkyl, C 6 -C 10 aryl, C 4 -C 9 heteroaryl, C 3 -C 7 cycloalkyl, C .C 7 cycloheteroalkyl or C 7 -C 12 aralkyl; and R 3 is selected from the group consisting of C 1 -C 8 alkyl; C 2 -Cg alkenyl having one or two double bonds; (C 3 -C 7 cycloalkyl)-CrH 2 r wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 CI-C 4 alkyl substituents on the ring portion; (C 6 -C 10 aryloxy)CI-C 8 alkyl; 3- or 4-pyridyl; and phenyl-CrH 2 r- 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 DO-P or D-S-P OR, OR, (Ib) or a pharmaceutically acceptable salt thereof, wherein D-0- 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 SUBSTITUTE SHEET POT"' S 9 2 /0223 11/ -229- a3 flad POT/PTO 14, JU i b I -P OR, moiety; D-S- is the residue of a drug having a reactive mercapto functional group, the sulfur atom of said functional oup being bonded to the phosphorus atom of the R 1 0 oc H-oCR, D-0-P moiety; RI 1 is C 1 -C alkyl, C 6 -C 10 aryl or C 7 -C 12 aralkyl, with the proviso that R 1 in formula 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 OCH-OCR D-O-P moiety, -OR 1 being the same as or different from R 2 Ss hydrogen, Cl-C 8 alkyl, C 6 -C 10 aryl, C 4 -C 9 heteroaryl, C 3 -C 7 cyclosikyl, C 3 -C 7 cycloheteroalkyl or C 7 -C 12 aralkyl; and R 3 is selected from the group consisting of Cl-Cs alkyl; C 2 -C 8 alkenyl having one or two double bonds; (C 3 -C 7 cycloalkyl)-CrH 2 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)CI-Cs alkyl; 3- or 4- SUBSTITUTE SHEE' PC JUS 92/0223 9 -230- 03 Rec'd PC/P: 1 4 JiUN 1,, 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 of the formula R 2 0 1 II 0 OCH-OCR, II/ OR, or a pharmaceutically acceptable salt thereof, wherein is the residue of a drug having a reactive functional gioup, said functional group being attached, directly or through a bridging group, via an oxygen-phosphorus bond to the phosphorus atom of the R2 0 I II O OCH-OCIR, OR, moiety; R, is CI-C 8 alkyl, C 6 -C 10 aryl or C 7 -C 12 aralkyl, with the proviso that when is the residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the Rl 2 O .OCH-OCR, OR, SUBSTITUTE SHEET POT/KL 92/02239 03 Rec'd PCT/PTO 14 JU 1W93 -231- moiety via.. oxygen-phosphorus bond, then R l 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, 0 0 OCH-OCR, 11Z P moiety via an oxygen-phosphorus bond, -OR 1 being the same as or different from R 2 is hydrogen, Cl-Cg alkyl, C 6 -C 1 o aryl, C 4 -C 9 heteroaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl or C 7 -C 1 2 aralkyl; and R 3 is selected from the group consisting of CI-C 8 alkyl; C 2 -C 8 alkenyl having one or two double bonds; (C 3 -C 7 cycloalkyl)-CrH 2 r- 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 1 aryloxy)C 1 -C 8 alkyl; 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; with the further proviso that cannot be the residue of a phosphate drug which is active per se or which is activated by further phosphorylation of the phosphate in vivo.
4. A compound of the formula S OCH-OCR, .OCH-OCR D-O-P or D-S-P S O R (Ia) OR, (Ib) SUBSTITUTE SHEiET PCOT/U 92/ 022 3 S232. .1-4 Ju 1993 -232- 0 4 or a pharmaceutically acceptable salt thereof, wherein D-0- 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 -P 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 R 0 1 II 0 OCH-OCR, ORt moiety; R, is C 1 -C 8 alkyl, C 6 -CIo aryl or C 7 -C 1 2 aralkyl, with the proviso that R, in formula 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 R2S OCH-OCR, O R, D-O-P moiety, -OR 1 being the same as or different from R 2 is hydfogen, C 1 -C 8 alkyl, C 6 -CIg aryl, C 4 -C 9 heteroaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkled or 7 -C 12 aralkyl; and R 3 is selected from the group SUBSTITUTE S8 -9 1 PCT/L. 92/0223 -233- 03 Rec'd FT.- consisting of CI-C 8 alkyl; C 2 -C 8 alkenyl having one or two double bonds; (C 3 -C 7 cycloalkyl)-CrH2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 Ci-C 4 alkyl substituents on the ring portion; (C 6 -C 1 0 aryloxy)C 1 -Cg alkyl; 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 I to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms; with the further proviso that D-O- or D-S- cannot be the residue of a phosphate drug which is active per se or which is activated by further phosphorylation of the phosphate in vivo. A compound of the formula R 2 0 O OCH-OCR, [ib- (I) ORt or a pharmaceutically acceptable salt thereof, wherein 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 R 2 0 I II o OCH-OCR, -P OR, moiety; R, is CI-C 8 alkyl, C 6 -C 10 aryl or C 7 -Cl 2 aralkyl, with the proviso that when is the residue of a drug having a reactive hydroxyl functional SUBSTrUT2 SiA2S PCT/"' 92/022 3 -23 "3 p~ i 1 4 J'U 1993 -234- U group, said functional group being attached directly to the phosphorus atom of the CR, OR "OR, moiety via an oxygen-phosphorus bond, then 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 h-eing attached directly to the phosphorus atom of the R 2 0 1 II 0 OCH-OCR, (D P moiety via an oxygen-phosphorus bond, -OR 1 being the same as or different from R 2 is hydrogen, CI-Cs alkyl, C 6 -Co1 aryl, C 4 -C 9 heteroaryl, C 3 -C 7 cycloalkyl, C3-C 7 cycloheteroalkyl or C-C12 aralkyl; and R 3 is selected from the group consisting of C 1 -C 8 alkyl; C 2 -C 8 alkenyl having one or two double bonds; (C 3 -C 7 cycloalkyl)-CrH2r- 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; 3- or 4-pyridyl; and phenyl-CrH 2 r- 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; with the further proviso that cannot be the residue of a drug of the nucleoside type. SUBSTITUTE SHEET J 92 0 3 2 3 5 n d i
6. A compound of the formula R 2 0 R 0 OCH-OCR 0 OCH-OCR, or D-S-P N OR, (la) OR, (tb) 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 R, 0 I I I 0 OCH-OCR, -P OR, 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 RI 0 I II OCH-OCR, NOR, moiety; R 1 is CI-C 8 alkyl., C 6 -C 10 aryl or C 7 -C 1 2 aralkyl, with the proviso that R, in formula 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 SUBSTmITUTE 3HEET 92 /0 2. 1 9 9' 2 -236- S OCH-OCR, D-O-P moiety, -OPR being the same as or different from R 2 is hydrogen, CI-C 8 alkyl, C 6 -C 0 o 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 Ci-Cg alkyl; C 2 -C 8 alkenyl having one or two double bonds; (C 3 -C 7 cycloalkyl)-CrH2r- wherein r is zero, onetwo or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C 1 -C 4 alkyl substituents on the ring portion; (C 6 -Co aryloxy)C 1 -Cg alkyl; 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; with the further proviso that D-O- or D-S- cannot be the residue of a drug of the nucleoside type.
7. A co; und according to Claim 2, wherein R, is methyl.
8. A compound according to Claim 2, wherein R 2 is hydrogen. 9, A compound according to Claim 2, wherein R 3 is CI-Cg alkyl. A compound according to Claim 9, wherein R 3 is (CH 3 3 C- or CH 3 (CH 2 4
11. A compound according to Claim 2, having formula (Ia).
12. A compound according to Claim 11, 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, anti- UCSSTTUT SHEEt .237- 03 Rec'd PCT/PTO 14A JUN 199 inflammatory steroids, nonsteroidal antiin flammatory agents/analgesics, antibiotics and CNS prostaglandins. 1.3. A compound~ according to Claim 6, having formula (Ia), wherein D-0- 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, anti- inflammatory steroids, nonstero-Idal antlinflamnmatory agents/analgesics, antibiotics and CNS prostagland'Ins.
14. A compound according to Claim 13, 'herein the drug is an androgenic, estrogenic or progestational. steroid sex hormone or an anti- inflammatory steroid. A compound according to Claim 14, 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, norvinistemvc), ethynodiol, oxogestone, tigestol, norethynodrel, cortisone, hydrocortisone, betamethasone, dexamethasone, flumethasone, fluprednisolone, methyl prednisolone, meprednisone, prednisolone, prednisone, triamcinolone, triamcinolone acetonide, cortodoxone, fludrocortisone, flurandrenolide or paramethasone.
16. A compound according to Claim 12, wherein the drug is an antiviral or an antineoplastic.
17. A compound according to Claim 16, wherein the antiviral or antineoplastic is of the nucleoside type. 18, A compound according to Claim 17, wherein the drug is zidovudine, ribavirin, (S)-9-(2,3-dIihydroxypropyl)adenine, 6-azaunidine, acyclovir,, 5, 6-dichloro- l-1-D-ribofuranosylbenzimidazole, 5 ,7-dimethyl-2- O-D-ribofuranosyl-s-tiazole (1,5-a)pyrimidine, 3-deazauridine, 3- SUBSTITUTE SHEP-T 90239 -238& PCrIPrO 1I !U deazaguanosine, ganciclovir, 6-azauridine, idoxuridine, dideoxycytidine, trifluridine, dideoxyinosine, dideoxydehydrothymidine, dideoxyadenosine, BVDU, FIAIJ, FMAU, FIAC, Ara-T, FEAU, cyclaradine, 6-deoxyacyclo- vir, 3-deazaaristeromycin, neoplanocin A, buciclovir, selenazofurin, 3- deazaadenosine, cytarabine, 5-FUDR, vidarabine, tiazofurin, 3'-fluoro- 3'-dideoxythymidine, 1 3-dideoxy-Ig-D-glycero-pent-2- enofuranosyl)thymine, 3 '-fluoro-2 3 '-dideoxy-5-chlorouridine, 5-(2- chloroethyl)-2 '-deoxyui-idine, 5-ethyl-2'-deoxyuridine, 1-hydroxy-2- chloroethyl)-2 '-deoxyuridine, 1-methc-y-2-bromoethy1)-2'-deoxyuridine, l-hydroxy-2-bromo-2-(ethoxycarbonyl)ethyl)-2'-deoxyuridine, 1- hydroxy-2-iodo-2-(ethoxycarbonyl)ethyl)-2'-deoxyuridine, 3 '-azido-2' ,3 3 '-azido-2', 3'-dideoxy-5-odouridine, 3 '-azido- 2' ,3'-dideoxy-5-methyluridine, 3 '-fluoro-2' ,3 '-dideoxyuridine, Ama-AC, pentostatin, dihydro-5-azacytidine, sangivamycin, 6-MMPR, azacitidine, uridine, thymidine, cyclocytidine, triciribine or fludrabine.
19. A compound according to Claim 18, wherein the drug is z idovudine. A compound according to Claim 15, having the structural formula 0 0 H 0 OPmOCHn 2 O%-C(H 3 3 CH 3
21. A compound according to Claim 2, having the structural formula OLa) w .erein RI, taken together with the adjacent oxygen atom, is the residue of a drug having a reactive hydroxyl function. $UST 11 UTE. SHEET PC"U'S92/0223 9 -239- 03 Rec'd 1 4 JUN 1993
22. A compound according to Claim 21, wherein -ORi and D-O- are identical drug residues.
23. A compound according to Claim 22, wherein each of -OR 1 and which are identical, is a residue of an antiviral or antineoplastic of the nucleoside type.
24. A compound according to Claim 23, wherein each of -OR, and D-O- is a residue of zidovudine. A compound according to Claim 23, wherein each of -OR 1 and D-O- is a residue of dideoxyinosine.
26. A compound according to Claim 21, wherein -OR, and D-O- are different drug residues.
27. A compound according to Claim 26, wherein each of -OR 1 and which are different, is a residue of an antiviral or antineoplastic.
28. A compound according to Claim 27, wherein each of -OR 1 and which are different, is a residue of an antiviral.
29. A compound according to Claim 6, having the structural formula (la) wherein R 1 taken together with the adjacent oxygen atom, is the residue of a drug having a reactive hydroxyl function. A compound according to Claim 29, wherein -OR, and D-O- are identical drug residues.
31. A compound according to Claim 29, wherein -OR, and D-O- are different drug residues.
32. A compound according to Claim 31, wherein one of -OR, and D-0- is a residue of an estrogen and the other of -OR 1 and D-O- is a residue of a progestin.
33. A compound according to Claim 31, wherein one of -OR 1 and D-O- is a residue of an antibiotic and the other of -OR, and D-0- is a residue of an antlinflammatory agent.
34. A compound according to Claim 28, wherein each antiviral is of the nucleoside type. SUESTITUTE SHEET PC~/U 92/0?2 3 c -240- 03 Rec'd PCT/PTO J4 JUN 1993 A compound according to Claim 26, wherein one of -OR 1 and D-O- is a residue of a nucleoside antiviral and the other of -OR 1 and D-O- is a residue of an enzyme inhibitor for preventing deactivitation of said antiviral.
36. A compound according to Claim 35, wherein the nucleoside antiviral is susceptible to deamination by adenosine deaminase, and the enzyme inhibitor is an adenosine deaminase inhibitor.
37. A compound according to Claim 35, wherein the nulceoside antiviral is susceptible to deamination by cytidine-deoxycytidine deaminase, and the enzyme inhibitor is a cytidine-deoxcytidine deaminase inhibitor.
38. A compound according to Claim 35, wherein the nucleoside antiviral is susceptible to cleavage by thymidine or uridine phosphorylase, and the enzyme inhibitor is a thymidine-uridine phosphorylase inhibitor.
39. A compound according to Claim 28, wherein each of -OR, and which are different, is a residue of an antiviral having activity against DNA viruses. A compound according to Claim 39, wherein each of -OR 1 and which are different, is a residue of an antiviral selected from the group consisting of ACV, BVDU, DHPG, Ara-T, and EtUdR.
41. A compound according to Claim 39, wherein one of -OR 1 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-OR 1 and D-0- is a residue of an antiviral selected from the group consisting of Am- A, IUdR, TFT, FUdR, FMAU, FIAC and Ara-C.
42. A compound according to Claim 39, wherein each of -OR 1 and 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.
43. A compound according to Claim 28, wherein each of -OR 1 and which are different, is a residue of an antiviral having activity against RNA viruses. SUBSTITUT Zr PC .US 92/0223 9 -24 1 03 Rec'd PCT/2'-
44. A compound according to Claim 43, wherein each of -ORi and 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-glycose, 6-mercapto-9-tetrahydro-2- furylpurine, zidovudine, dideoxyinosine, dideoxyadenosine, DDC and D4T. A compound according to Claim 44, wherein each of -OR, and which are different, is a residue of an antiviral selected from the group consisting of ribavirin, selenazofurin and tiazofurin.
46. A compound according to Claim 44, wherein each of -OR 1 and which are different, is a residue of an antiviral selected from the group consisting of zidovudine, dideoxyinosine, D4T, DDC and dideoxyadenosine.
47. A compound according to Claim 46, wherein one of -OR, and D-0- is a residue of zidovudine.
48. A compound of the formula 14 JUN 19 O W (la) or a pharmaceutically acceptable salt thereof, wherein D-O- is the residue of a hydrophilic drug having a reactive hydroxyl functional group, the oxygen atom of said functional group being bonded to the phosphorus atom of the R 0 o OCH{-OCR, II/ -P NORt moiety; -OR 1 is the residue of an essentially inactive and nontoxic lipophilic alcohol; R 2 is hydrogen, C 1 -Cg alkyl, C 6 -C 1 0 aryl, C 4 -C 9 heteroaryl, C 3 -C 7 cycloalkyl, C3-C 7 cycloheteroalkyl or C7-C2 aralkyl; SUBSTITUTE SHEET PC US 92 /0223 9 -242- 03 Rec 14 JUN I199 and R 3 is selected from the group consisting of C 1 -Cg alkyl; C 2 -C 8 alkenyl having one or two double bonds; (C 3 -C 7 cycloalkyl)-CrH 2 r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 CI-C 4 alkyl substituents on the ring portion; (C 6 -C 1 0 aryloxy)Ci-C 8 alkyl; 3- or 4-pyridyl; and phenyl-Crt 2 r- 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.
49. A compound according to Claim 48, wherein the lipophilic alcohol is a sterol, a long chain aliphatic alcohol, a carbocyclic alcohol or a polycarbocyclic alcohol. A compound according to Claim 49, wherein the lipophilic alcohol is a sterol.
51. A compound according to Claim 48, wherein the hydrophilic drug is an antiviral of the nucleoside type.
52. A compound according to Claim 51, wherein the lipophilic alcohol is an innocuous naturally occurring sterol.
53. A compound according to Claim 52, wherein D-O- is the residue of zidovudine and -OR, is the residue of cholesterol.
54. A compound of the formula OCHOC&R D-O-P 0R or a pharmaceutically acceptable salt thereof, wherein D-0- is the residue of a hydrophilic drug having a reactive hydroxyl functional group, the oxygen atom of said functional group being bonded to the phosphorus atom of the SUBSTITUTE IW-GTr PC J 92/0223 9 -243- 03 N 11993 R2 0 0 OCH-OCR, OR, moiety; -OR 1 is the residue of an essentially inactive and nontoxic lipophilic alcohol; R 2 is hydrogen, CI-C 8 alkyl, C 6 -C 1 0 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 Ct-C alkyl; C 2 -C 8 alkenyl having one or two double bonds; (C 3 -C 7 cycloalkyl)-CrH2r- 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 0 aryloxy)C 1 -C 8 alkyl; 3- or 4-pyridyl; and phenyl-CrI- 2 r- wherein r is zero, one, two or three an o' ,nyl is unsubstituted, or is substituted by 1 to 3 alkyl each having 1 to ;arbon 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; with the proviso that D-O- cannot be the residue of a phosphate drug which is active per se or which is activated by further phosphorylation of the phosphate in vivo.
55. A compound according to Claim 54, wherein the lipophilic alcohol is a sterol, a long chain aliphatic alcohol, a carbocyclic alcohol or a polycarbocyclic alcohol.
56. A compound according to Claim 55, wherein the lipophilic alcohol is a sterol.
57. A compound of the formula D0 0CH-OCR, D-O-P S OR, (Ia) i!lsTITUlTE SHEET T 92/022 39 -244- 03 14 JUN 1993 or a pharmaceutically acceptable salt thereof, wh eein D-O- is the residue of a hydrophilic drug having a reactive hydroxyl functional group, the oxygen atom of said functional group being bonded to the phosphorus atom of the R 2 0 I 11 SOCHI-OCR, OR, moiety; -OR 1 is the residue of an essentially inactive and nontoxic lipophilic alcohol; R 2 is hydrogen, C 1 -C 8 alkyl, .C-C 10 aryl, C 4 -C 9 heteroaryl, C 3 -C 7 cycloalkyl, C,-C 7 cycloheteroalkyl or C 7 -C 12 aralkyl; and R 3 is selected from the group consisting of C 1 -C 8 alkyl, C 2 -C 8 alkenyl having one or two double bonds; (C 3 -C 7 cycloalkyl)-CrH 2 wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 Ct-C 4 alkyl substituents on the ring portion; (C 6 -C 10 aryloxy)C 1 -C 8 alkyl; 3- or 4-pyridyl; and phenyl-CrH 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, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms; with the proviso that D-O- cannot be the residue of a drug of the nucleoside type.
58. A compound according to Claim 57, wherein the lipophilic alcohol is a sterol, a long chain aliphatic alcohol, a carbocyclic alcohol or a polycarbocyclic alcohol.
59. A compound according to Claim 58, wherein the lipophilic alcohol is a sterol. SUBSTTUTE SHE E OCT/US 92 /02239 1 0i 4JU i993 A compound of the formula D-C-O-Z.-ro- O R, (Ic) 0 11 or a pharmaceutically acceptable salt thereof, wherein 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 bridging group, to the phosphorus atom of the 0 II 0 ,OCH2-OCR, OR, moiety; wherein Z is -alkylene- wherein the alkylene group contains R' 2 1 to 3 carbon atoms and R' 2 is defined below; or Z is C 3 -C 8 cycloalkylene in which two adjacent ring carbon atoms are each bonded to a different oxygen atom in the bridging group; R, is CI-C 8 alkyl, C 6 -Co 1 aryl or C-C 12 aralkyl; R' 2 is hydrogen, Ci-C 8 alkyl, C 6 -CIo aryl, C 4 -C 9 heteroaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl or C7-C 12 aralkyl; and R 3 is selected from the group consisting of CI-C 8 alkyl; C 2 -C 8 alkenyl having one or two double bonds; (C 3 -C 7 cycloalkyl)-Cr 1 2r wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 CI-C 4 alkyl substituents on the ring portion; (C 6 -C 10 aryloxy)C 1 -C 8 alkyl; 3- or 4-pyridyl; and phenyl-CrH 2 r- 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 4- rTIUS 92/02 239 *1 4 JUN' 1993 atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms.
61. A compound according to Claim 60, wherein R, is methyl.
62. A compound according to Claim 60, wherein Z is -CH 2 or -CII-. CH 3
63. A compound according to Claim 60, wherein R 3 is C1-C 8 alkyl.
64. A compound according to Claim 63; wherein R 3 is (CH 3 3 C- or CH 3 (CH2) 4 0 A compound according to Claim 60, wherein Dj-C- is the residue of a drug having a reactive carboxyl functional group, said 'drug being selected from the group consisting of anticonvulsants, antintoplastics, antibiotics, diagnostics and nonsteroidal antfinflammatory agent
66. A compound according to Claim 65, wherein the drug is an antibiotic.
67. A compound according to Claim 66, wherein the antibiotic is of the penicillin type.
68. A compound according to Claim 67, wherein the drug' is amoxicillin, phenoxymethylpenicillin, benzylpenicillin, dicloxaillin, carbenicillin, oxacillin, cloxacillin, hetaciltin, methicillin, nafcillin, ticarcillin or epicillin.
69. A compound of the formula C 0 OcH-OC 1 D IN.CH-0.P C K2 R, (1d) SUBSTITUIT SHEET C 0JS9202 23 9 4 03 Rec'd JU 993 or R 0 D-C-N-CH-O-P, R. 0OR, (le) O C or a pharmaceutically acceptable salt thereof, wherein D N- is 0 the residue of a drug having a reactive imide functional group and 0 II D-C-N- is the residue of a drug having a reactive amide function group, R4 the nitrogen atom of the imide or amide functional group being linked, via a -CH-O- bridging group, to the phosphorous atom of the I R 2 RR2 I II 0 o -CR, -i/ OR, moiety; R 1 is C 1 -C 8 alkyl, C 6 -C 10 aryl or C 7 -C 12 aralkyl; each of the R 2 groups, which can be the same or different, is hydrogen, CI-C 8 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 1 -C 8 alkyl; C 2 -C 8 alkenyl having one or two double bonds; (C 3 -C 7 cycloalkyl)- SUB STITUTE SHEET PCT/lS 92/02 23 2"L 03 Rec'd PCT/. 1 4 JUN 1993 CrH2 wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C 4 alkyl substituents on the ring portion; (C 6 -CIo aryloxy)Ci-Cg alkyl; or 4-pyridyl; and phenyl-CrH 2 r- 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. A compound according to Claim 69, wherein R 1 is methyl.
71. A compound according to Claim 69, wherein R 2 is hydrogen at each occurrence.
72. A compound according to Claim 69,_wherein R 3 is Ct-C 8 alkyl.
73. A compound according to Claim 72, wherein R 3 is (CHI) 3 C- or CH 3 (CH 2 4 0
74. A compound according to Claim 69, wherein D N- 0 0 O II or D-C-N- is the residue of a drug having a "-active imide or amide R 4 functional group, said drug being selected from the group consisting of tranquilizers, sedatives, anticonvulsants, hyponotics, antineoplastics, antivirals, antibiotics, barbiturate antagonists, stimulants, antihypertensives and antidepressants.
75. A compound according to Claim 74, wherein the drug is a tranquilizer, anticonvulsant or sedative.
76. A compound according to Claim 75, wherein the tranquilizer, anticonvulsant or sedative is of the hydantoin type or the barbiturate type. SHEET ~cfi/US 92/02 239 '03 Rec'd PCT/H P 1 4 JUN 19
77. A compound according to Claim 76, wherein the drug is phenytoin, phenobarbital, amobarbital or butalbital.
78. A compound of the formula O II II D-N-C.OCH-O-P II R, R, OR, (If) or a pharmaceutically acceptable salt thereof, wherein D-N- is the residue R4 of a drug having a reactive primary amino or secEndary amino functional group, the nitrogen atom of the amino functional group being linked, via a 0 II -C-O-CH-O- bridging group, to the phosphorus atom of the I R"2 0OCHOCR, -P oRt OR, moiety; R 1 is CI-C alkyl, C 6 -Co 1 aryl or C 7 -C 12 aralkyl; R" 2 is hydrogen, CI-C 8 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 1 -Ce alkyl; C 2 -Cg alkenyl having one or two double bonds; (C 3 -C 7 cycloalkyl)-Cr-H 2 r- 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 1 0 aryloxy)Ct-Cg alkyl; 3- or 4- pyridyl; and phenyl-Cr 2 r- wherein r is zero, one, two or three and ;henyl SUBSTITUTE SHEET 250 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.
79. A compound according to Claim 78, wherein R 1 is methyl.
80. A compound according to Claim 78, wherein R" 2 is hydrogen or methyl.
81. A compound according to Claim 78, wherein R 3 is C 1 -C 8 alkyl.
82. A compound according to Claim 81, wherein R 3 is (CH 3 3 C- or C11 3 (CH2) 4
83. A compound according to Claim 78, wherein D-N- is the residue of a I R 4 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 amino acid units, dopaminergic agents and antibiotics. 16 84. A compound according to Claim 83, wherein the drug is an antiviral. A compound according to Claim 84, wherein the antiviral is amantadine or rimantadine.
86. A compound according to Claim 83, wherein the drug is a small peptide.
87. A compound according to Claim 86, wherein the small peptide is an enkephalin or an endorphin.
88. A mixed phosphate derivative of a drug substantially as hereinbefore described with reference to any one of Methods A to M or any one of Examples 1 to 22.
89. A method for site-specifically and sustainedly delivering a drug species to a S 25 target organ, comprising administering to an animal in need of such treatment a quantity of a compound as claimed in any one of Claims 1 to 88 sufficient to release a pharmacologically effective amount of said drug species to the target organ.
90. 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 any one of Claims 1 to 88 sufficient to release a pharmacologically effective amount of said centrally acting drug species to the brain.
91. A method according to Claim 89 or Claim 90, wherein the compound is administered in the form of a pharmaceutically acceptable sustained release composition 35 or wherein the compound is administered via a route of administration capable of slowly releasing the compound into the body. r\ V? [N:\LIBVV]00395:rnk:I W 251
92. 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: an amount of a compound as claimed in any one of Claims 1 to 88 sufficient to release a pharmacologically effective amount of a drug species to the target organ; and (ii) a nontoxic pharmaceutically acceptable carrier therefor.
93. 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: an amount of a compound as claimed in any one of Claims 1 to 88 sufficient to release a pharmacologically effective amount of a centrally acting drug species to the brain; and (ii) a nontoxic pharmaceutically acceptable carrier therefor.
94. A pharmaceutical composition as claimed in Claim 92 or Claim 93, said composition being formulated for sustained release. A process for the preparation of a compound of formula as claimed in any one of Claims 1 to 88, said process comprising reacting a phosphoric acid derivative of the formula O II OH OR where and R 1 are as defined in any one of Claims 1 to 88, with the cesium fluoride or an equivalent cesium salt and a compound of the formula O R 3 CO-CH-1 i R2 wherein R 2 and R 3 are as defined in any one of Claims 1 to 88, in an organic solvent. 25 96. A process for the preparation of a mixed phosphate derivative of a drug substantially as hereinbefore described with reference to any one of Methods A to M or of any one of Examples 1 to 22,
97. The product of the process of !aim 95 or Claim 96. Dated 8 March, 1996 University of Florida Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON tN.\LIBVV]00395rk:rTcW INTERNATIONAL SEARCH REPORT International Application No. PCT/US92/02239 I. CLASSIFICATION OF SUBJECT MATTER (if several classification symbols apply, indicate all) 3 According to International Patent Classification (IPC) or to both National Classification and IPC IPC Please See Attached Sheet. US CL Please See Attached Sheet. II. FIELDS SEARCHED Minimum Documentation Searched' Classification System Classification Symbols U.S. 514/47; 514/48; 514/51; 536,27; 536/28; 536/29 Documentation Searched other than Minimum Documentation to the extent that such Documents are included in the Fields Searched III. DOCUMENTS CONSIDERED TO BE RELEVANT14 Category* Citation of Document,' 1 with indication, where appropriate, of the relevant passages' 7 Relevant to Claim No. Is A US, A, 4,837,311 (TAM ET 06 June 1989, see whole 1-81 document. A WO, A, 90/06319 (SAKSENA ET 14 June 1990, see 1-81 whole document. A EP, A, 0,284,405, (FROST ET 28 September 1988, 1-81 see whole document. A AIDS RESEARCH AND HUMAN RETROVIRUSES, Volume 4 No.6 1-81 issued 1988, Busso et al., "Nucleotide Dimers Suppress HIV Expression In Vitro," pages 449-455, see whole document. Y US, A, 4,968,788, (FARQUHAR), 06 November 1990, see 1-81 whole document. Y J. PHARMACEUTICAL SCIENCES, volume 72 No.3, issued 1-81 March 1983, Farquhar et al., "Biologically Reversible Phosphate Protective Groups," pages 324-325, see whole document. Special categories of cited documents:1 6 later document publishad after the international filing document defining the general state of the art which is date or priority date and not in conflict with the not considered to be of particular relevance application but cited to understand the principle or arlier document but published on or after the thory underlying the invention international filing date document of particular relevance; the claimed document which may throw doubts on priority claim(s) cnsi renton annot dd nove r cannot be or which is cited to establish the publication date of considered to involve en Inventive step another citation or other special reason (as specified) Y document of particular relevance the claimed Sinvention cannot be considered to involve an document referring to an oral disclosure, use, ehibion nventive stp when the document is combined ith or other means one or more other such documents, such combination document published prior to the nternational filing date being obvious to a parson skilled in the art but later than the priority date claimed document member of the same patent family IV. CERTIFICATION Data of the Actual Completion of the International Search 2 Data of Mailing of this International Search Report 2 JUNE 1992 4 JU 199 International Searching Authority Signature of Authorized Offic er 2 ISA/US ERIC L. CRANE Form PCTIISA/210 (second sheat)(May 1986) B S International Application No. PCT/USS 2/02239 FURTHER INFORMATION CONTINUED FROM THE SECOND SHEET BIOORGANIC CHEMTSTRY, volume 12, issued 1984, Srivastva et al., "Bioreversible Phosphate Protective Groups: Synthesis and Stability of Model Acyloxymethyl Phosphates," pages 118-129, see whole document. J. MEDICINAL CHEMISTRY, Volume 33, issued 1990, et al., "Synthesis and Biological Properties of Novel Phosphotrieters: A New Approach to the Introduction of Biologically Active Nucleotides into Cells, pages
1400-1406, see whole docUment. 1-81. 1-81 V.0 OSSERVA'fOQS WHERE CERTAIN CLASAS WERE FOUND UNSEARCHABLE 1 Cilm numbes., becaus they reate to parts of the International apiation that do not comply with the prescribed requirrmnts to such an exteiit that no masningful internatoa sarch can be carrad out saciicWy Claim numbers because they are dependent claims not drafted In accordance with the second and third sentences of PCT Rule 6,4(a), VI. 0 OBSERVATIONS WHERE UNITY OF INVENTION IS LACKINCG This International Searching Authority found multiple Invontions In this International application as follows: I~ As all requred additional search foes wooe timely paid by the applicant, this International search report covers all searchable claims of the IKiernational spplictio. 2. 0As only some of the required additiona search fees were timely paid by the applicant, this international search report covers only those claims of the International sjpplicatkre t'or which tees ware paid# specifically clms., a3. 0No required additional search fees were timely paid by the applicant. Consequontly ,this International search report Is restricted to the Invention first mentioned In the claims; It Is covered by claim rsxrbers:, As all searchable claims could be searched without effort Justifying an additional fee, the International Search Authority did not Invite paymeant of any additional fee. Remark on protest 0The additional search fees were accompanied by applicant's protest, 0No protest accompanied the payment of additional search fes. Form PCTIISAl21O (supplemental sheet(2)H(Rev, 4-90) S International Application No. PCT/US92/02239 Ill. DOCUMENTS CONSIDERED TO BE RELEVIANT ICONTINUED FROM THE SECOND SHEET) Category* Citation of Documnent, 16 a wi~h indication, where appropriate, of the relevant passages 17 Relevant. to Claim No. 0 Y TETRAHEDRON LETTERS, Volume 22 No.39, issued 1981, van 80-81 der Marel et al., "A New Approach to the Synthesis of Phosphotriester Intermediates of Nucleosides and Nucleic Acids," pages 3887-3890 see whole document. Y NUCLEIC ACIDS RESEARCH, Volume 11 No.23, issued 1983, 80-81 Wreesmann et al., "Synthesis of Short RNA Fragments by the Benzotriazoly. Phosphotriester Approach, pages
8389-8405, see whole document. Y ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Volume 34 No.6, 1-81 issued June 1990, Schinazi et al., "Activities of 3'- azido-31 -deoxythymidine .1J-ucleotide Dimers in Primary Leukocytes Infected with Human Immnunodeficiency Virus Type pages 1061-1067, see whole document. A J. MEDICINAL CHEMISTRY, volume 29, issued 1986, 1-81 "Synthesis and Antiherpes Virus Activity of Phosphate and Phosphonate Derivatives of 9[(l,3-Dihydroxy-2- propoxy)methyllguanine," pages 671-675, see whole document. Y US, A, 4,816,570 (FARQUJHAR), 28 March 1989, see entire 1-81 document. Form PCT1ISA121O lextra sheet)lMey 1S86) 12 Internationil Application No. PCT/US921O2239 FURTHER INFORMATION CONTINUED FROM PREVIOUS SHEETS I. CLASSIFICATION OF SUBJECT MATTER: IPC A61K 31/70;C07K 19/073, 19/173 I. CLASSIFICATION OF SUBJECT MATTER- US CL S14/47; 514/48; 514/51; 536,27; 536/28; 536/29 Form PCTI1SA/210 (continuation shoat (1)(Oct 1991)) f&
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US4816570A (en) * 1982-11-30 1989-03-28 The Board Of Regents Of The University Of Texas System Biologically reversible phosphate and phosphonate protective groups
US4837311A (en) * 1987-06-22 1989-06-06 Hoffman-La Roche Inc. Anti-retroviral compounds
US4968788A (en) * 1986-04-04 1990-11-06 Board Of Regents, The University Of Texas System Biologically reversible phosphate and phosphonate protective gruops

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Publication number Priority date Publication date Assignee Title
US4816570A (en) * 1982-11-30 1989-03-28 The Board Of Regents Of The University Of Texas System Biologically reversible phosphate and phosphonate protective groups
US4968788A (en) * 1986-04-04 1990-11-06 Board Of Regents, The University Of Texas System Biologically reversible phosphate and phosphonate protective gruops
US4837311A (en) * 1987-06-22 1989-06-06 Hoffman-La Roche Inc. Anti-retroviral compounds

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