CA2108041A1 - Targeted drug delivery via mixed phosphate derivatives - Google Patents

Targeted drug delivery via mixed phosphate derivatives

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Publication number
CA2108041A1
CA2108041A1 CA002108041A CA2108041A CA2108041A1 CA 2108041 A1 CA2108041 A1 CA 2108041A1 CA 002108041 A CA002108041 A CA 002108041A CA 2108041 A CA2108041 A CA 2108041A CA 2108041 A1 CA2108041 A1 CA 2108041A1
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Canada
Prior art keywords
drug
alkyl
compound according
residue
functional group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002108041A
Other languages
French (fr)
Inventor
Nicholas S. Bodor
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University of Florida
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Individual
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Publication date
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Publication of CA2108041A1 publication Critical patent/CA2108041A1/en
Abandoned legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
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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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    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
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    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
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    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • C07F9/65068—Five-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems
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    • 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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Abstract

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

Description

.. 1 7 1 85 Pcr/uS92/0223s The prescM inven~ion rclata to an anionic scquestration type of S drug modification designed to enhancc dclivery of thc activc drug sp:ies to the dcsired sitc of action, cspccially to the brain. More cspecially, ~he presens invention rclata to the discovcry that a biologically ac~ve compound coupled to a lipophilic carri moicty of thc acylo~yallcyl mLxcd phosphate type rcadily pcnecata biological membrana such as thc blood-10 brain bar~ier ~BBB) and enten the targe~ organ; clcavage of the mL~edphospha e casrier/drug enuty in, vo providcs a hydrophilic, negati~ely charged intcrmediate which is ~loclced in~ the bra~n or other organ and which provides significant and sustained dclivery of the acti~ve drug species to the targa organ.

BACKGRQUND OF TEIE IN~ON:

Thc delivery of drug specia to the brain and other organs is often ser.iously limited by transport and metabolism factors, including biological membrancs; spocifically, in the casc of the brain, deli~.rery is limited by thc functional bamer of the endothclial bsain capillary wall, i.e. thc blood-'O bwn barsi or BBB. Site-spocific and sustained ddi~ery of d~ugs to the brain or other organu, i.e. targcted drug teli~vcry, is cven morc difficult.
Many drug~ ar hydrophilic and are unable to peneffatc the brain to any considerable e~ctent. Other drugs which are lipophilic and/or for which particular ~ansport mechanisms e~ist may bc able to cr~s~ the BBB and 'S rcach thc brain, but the very lipophilicity which enabla their en~y l~ewisc SVBSmUTE SHEET

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'acilitatu thar e~in It is thuY necessary to ad3T~inistcr large doscs of drugs to achieve adequate brain levels (if, indeed, such is even possible), and this in turn overburdens non-targeted loci and results in signifiG~nt to~icity.
It is now well-known that numerous drugs eIer~ their biological e~fect~ through cen~ally-mediat~d mechanisms. Thus, a brain-targeted approach is a desirable mcans of delivery for a wide diversity of drugs, ;ncluding neurotransmitsers, stimulants, dopaminergic agents, tranquili~ers.
antidepressants, narcotic analgesics, narcotie antagor~ists, scdatives, hypnotics, anesthetics, antiepileptics/anticonvulsants, hormones such as ~he 10 male and female se~c hormon, peptidu, anti-inflarnmatorS steroids, non-steroidal anti-inflammatory agents/non-nareotic analgesics, memory enhancers, antibactenals/antibiotics, antineoplastics (anticancer/anntumor agents) and antiviral agents.
In rcoent years, the need for more effective treatment of a number 15 of visal dis~ase statu has beeome increasLngly urgent. The generally poor therapeudc accessibility of viral hfeedons can be traced to three major facets including the viRl life cycle, the laclc of efficaeious pharrnacologically-acdve agents ant, finally, the inability to deliver those agents which are ava~able to the central nervous system (CNS) for '0 sustained periods and in significant a nounts.
Viruse~ are submieroseopie pathogens which depend on ~he cellular nucleie acid ant protein syn~hesinng mechanisms of its host for propagation. In general, viruse~ invade cells by first intacdng at a recognizabb surfacc protein, penetrating thc ccll membranc and ~S subsequently releashg themselves from a protective polypcptide coat to eject the core of the Vinl5. The heart of these pathogcns i genetic material, either DNA or ~NA, and ~e type of nucleie acid give5 rise to the system of nomenelanlre for these entitic~. The viral DNA and RNA can inuraet with cellular components to produce daughter genetie material a~
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~elease, the vi~l progcny may infect other cclls, yielding discase or ultimately death.
DNA viruses are subdivided into five families and include the pathogens responsible for labial and genital herpcs, herpc~ enccphalitis.
human cytomegalovirus infection, chiclcen po~, shingles and mononu-cleosis. RNA viruses are prcscnt in morc numcrous forms and are subdivided into tcn families. I~hese viruscs are unusual in that they reverse the usual DNA--RNA--protem sequence which occurs in highcr life forms. RNA viruses are unusually dangerous for sevesal reasons, including their lethality and the lack of effective treatments. RNA viral diseascs include acquired immune deficiency syndrome, hemorrhagic fevers of vanous descriptions, Denguc fc~, I~ssa fe~rer, and numerous cnccphalitic maladiu including Japancsc B encephalitis.
Chemotherapeutically, very few anti~riral agents have becn lS developed that ha~ve high i~ ~m activity against thesc viruSes. One notable advance in the field was the adven~ of ribavirin or 1-B-D-ribofuranosyl-1,2,4-triazole-3 carbo~amidc, synthcsized in 1972. Ribavinn has a broad range of activity agahst both DNA and RNA ~iruses. This riboside, which contains an unnatu~al triazole base, significantly suppresses 'O the infecd~vity and cytopathicity of se~ e~ iral pathogens by mechanisms which are as of yet unclear. Se~reral intcsactions have been suggestcd including inhibition of ~iral RNA polymcrasc, the inhibition of inosine monophosphatc dehydrogenase by riba~nnn anaboLites and hterference of mRNA cap formation by the S'-~riphosphate of ribav~rin.
2S Riba~irin is active against se~cral hfluenza ~riruscs ant respiratory syncy~ial ~ and as such is used h an aerosol form to treat thcse discasa. Riba~nrh is also used h thc treatmcnt of ~ssa fe~ cr which rages in epidemic p~oportions h Sierra Leonc. Unfortunately, while peripheral vi~l hfections can be successfully treated with riba~rinn and otha riboside demrati~ra, encephLitis i~ immune to the action of these trugs. The inabiLiq of anti~iral drugs, which are highly potent ~ vitro, to e~ert - SUBSmUTe SHEFT

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2~ ~33~1 acnvi~y in thc CNS is at~ibutable to thei~ exclusion from the brain. The basis of this impermeability is thc blood-brain barrier (BBB), which effectivelv separates the sys~emic circulation from the brain parenchyma.
.~.s this barTier is lipoidal in nature, the BBB restncts the entry of materialswhich do not have high affinity for the phospholipid matrL~ and consequemly hydrophilic compounds are e~cluded. Thus, drug molecules must be intnnsically lipophilic if they arc to gain access to the CNS. This is the restriction which rendcrs ribavtrin, which has a log P of only 2.06, ineffective in treating viral diseascs of the brain.
Many antiherpctic agenu e~hibit poor penetration acmss biological - bamers such as the BBB and the ocular ant s~n bams, achieving concentrations well below therapeutic lcvel~. Impr~red dclivery of an antihe~petic agen~ across these barrier~ would offer a significant advantage in the trealment of such seriou~ and debilitating diseasa as enccphalitis, ophthalmic infections caused by herpes s~ nple~c such as herpetic uveites, keratitis etc. and cutancous hcrpcs infcctions such a~ genital and orofacial hcrpes.
Vidarabhe (9-,B-D-arabinofuranosyladcnine, Ara-A, adenine a~btnoside) is a purine nucleoside analog with a broad spoctrum of ~0 antiviral acti~ity against a numbcr of DNA v~ uses, including HSV-l and 2, cytomegalo~ and varicella zoster virus. The drug ha~ been shown useful in the trea~nent of brain biopsy-provcn herpes simple~ encephalitis (HSE), resulting tn a statistically significant reduction in morta~ity. Ara-A
has demon~a~d cltnical utiltty as a topical agent for hcrpes lce~atitis of the 'S eye. Howcv, when applied loa~y to the sl~in, vtda~abtne ha~ provided no benefit in gcnital or oraf~cial HSV infection. In immunocompromised patients with localized herpes zoster, A~-A ha~ demon~atet a beneficial effect in accelerating cu~neous healing and decra~ing the rate of cu~aneous dissemination.
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the incorporation of the drug into vi~al DNA. To e~cen its antiviral action.
vidarabine must first be phosphorylated by cellular enzymes to the ~riphosphate which competitively inhibits HSV DNA polymerase. Some investigaton havc found that the viral DNA polymerase activiq is more sensitive to inhibision than that of cellular DNA polymerascs an obsen~auon that could explain some of the selective to~icity of the dmg and i~s dose-related to~icity. Vida~binc triphosphate is incorporated into both cellular and viral DNA where it may ac~ as a chain ter~ ator for newly synthcsized HSV nuckic acid.
Despite its pro~en efficacy Ara-A doe suffer from a number of limitations including low lipophilicity as evidenced by a negative log P
(octano~lwater) which rcsulu in a failure to be atequately transported across biological membrana.
Herpa simple~ virus is a causative factor for encephaLids. Its lS involvement h thc CNS rcpr~enu the most common cause of nonepidemic fatal encephalitis h thc Unitet States. An estimatot l 000 to 5 000 cases occur each yeat in the U.S. with teath in over one half of those who are untreatet. He~pa simple~c virus type 2 causa enceph~lids h padents with thymic typl~ia and otha severc immunodefi~ency statu. EncephaLi~s 'O also is a common oppottutusdc infe~ion usoaated with AIDS.
The acute severe enccphalitis duc to herpcs simple~ typc 1 in humans rnay reprcsent a pdmary hfection a reinfection or an activation of laten~ hfeaion. The pnmaty mode of viral ttantport hto the CNS has not becn cleatl~ emblished. However it h~ been shown that following 'S e~t~ana~ inomla~ion thc ~us gainet acce~ to the CNS by both hematogenow and neud pathways. Thc neural p~thway of t~anspott in man is suppor~d by the fact that the ~r~rut can bc isoLated from e~plants of both ~igeminal ganglia in the majority of routinc autop~ia.
Hcrpe~ simple~ encephalitit i~ the mott common causc of sporadic 30 fatal encephalids. Both thc high morraLity ratc and the ris~ of se~ere sequelae in the survivor have promp~ attempu at thaapy wi~ anti~iral SUBSmUTE SHEET

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compounds. In order tor the antiencephaLitic agent to e~ert its effect, it is necessary for the drug to be present in the CNS wherc the vurus is lodge~
at an optimum concent~tion and for a sufficient period of time.
.',Iainta~r~ing a therapeutic level of the drug over a prolonged penod at the site of action is essential in optimal reduction of vi~l concentrations.
Resistance of virus in the brain after treatment has been reparted in almost all or the case~ studied so far. Only very rarcly ha~ total remission been achieved.
The main reason for thc laclc of successful trcatrnent is the 10 inefficient method of drug delivery to the brain, the major impedimen~ to drug delivery to the brain being the blood-bra~n barrier. Antiviral agents such as iododeo~yuridine and vidarabine e%hibil linle acriviq and high toxicity in the trea~ment of encephalitis. This is primarily due to their inabiliq to cross the blood-brain barrier at optimum concentrations. In the 15 case of other antivirals such as acyclovir, drug resistance has been observed. To overcome such problem~, a new family of fluorinated nucleoside analogs has ~een synthe~ed. This family includ 1-(2'-deoxy-2'-fluoro ,B-D-arabinofuranosyl) deriva~v of 5-methyluracil (FMAU), 5-iodocytosine (FIAC) and S-iodou~acil (FIAU). FIAU is a meta~olite of 'û FIAC. These compounds have been shown to display significant antiviral activiq against he2p v~ruses iD ~m and in some Ul vivo espesiments.
The mechanism of anti~riral activity depcnds in part on the phosphorylation of these agents by viral-spocified thymidine Icinase. These agents are rapidly ~ up and phosphorylated only to the S'-monophosphate in HSV-~5 infected c~ ; the monophosphates are presumably further phosphorylated by cellular enzymes to the cor~esponding triphospha~. Phosphorylation of these agents by thc virus-coded thymidine l~inase i3 much bettcr than by the cellular enzymes. These anthriral agents are incorporated hto tern~isli and internucleoside linlcages of viral DNA much more than into the DNA of 30 uninfected cells. Since IT~Cimum selecti~ity would improve the the~pcutic potential of any new and~al drug, rc~ativcly low to%iciq with norrnal cells SUBSmUTE SHEET

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, , is mandatory lhe low cytoto~iciN e~hibited by these agents with uninfected cells indicate selectiviry of acuon.
~lthough these nucleosidc analogs e~hibit high selectiviry toward ~iral cells, they are quite polar and thcrefore their abilirv to penetrate the BBB is greatly minim~ed. They must be administered in high doses to attain an etfective level in the brain, resulting in scverely to~ic side-effects.
For e~ample, FMAU, considered the most potent antiviral agent of its class (thera~eutic inde~ greater than 3,000) in treating encephaLitis, produces irreversible neurological darnage at doscs greater than 32 mg; other side effects include diarrhea, nausea and blood count depression. High doses of FIAU have resultcd in cardiac fibrosis, myelosuppression and Iymphoid deplcrion. In the case of FIAC and FMAU, sigrlificant reducrion 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.
IS I~ is known that FIAC is metaboliz~d e~tcnsively Ul vivo and that its meubolita retain their antiviral activity in cell culture. The major metabolit of FLAC includc the dcaminated specie~ FIAU, the deiodinated specia 2'-Quoroarbinosylcytosinc (FAC) and 2'-fluoroarabinosyluracil (FAU) and their glucuronides. ~wo metabolita of FMAU have been ~0 isolated from the urine of micc. Thesc include 2'-fluoro-5-hydro~yme~hylarabinosyluracil (FHMAU) ant a glucuronide of F~LAU.
FMAU, FL~U and FIAC have becn found to e%hibit morc potent antiviral acdvity than acyclovir. The meubolitcs of thesc compounds, even though poten~ inhibiton of HSV-2 h cell cultura, are asentially devoid of 'S andviral acti~ity In ~vo in thc encephalitis model. Ihi~ dichotomy between ~ ~m activity and Ul lvo activity suggests that thesc agents do not cros~ hc BBB in sufficient conccntranon to c~crt aetivity.
(E)-5-(2-bromovinyl)deo~cyuridinc (BVDU) is also a polar antiviral agent effective against enccphalitis caused by hcrpa zoster virus and HSV-1. This agent crossu the BBB in low levels only at ve~y high concentrationX as a result, it ha~ been shown to intuce sister chromatid SU~SmUTE SHEET

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wo 92/17185 ~ Pcr/US92/0223s exchange~ Osher side-e~ects include to~cici~y ~o liver, bone marrow tunction and gonads.
Dihydro~cypropo~vmethylguanine (DHPG) belongs to the se class o~ antiviral agents as acyclovir. E~owever, DHPG has been shown to be at S least l00 fold more effectivc than acyclovir in the trcatment of encephalius !n vitro and ~n vivo. DHPG is more efficicntly phosphorylated in infecsed cells than is acyclovir. As with acyclovir, he~ virus-spccific thymidine kinase phosphorylates DHPG to i# monophosphate, which is further phosphorylated to i# di- and triphosphate by cellular guanylate kinase and 10 other c~lularenzymes, respoctively. However, DHPG i5 transported to the brain only at high dosa, which in tum producc high plasma levels ot the drug which e~cert cytoto~ic effects on nonnal human mycloid cells.
Studies have shown that acyclovir crossu ~he BBB poorly, and at higher doses causa problcms such as renal blocl~agc.
lS Human cytomegalovirus (HCMV) i5 a vi U5 of the herpes group which includa herpa simple~ I and II, Epstein-Barr nrus, and vancella zoster nn~s. In common with the oth memben of its group, infection with HCMV leads to a latent sutc h which thc ~ri~l genome becomes incorporated h thc host DNA, ant h which rocu~rcnt infections are 'O common. Vi~al infection with HCMV is quitc widesprcad, with appro~imately S0% of Americans show~ng seropositivity by age 30. In the majority of case~ the vuus doa not causc an overt diseasc statc, but can be dctected through serological and other laboratory procedurcs h otherwise hcalthy individual~. In the absencc of complica~ing facton, e~posure to the 2S virus can ~ult h a clinical prenution ranging from asymptomatic seroconve~ion to a diseasc state ~aembling infectious mononucleosis.
In cont~a~t to ~ hfection in norm~ adults, HCMV in the fctus or neonate can result h severe clinical maniftations. The virus in these casa it acquired congenit~y, often f~om asymptoma~c mothen. Thc 30 virus has been said to be the shgk most frequent causc of ~riral infections in newbonu. The a= of HCMV in neonates is from 0.S% to 4%

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WO 92/17185 2 1 ~ 8 ~ 4 1 P~/~lS92/02239 ! . _9_ of all live bi~hs, but only 10% to 2070 of thcse will have clinical manifesutions of cytomegalic disease, which maislly involve the C~S and which can result in permancnt. debiliuting brain damage or auditory degeneration.
Wllen the host immune system is supprcssed, HCMV becomes a much more scnous infective agent. In this sute, a latent HC.~IV infecuon may recur, or a primary infection may be unusually scvcre.
~mmunosuppression can occur in several circumstanca, for example, during use of immunosuppressive drugs, such as corticostcroids, 10 azathioprinc, and thymocyte immune globulin which are given to prevem rejcction of a transplanted organ when a patient ha~ undergone organ transplant surgery. Along with otha compiications, cytomegalic diseasc is a common and sometim especially scrious problem which can follow successful Icidncy, bonc marrow, and hea t transpbntation. The 15 manifcsution~ of cytomegalic disease follow~ng transplant surgery can include, but arc not limitcd to, rc~nitis ant pneumonitis. Another particularly serious complication occurring during immunosuppressive therapy i5 Kaposi's sarcoma (~CS). A strong correlation is ~nown to cxis~
between KS and HCMV, to the e~ctcnt that it has becn postulated that 'O HCMV causa KS, analogously to thc rchtionship bctween Epstein-Bb~
virus ant Burlcitt's lymphoma. However, a causal rolc for the virus has not becn definiti~cly atablished.
An immunosupprscd s~atc i~ the hallrnarlc of acquired immunodeficuncy syndrome (A~S), and HCMV ha~ been shown to ha~c ~S an c%traortiD~ry p~evalence in thi~ population, app~oaching 94%. In addition, cytomegalic disease and its complication~ arc among thc primary cause~ of much of the suffcnng from AlDS a~ well a~ a major factor causing death. HCMV i~ Icnown to result in a suppression of cell-mediatcd immuniq through deprsion of le~els of T-helper cells with an increase in 30 suppressor/cytoto~ic T~lls. Bcforc the discovery of human immunodeficicncy ~rirus (HIV), the list of candid~ for the cause of AIDS

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wo 92/17185 Pcr/us92to2~3s 2l~a~ ~ 10 includcd HCMV. The consequenca of HC~ infection in A~DS are manifold, .vith neural and especially ocular involvement being predominant. Ocular involvement is presented as a hemorrhagic retinitis nrst evidcnccd by blumng of vision. This retinitis is so common that it has been proposed that i~ be the primary diagnostic cvidence for the presence of AIDS. Neural involvement resulting in viral enccphalitis is also common and presents itself post-mortem in thc microglial nodules which are r~pical of HCMV intection. In AIDS, this neural involvement is concomitant with HIV infecrion of the CNS, often manif~sting as subacu~e encephalopathy.
An antiviral agent which has shown promise in the treatment ot HCMV infections in immunosuppressed sutes is DHPG. As menuoned above, DHPG is strucrurally similar to acyclovir (ACV), a sa~e and efficacious antiherpctic agcnt. The primary me~chanism of DHPG action IS against CMV is inhibidon of the rcplication of vi~al DNA by DHPG-triphosphate. This inhibition includa a selectivc and potent inhibition of the viral DNA polymes~e. Shce HCMV does not encodc a ~irus-specific thymidhe Icinase, phosphoryladon of DHPG is presumably accomplishcd by the host-ccll cnzym, primarily vanous nucleoside l~nasa, which have 'O been shown to be ele~ated h HCMV-hnfocted ccll~. The mar~cedly increa~sed activitx of DHPG toward CMV compared with ACV appears to be due in p~t to thc cfficicnt intracellu~ar mctabolism of D~G to its mono and triphosphate in CMV-infected ccll~. The ~elative i~ ~Q
activitia, a measured by the IC~o values of DHPG vs ACV arc of the ~5 sarne ort against herpe~ simplac sri~us (HSV), namcly 0.2 to 0.8 ~LM.
Ho~vcv, agaL~st HCMV ~he IC~o for D~PG is aypm~umatdy 2.S I~M.
Thus, DHPG ha~ significant activiq against HCMV in vitro. These promising ~sults have bcen e~tended in animal modcl~ as well as in clinical trials.
As mentionet abo~ e, onc of thc first clinical sign~ of AIDS
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WO 92/17185 2 1 0 ~ o a~ 1 Pcr/uss2/o223s dramanc recen~ clinical demonstratlon~ o~ antiviral activi~y has been in a study ot the etfects of intravenous DE~PG in AIDS patients who were sutfenng from progressive blindness caused by cytomegalic infe rion ot ~he retina. In these patients, not only did viral titers drop to an unobservable S level, but clinically observable improvement in sight was achieved. ln other studies, significant improvement in other arca~ of cytomegalic infection was shown. These includct improvement in ~he cytomegalic pneumonitis ant enccphalitis, as well as gastrointcs~inal 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 compount (5. l mg/ml. at 37C) necessiutc the use of the sodium salt f~r the intravenous adminis~ation of thc dNg. This induces pain or phlebitis at the infusion site, sincc the pH of thc solution is about 11. In humans, oral bioavailability of DHPG is only 3~.6% based on urinary cxeretion, with 99% of thc drug being exereted unehanged by the Icidneys. The pharmaeoldnetie disposidon of intravenous DHPG in human~ is similar to that observed h rat~ and dogs, with the finding of a biphasie clim~nation with an ~-ph~c half-lifc of 0.23 hours and a ,B-phasc of 2.S3 hours. These 'O valucs are quite similar to thosc for aeyelovir, and show that rcpeated dosing is necessary to mamtain cffeetive plasma eonecntration.
Neutropcnia is the most froquent dose-dcpcndcnt to~ieiq assoeiatcd with DHPG thcrapy.
DHPG is a hydro~ymethyl analog of aeyelovir and eonsequently is 'S more polar and is e~;peeted to pass throug~l the blood brain barri (BBB) cven les~ ~atily. In rodent models, it ha~ b~en shown that acyclovir distribut into most organs, with the highat levels found in renal tissue and thc'lowest levds found in bain tissuc. Phanna~olcinetie studia of DHPG in the rat and dog have demons~atcd behavior similar to aeyelovir.
Human pharmacol~neties of intravenous D~G indieate eercbrospinal fluid (CSF) coneen~ations equivalent to 24% to 67% of phsma eoneentrations.

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wo 92/t7185 Pc~r/US92/02239 2 1 0 ~ ~ 4 1 -- ~2 -- !-Howeves since CSF levels may reflect transport through the choroid ple~us some uncertainty regarding spocific brain levelI of DHPG e~ists.
Regardless of the efficiency with which DHPG crosses the BBB however.
i~ is to be e~pected that it may Ieave the CNS by the same mechanism with ~qual facility. In view of rhe significant role played by CMV in AIDS
patient~ with severe neurologie eompLications and the possibility that C.~V
could create a reservoir of persistent infection of the CNS even if peripheral clea~ance were realized there e~iss a rationale for identifying antiviral drugs that can penetrate the BBB and accumulate in the brain thereby providing a sustained release of the anti~iral to maintain a therapeutieally effective coneentration.
Acquired immune deficiency syndrome (AIDS) was first descnbed as a dis~inct clinical entity in 1981. As of October 1989 110 000 cases of AIDS as defined by the Center for Disease Control (CDC) have been diagnoset ant 6S 000 people have died from the disease. This insidious and pernieious malaty ha a 2-3 year fatality rate of almost 100% and is e~peeted lo stril~e between 13S 000 and 270 000 people by 1991 alone.
AIDS is now the leating eause of premature mortaliq in a number of areas and in sevenl subpopulations in the US; by 1991 i~ is e~cpectet to be a 'O major I~ er. In oth arets of the world a similarly gTim picture is developing. In central Africa whcre thc AIDS pathogcn evolvet the disease is entemie and in scveral locations the inerease in ineidence of infeetion acceeds 0.75æ of the total population per year. AIDS is caused by a retrov~ms rel~ed to the Ientivirinae family and has been designated 'S human immunodefieieney virus ~V-I). nlis pathogen seleeti~ely infeets Iymphoeytes beanng a T4 surfaee antigen. These helper/inducer T~lls arc respontible for containing and elimina~ng va~ious qpe~ of infcction ineluting those preeipitated by Pneumocys~ ~ ~Ym.a eQ~ii.
Cry~Q~aLl ~ ~a~aa~ Mycoba~yma~ium-= ant othcrs. The destruc~ion of ccllular immuniq induccd by ~V-l causcs the normally blign infections resulting from the abo~re-SUBSmUTE SHEET

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;.`- - , ` -wo 92/17185 Pcr/uss2/o2239 ~ 210~0~1 mcntioned pathogcns ~o run more fulminau courses. I?lcse opportunistic infec~ions are generally the causes of death in patients wi~h AIDS.
Early in ~he course of the AIDS epidemic, cli~Licians noted that pa~ients were depressed and initially thi5 was attributcd to a normal psychological responsc to learning that onc had a tern~inal discase. Later, however, it was realized that cogniti ~c impairment and demen~ia werc associated with AIDS. nlese CNS-associated symptoms of AIDS are now well-recogni~ed and affect 40% of all AIDS patients at some point in ~he course of the disease.
In A~)S, the CNS, like the pcnphery, is susc~ptible to opportunistic infections and unusual ncoplasms. Se~ eral of .these have been idenufied.
including cerebral toxoplasmosi!~, cr~fptococcal infection, candidiasis.
cerebral tuberculosis, progressive multifocal Iculcocnccphalopathy, cytomcgalo~iru encephalitis and primary bra~n lymphomas. Intercstingly, 15 these occur in less than 30% of neurologically-impa red AIDS patients. In addition, symptoms caused by thcsc pathogcns arc gcncrally focal in nature and are e~cprased as scizures. In the majori~y of AIDS paticnts, neuropsychia~ric changcs are characterizod as an insidiow, progressive demcnti~ rel~d to difA~e parcnchymal b~ain dysfunction. Early 'O symptom~ of thi~ discase include impaircd cognitive, motor and bchavior function~, incluting the inability to concentratc, difficulty in recalling recent evenu, losing one'~ t~ain of thought in midsentence and general mental slowing. Motor impainnenu inclute leg weakness ant problems in propnoception. E~viorally, victim~ bocomc apathctic, withdrawn and ~S distraught. Later sgmptoms includc global cognitive dysfunction with psychomotor retartation. Victims are auti~tic, mutc, lcthargic and quictly confuset. Paticnu manifcst ur~nary and fecal incontinence and may bc afflicted by painful pesipheral neuropathies including bun~ing sensations or numbncss. Neurohistopa~hologically, the picture i~ even worse. While 30 only 40% of AlDS paticnu are recogn~ed as demons~ating b~ain dysfunction. 80-9SX of thc brain~ from AlDS pa~enu arc abnormal at SUBSmUTE SHEET

wo 92/17185 Pcr/us92/0223s 21~8 ~ ~ 1 -11 au~opsy. Gross changes include decreased brain weight and general cerebral atrophy. His~opathologically, several unique abnormalities are consistently seen in demented AIDS patients. Most of these are white marter changes and include a diffuse pallor, penvas~ular and parenchvmal sites that contain lymphocytic and maerophage infiltrat~ and vacuolation.
Other changes inelude the presence of microglial nodul whic infect both ~ray and white matter and bizarre giant multinucleated cells. Il~e presence and numbor of these cells whieh contain HIV-l viron give e~eellent correlation with the severity of the dementia. The ageslt responsible for 10 subaeute eneephalitis, also lalown as A~l)S enccphalopathy, has been shown ~o be HIV-l. Several direct and indireet lines of evidenee suppon this etiology.
rhis eentral infeetion will have a detrimental impaet on possible therapi direeted at AIDS. The CNS is proteeud by the BBB and is not 15 drained by the lymphade system, ma~ng it an e~eellent loeation for eluding the immune system. If, therefore, agents are found that reeonsdtute the immune system, periphe~l manifestation of AIDS, ineluding many opportunisde infeedons, ean be eured but the central infecdon will persist. Thc rcsult of thi~ could bc a physically healthy but 'O severely demented inti~ridual. In addition, host~ell res~ietion, i.e. par~ial e~pression of the viral genome, may cause viral lateney in the CNS for many yean. Also, oncc proviral DNA is incorporated, the only hope of containing the diseasc is by preventing the sprcad of further eellular infecdon. This implia, bascd on acdve ~ vitro doses, that for andvi~al 'S therapia to ~e effective, agcnts must pass the BBB and achicve reladvely high sustainet level in neurâl tissue. The neu~otropic naturc of ~V-l and the fact.that thc brain probably acu as a viral rcsavoir ma~
implementing the pree~ing statement imperative. Of agents presently available, azidothymidine (also hown as zidovudine or AZr) hat been 30 clinically shown to be the most useful in mitigating the effects of the AIDS

SUBSmuTE SHE~T

wo 92/17185 2 1 0 8 ~ 41 Pcrtus92/o2239 -lS-irus. AZI inhibits retroviral transcnptase, ~he enzyme responsible tor initiating viral replication.
A~ has been shown to improve the immunological piaure in A~DS
a~ients. In various clinical studics, T~ell lymphocytes (T4 ) were shown o increase in numba, opportunistic infcction~ spontaneously disappeared and pauents gained weight due to increased appetite. Also, fever subsided and skin hypersensitivity returned. At high doses of AZT, viremia disappeared and T-cell function was restored. The bioavailability is about 60æ. Thc drug is generally well-toleratet, 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 e~citing. In a double blind study, 16 out of 137 died in the placebo group while only one patient out of 145 died in the AZI treatmcnt group (250 mg/4 hrs). T4~ lymphocytes were higher in the treated ~roup and fewer opportunistic infections occurred. As before, a reversible bone marrow deprcssion resulting in gRnulocytopcn~a, thrombocytopenia, etc..
was observed. Recently, dideo~yinosinc has also been shown to be effectivc in reducing thc cytop~thiaity and infecei~ity of HIV i~ ~vo. The effect of AZI on thc neurological manifestation of AlDS has been reportcd by Yarchoan al, I~, i, 132 (1987). In a scries of four ~Se reports, AZI was shown 'o improvc immunological and neurologic functioning.
T4 ' cells inc~sed in number, motor symptoms improved, gait beca ne Iess at~ic and musck strength retumed. Attcntion span incrcasot in one casc and verbal sldll~ improved. Unfommucly, when the drug wa~s stopped in casa of anemi~, all improvcment5 di~d and mental func~ion declined. Tlli5 initial report indicatcd that AZI can at least partially rcverse neurological dysfunction. The authon noted at the end of the paper that ~cven modest enhancement of BBB penetration might have very impo~ant clinical consequcncc~.-SUBSmUTE SHEET

wo 92/1718~ Pcr/US92/02239 2 ~ 0 ~
-1~
Thesc limited improvemenu in neurological symptomatology are consistent wiLh ~he similarly limited ability of AZT to pass in~o Lhe CSF.
Unfortunately, CSF levels ot a drug may be a poor indication of brain tissue levels. Several studics have shown that Lhe correlation berween CSF
and parenchyma concentrations are not neccssarily significant. In general, polar compounds such as AZT arc Lhe most deccptive in this respect. The reason for this is that if a hydrophiLic compound is taken up primarily via an unprotected area like thc choroid ple~us, detecublc concentra~ons may indecd reach the CSF but the compound may not partition into the lipoidal 10 brain parcnchyma and as a rcsult may be restricted to the CSF. This would be manifested by apparently ade~uate AZT levels as measured by CSF sampling but inadoquate levels in brain tissue where the drug is nceded. This assumption has been borne out in a reccnt paper by Terasah et al, L I~ . ~, 630 (1988). In it, ~he BBB pcnetra~on of AZT was shown to be ve~y low, close to the uptake of sucrose, a vascular marker.
The high concentrations of AZT found in CSF are prcsumably due to active transport of AZT at the choroid ple~cus ~ia the thymitine pump. Again, Lhese CSF levels represent AZT which is nQS in equilibrium with the brain intcrstitial fluid and therefore is not accessiblc to infected sites. It is clear 'O that high levels of AZT are required to provide even margi~ improvement in AII)S encephalopathy and that these doses are peripherally to~ic.
The prc~rious discussion ha~ indicated that the AIDS visus is neurotropic and that the resulting bra;in infection by this pathogen is disastrous. Various agcnts havc been identifiet which inhibit infection and 2S abolish cytopathology in the AIDS vws. In some insuncw thcsc compount~, lilce AZT, pass the BBB and achieve quantitati~re levcls in CSF. Clinical rcsults suggat, howc~er, that high sustained dnug levels.
i.e. thosc that approach ~n ~m inhibitory concentrations, arc required in the brain. Importantly, CSF levels do not reflect b~am tissue concentration of A ZT. Unfos~unatcly,simply incrclsing the dosc propor~on~lly to achicve thac cnd~incrcascs blood conccntracons and lcats UD ~arious SUBSmUTE SHEET

wo 92/~7t85 Pcr/us92/0223s ~ 2108~

I, dose-rclated toxicicies. .~ncmia has proved to be dose-limiting in manv cases with AZT. Increasing brain levels of the nucleoside is possible bv administenng lipophilic esters of AZT leading to an increase in brain .oncentration of the nucleoside. Thesc prodrugs are. however, ~Q~
o~timized in terms of ~harmacol~netics and gs~ gis~i~C- Thus.
while it is true that by increasing thc lipophilicity of AZT, thc drug will morc casily pass the BBB and cnter the CNS, the increascd lipaphiliciN
will incrcase thc distribution of thc compound in general, leading to an even greater tissue burden in all locations. This has ramifications in terms 10 of peripheral to~cicity such as anemia, i.e. a bad siruation is made even worse. The other major drawbacic of simply increasing the lipophilicirv or AZT is that while influ~c to the CNS is increased, the efflu~ is also grea~er.
with the result being pOOt rctention in the CNS and a ~herapeutically insufficient biological half-life. I~cse two objections to simple antiviral 15 prodrugs, namely: 1) incrcased tissue burden with littlc tissuc specificity, and 2) poor CNS retention, point to the need for a more sophisticated approach, i.c. a chanical dcli~ery system for bf~ targcted dfug tclivery.
A dihydropyritinc pyridinium salt redo~ carricr system has recenfly been successfully applied to bf~n-targeted delivery of a vafiety of 'O drug speciu. Genefally speal~ing, according to that systcm, a dihydropyndinc carri moieq is co~alently bontcd to a biologically active compound, which derivative can entcr the CNS through the blood-brain barA following its systcrnic adminis~ation. Subsequent o~idation of the dihydropyAdine specia to the corresponting pyridinium salt leats to 'S delivery of thc drug to the brain.
More sp cifically, the redo~ carAer system provida for b~in-targefed dlug delivery by means of carrier-drugs, which in their reduced fosm, which is the form intended for adminisfration, can be r~pf~sented by the formula rD-DHC

SUBSmUTE SHEET

-wo 92/17185 Pcr/os92/o2239 2 1 a ~

wherein ~Dl is a centraLly acting drug speciu and [DHC] is the reduccd.
bioo~idizable, blood-brain barrier penetrating, lipoidal forrn of a ~ihYdropyridine ~- pyridinium salt redo~c carrier. In their o~dized form.
which is the form ~'locked~ in the brain from which the active drug is ltimately released. the carrier~rugs can be rcpresen~ed by the forrnula [D-QC~- X
wherein X is the anion of a non-toxic pharrnaceuucally acceptable acid, [D] is a centrally act~ng drug species and [QC~ is the hydrophiLic, ?ositively charged ionic pyridinium salt forrn of a dihydropyridine pyridinium salt redo~c carrier.
Various aspects of the redo~ camer system have been described in detail in Bodor United States Patent No. ~,479,932, issued October 30~
1984; Bodor United State Patent No. 4,540,564, issued September 10, 198S; Bodor e~ al United States Patent No. 4,617,298, issued October 11, 1986; UNIVERSlTY OF FLORII)A's International Application No.
PCI/US83/0072S, published under Intensa~ional Publication No.
W083/03968 on November 24, 1983; Bodor United States Patent No.
4,727,079, issuet February 23, 1988; E~odor United States Patent No.
~,824,8S0, issued April 2S, 1989; Bodor Unitcd States Patent No.
~0 1,829,070, issued May 9, 1989; A~iderson et al United Stata Patent No.
~,863,911, issueq Scptcmber 5, 1989; Bodor United States Patent No.
1,880,816, issucd November 14, 1989; Bodor United State~ Patent No.
1,880,921, issued Novcmber 14, 1989; Bodor Unitcd State~ Patent No.
1,900,837, issucd February 13, 1990; IJNIVE~lTY OF FLORlI)A's '5 Europ~ Patcnt Application No. B8312016.4, published under European Pub1~cation No. 0327766 on August 16~ 1989; IJNlVERSllrY OF
FLOR~DA's Europcan Patcnt Application No. 89302719.3, published under Europcan Publication No. 0335S45 on Octobcr 4, 1989; and numerous related publication~. Among the redo~c carn drugs pr~nnded by the earlicr chemical dclivcry systcm are dihydropyridine/pyridinium salt dcri~ra~re~ of dopan~ne, tcstos~nc, phcnytoin, GABA, valproic acid, SUBSmUTE SHEE-r wo 92/17185 2 ~ ~ ~ 0 4 1 PCr/US92/0223s ' -- 1 9 --rvrosme, methicillin~ o~acillin, benzvlpenAcAAAin, clo~acAIlin, diclo~acAlAin.
desipram~ne, acyclovir. tnfluorothymidine, zidowdine, hydroxy-CCA~U.
~hlorambucil, tr~ptamine, dexamethasone, hydrocomsone, ethinyl estradiol.
~orethndrone, est~diol. ethisterone, norgestrel, estrone, estradiol 3-methvl
3 e~her, estradiol benzoate, norethynodrel, mestranol, indomethacin, napro~en, FAENU~ HEANU~ 5-FU and many others.
The dihydropyridinc redo~ carrier system has ach~AcYcd remarlcable success in targeting drugs ~o the brain in laboratory tests. Unfortunately, the dihydropyrAdinc-containLng derivatives suffer fTom stability problems.
since even in thc dry state thcy are very sensitive to oxidation as welA as to watcr addition. Such problems havc significantAy complicated attempts to commercialize tlle system. TI~AUS~ a different carricr approach to braln-uArgeted drug delivcry which would not include thc inherently unstable dihydropyridine system would be desirable.
A few mixed phosphate derivatives of antiviral agents havc been previously described, but such are structuA~alAy distinct from thc mi~ed phosphates to which thc present invention rclatu.
Thus, Farquhar et al, in J.Phann. Sci. Vol. 72, No. 3, 324-325 (March, 1983), have descsibed bis(acylo~cymethyl)phosphotrAcsters of the ~o type R lCOCH 2\

o wheA~e ~ is, for c~amplc, -CH3 or -C(CHl)" and R is phenyl (as a model rcsiduc). Synthesis of two bis(acylo~cymethyl)phosphotriesters of two nuclcosid i~ disclosed, i.c. tlle compounds of thc forrnula SUBSmUTE SHEET-, -WO 9~/17185 . PCr/US9 /02239 .. --21~8~ 20- ~

O~ O
(CH;) jCCOCH ,O o HN~R

(CH3)3C:COCH20 CH2 O~N~
~\J

wherein R is -CH3 or F. In another report on the samc work, Srivastava and Farquhar, in Bioor~anic Chemis~.~, 118-129 (1984), discuss the synthc~is and stability of model acylo%ymethyl phosphatu, including six bis(acyloxymcthyl) estcrs of phenyl phosphate and ben~yl phos~phate and three acylo~ymethylbenzylphenyl phosphatu. The authors present their study as ~a guideline in developing a neutral phosphotricster which conceivably could traversc cell membranc~ by passive diffusion and then revert biologically, possibly in~acellularly, by enzymatic cleavagc of the protec~ve group to the parent phosphomonoes~r." Although further studie3 using 2'~eo~cy-5-fluorouridinc~ 5'-monophospha~c were said to be in progres~, to ahe present applicant's knowledge, such have not becn rcponed.
Very recently, Fa~Tow ct al"n L hfed. Ch~m. 33, 1400 1406 (1990), have r~ported on a series of aryl bis(3'-~acetylthymidin-5'-1~ yl)phosphates synthesized in an a~tempt to find an aryl dcri~a~re which would hydrolyze under physiological condition~ to the bis(nucleos~d-5'-yl)phosphau. The compounds synthesized have thc formula SVBSmUTE SHEET

.

PcTtus92/o~3s wo g~/17185 210 ~

OR
R ~o--P--o OR

where R is a 5'-linked nucleoside and R' is a group designed to possess suitable hydroly~c properties. As model compounds, thymidin-5-yl was select d for R and several substituted phenyl groups as R', i.e. 4-(methyl~io)phenyl, 4~hlorophenyl, 2~hlorophenyl, 4-S (methylsulfonyl)phenyl, 2,S~ichlorophcnyl and 4-nitrophenyl. The following 5'-S'-linked triester derivatives of (E)-5-(2-bromovinyl)-2'-deo~yuridine (BVDU) and acyclovir (ACV) were ~hen syn~hesized and studied for their antivi~al effects:

S~JB5 111 UTE SHEET
.. ~ .

wo 9~/17185 . Pcr/US92/02239 21~0~1 - 22 -o o~ ~a r H ,N l `l ~'~
0~,o~l 0~"

R'O-?=O R' -O--P=O O

o ~ ~2 0~ ~0~

OR~

where R' is 4-(me~hyl~io)phenyl or 4-(me~hylsulfonyl)phenyl or ~-chlorophenyl and R"is H or Ac. rhe data are consistent with a conclusion tha~ the triesters simply act as prodrugs for BVDU and ACV, respccnvely.

SU~I~,LOF 1~ r VE~:
S The present invention provid novel mLlcod phosphate deriva~ves.
adapted for targcted drug de~ivery, which havc the formula ~ O
q/ OCH-OCR, [~P~ (I) OR, SUBSmUTE SHEET

. . .
., , ,~
... `~.. , , .. ` ...... ~ ,. ........ .. . .. . .
., ~, , , .

. , - . , :: - ` : : `: ::

w~ 92/17185 Pcr/us92/0223s 2~0sa4l -23- , .
wherem l~] is the residue of a drug having a reactive funcncnal group, said functional group being a~tached, directly or through a bndging group, ia an o~ygen-phosphorus bond to the phospho;us atom of the ~ R
R/ OCH-OCR, OR~

moie~; R, is C,-C, alkyl, C~,-CI0 aryl or C,-CI2 aralkyl, with the proviso S ~hat when ,1~] is the residuc of a dn,g havin& a rucsve hydro~vl functional group, said functional group being attach,-d directly to thc phosphoius atom of the OR, moie~,y via an o~tygen-phosphorus bond, tnen R" ,~kcn togetner with the adjacent o~cygen atom, can also 'oe ,~he xsiduc of a drug having a reactive hydro%yl functional group, said functional group being attached directly to the phosphonts atom of the ,R2 1l R/ OCH-O~R, r~P~

moicty via an o~cygen-phosphorus bond. -OR, being the same as or diffesent from [D]; R2 is hydrogen, Cl-C, alkyl, C"-CI0 aryl, C4-C9 heteroaryl, C3-C7 cycloallcyl, C3-c~ cyclohcteroallcyl or C~-C~2 arallcyl; and 1~ R3 ~5 selected from uhe group consisting of C,-C, allcyl; C~-C, al~enyl SU8ST~UTE SHEET

.
.

wO ~2/17185 PCI/US92/02239 21~8~

having one or two double bonds; (C3-C, cycloalkyl)-C H.,- wherem r is zero. one, two or three. the cvcloalkyl ~ortion being unsubstituted or beanng 1 or 2 C,-C, aLkyl subsu~uents on the nng portion; (C6-C1o arvloxy)CI-C~ alkyl; ~-, 3- or 4-pyridyl; and phenyl-C~,.- wherein r is zero, one, two or three and phenyl is unsubsti~uted or is substituted by l 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.
Illc invention furthcr provides a genenc method for target-enhanced delivery to the brain and other organs of a wide varicty of drug spccies via ~he bidirectional transport of thc drug species into and out of the organ bv anionic sequestration via novel mixed phospbate denvatives.

D~:T~n,Fn DESCR~PrIO~ OF l~ IVENTION:
In a preferred aspoct, the present invention provides novel mixed phosphate derivatives of hydro~cy-containing drugs, which derivatives have the fonnula 1l ~ OCH-OCR, (Ia) D-O-P
\ OR, SUBSmlJTE Sl-lEET

~ WO 92/t7185 PCl`/US92/02239 2 1 ~
-2~
wherein D-~ is the residuc ot a drug having a reactivc hydro~Yl functional group, the oxygen atom of said functional group being bonded to the phosphorus atom of the 0/ OCE~-OCR, \OR~

moicty, and wherein R" R. and R3 are as defincd with formula (1).In another aspect, the present invention provides novel mixed phosphate derivatives of mercapto-containing drugs, which derivatives have the forrnula R2 l D-S-P\ (Ib) ORI

whcrein D-S- i5 thc rcsidue of a dmg having a reactive mercapto functional group, the sulfur atom of said functional group being bonded to the phospho~u~ atom of the 1 2 fi\
O~OCH~, OR, moicty, and wherein R~, R, and Rl are as dcfined with formula (I).

SUBSmUTE SHEET

.. . . ` .

:, . .

wo 92/17185 Pcr/US92/02239 21g~ 2~ ' The present invention nur~her provides novel mL~ed phospha~e denvauves of carboxyl~ontaining drugs, which derivatives have the rorrnuia o 1l 0~ OCH2-OCR, D-C-O-Z-O-P (Ic) \ ORI

3 wherein D-C- is the residue of a drug having a reac~e carbo~yl funcuonal group, the carbo~yl carbon a~om of said functional group beutg linked. vla an -O-Z-O- bridging group, to the phosphoru~ arom of the I~ ~ OCHIOCR, _p \ QR, moiery; wherein Z is -a~lene- whcrein thc allcylenc group contains R' I to 3 carbon atoms and R2 is defined as is R2 with formula (T); or wherein Z is C,-C, cycloallcykne in which two adjacent ring car~on atoms are each bonded ~o a differcnt o~ygen a~om in the -O-Z-O- bridging gsoup; and whcran R, and R~ are a~ tefined with forTnula (I).
S~ll funh~, the hvention pro~des no-rd mLlced phosphatc lS derivativa of drug~ containing imide or an~ide functional groups, which derivatiY have the formulas SUBSmUTE SHEET

.. . .
- .- . .. . .

` . ~ - ~ , .1 ;
... . , `.

wo 92/17185 Pcr/US92/02239 210~Q~ll -2~-~ ~ 101~CCH-~, D /.~-(~-O-P\ (Id) ~0 ORI

R R/~-~, and D-C-N-CH-O-P\ (Ie) wherein D N- is thc residue of a drug having a reactive S O

Il imide functional gNUp, D-C-N- is the residue of a drug having a reactive R~
amide func30nal group, thc nitrogen atom of thc irs~ide or amide functional 10 group being linked, via a -CH-~

bndging ~roup, to the phosphorus a~m of ~e pR~
ORI

SUE~SmUTE SHEET

,~

.

Wo 92/1718~ P~r/uss2/~223s 2 ~
-2~
:noiery; ~ is prescrably H but may also be C, C~ aLkvl or combined wlLh o D-C-~- to forrn a cyclic amlde; and wherein the R, groups !n forrnulas (Id) and (Ie), which can be the sarne of different, are as defimed with formula I); and R, and R3 are as defined with forrnula (r~.
~e present invention also provides novel mLl~ed phosphate deri~,auves of arnino-containing drugs, which denvatives have the formula fi' ~/oc~2-~cR~
D-N-C-OCH-O-P (~
R~ R 1 \ OR, wherein D-N- is the residue of a drug having a reactive pnmary R.
amino (R~=H) or secondary an~no (R, = other than H, but prcferably C,-C7 alkyl or combined with D-N- to form a cyclic socondary amine) group, the nitrogcn atom of the an~ino functional group ~eing lis~ked, via a o -C-O-CH-~ bridging group, to the phosphorus a~om of the R

o,/o~,-oc~, ~OR, moie~y; wherein R 2 i!~ define~ ~ is R2 with formula (I); and wherein Rl and R3 are ~ dcfined with formula ~. The identiq of the R~ gsoup (R~ =
other than H) in drugs ha~ing reactive sccondary amino groups, while osten Cl-C, lower allcyl, is immaterial to the inven~ion, since R, is of course part ~0 of the drug residue i~self and is left unchanged by the conversion to ~e formul~ (If) c~mpound.

SUBSmUTE SHEET

`
.

wo 92/l7185 21 0 ~ Pcr/uss2/o223s -t~
More par~icularly, in accord with the prescnt inven~ion, the rollowing defini~ions are applicable:
The terrn "lipoidal" as used here is intended to mean lipid-soluble or I ipophilic.
The tcrm "drug" as uscd hercin means any substancc intended for use in the dia~,,nosis, cure, mingation, trcatrnent or prevention of disease or in the enhancemen~ of desirable physical or mental development and conditions in man or animal.
By "centrally acting" drug, drug species, acuve agent or compound as used hcrcin, therc is of coursc intended any drug species or the like, a significant (usually, principal) pha,rmacological activity of which is CNS
and a re~ult of direct action in the brain. Cent~ally acting drugs are preferred for derivation in accord with the prescnt invention, brain-targe~ed drug delivery being the prefe~ed goal of the invenion.
lS Thc e~pression "drug having a rcactive functiona~ group" as uscd herein means that the drug pos~csses at least onc functional group which is capable of covalently bonding to thc phosphoru~ atom in the phosphate moie~, either directly or through a bridging group, in such a manner that an active tsug specie~ will ultimately be released at the desired site of ~0 action, e.g. the brain. Such rcactive functional groups include hydro~vl, carboxyl, mcrcapto, am~no, amide and irnide func~ions.
The word "hydro~yl" means an -OH function.
The word "carbo~yl" mcan~ a -COOH function.
The word "mcscapto" means an -SH function.
~S The word "amino" mcan~ a primary or seco~dary amino function, i.e. -NH2 or -N~. The ~econdary amino function i~ 50 re~e~cnted her~in as -NH-, particularly sincc thc e~act identity of the R, portion of -N~ is immaterial, R, being a part of thc drug rcsidue itself which is left unchanged by conversion of the drug to the phosphate canier system.
The word ~amide~ means a carba noyl (-CONH2) or substituted carbamoyl (-CON~) or a 3ulfarnoyl (-SO.NH.~ or substituted sulfamoyl - SUBSmUTE SHEET

-.. --- :. ` `

wo 92/17185 Pcr/US92/02239 -3~
(-SO,l~) func~onal group. rhe -CON~ and -SO.N~ groups may also be represented herein as -CONH- and -SO~NH-, respcctively, since the identity of R~ is immaterial. R, being a part of the drug residue itself which is le~t unchanged b~ conversion of the drug to the phosphate carrier system.
Il~e word "inu;ide" means a functional group ha~ing the structure ~H
--C /
~0 that is, the structure which character~za imidu (i.e. compounds having a succinimide-typc or phthalimide-typc structure).
It will bc apparent from thc known structura of the many drug 15 species e~cmplified hercinbclow, tha~ in many casu the selectcd drug will possess morc than onc reactive functional group, and, in particular, that the drug rnay contain hydro~yl or carbo~yl or amino or other functional groups in additicn to thc groups to which the mi~ccd phosphatc carri will be link~d, and that the~c adtitional groups will at timu benefit from being 'O protected dunng syn~hais and/or during administration. The nature of such protoction is detcsibed in more detail hcreinafter. Ob~iously, such protected drug spocia are encompasscd by the definition of ~drug" set forth hereinabo~e.
.The e%pression ~a bndging group" a used hesan refen to a 'S bivalent group used to at~ach the mi~ted phosphate ~rncr moiety to the drug when the drug doe~ not contain a functional gss~up susccptible to dLroc~t bonding to thc phosphorus atom to form a linl~gc which will ultimatcly cleave to relea~e an active drug specie5 in the target organ.

SUBSmUTE SHEET

.: :. ~ .... .
. . " ~ . . .
,.:.~.~,, wo 92/17185 2 1 ~ 8 0 ~ 1 Pcr/US92/02239 - .

Drugs containing rcac~ve hydro~yl and mercap~o groups are capable or direct bonding ~o the phosphorus atom to form the desired linkage; other reac~ve runctional group require appropnate bndging groups, for example as shown in structures (Ic), (Id), (Ie) and ,~n hereinabove.
The term ''Cl-C, alkyl" as used herein includcs straight and branched~hain lower alkyl radicals having up to eight carbon atoms. e.g.
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ~-butyl, pentyl, hexvl and the lilce.
The term ''C~-C,0 aryl~ includes aromatic radicals having the indicated number of carbon atoms, e.g. phenyl and naphthyl.
The term "C,-C,2 a~lkyl" dcsignates radica~s of the rype -alkylene-aryl wherein the aryl porcion is phenyl or naphthyl and the alkylene portion, which can be straight or branched, can contain up to 6 carbon atoms, e.g.
15 methylenc, ethylene, propylene, trimethylene, 1,2-butylene, 2,3-butylene, tetramethylene and the lilce. A typical arallcyl group is benzyl.
The tenn "C,-C~ heteroaryl~ refers to aromatic radicals having the indicated numb of carbon atoms and addit onally containing 1 or 2 hetero atoms in the ring(~) selectcd from the group consisting of N, O and S.
~0 Illustrative radicals of this type include furyl, pyrrolyl, imidazolyl, pyridyl, ' indolyl, quinolyl and thc ILbe.
The tcrm ~C,-C~ cycloaLlcyl~ designatcs saturated alicyclic hydrocasbon ~adicals containing the indicated number of carbon atoms. c.g.
cyclopentyl and cyclohe~yl.
~S ,The terrn "C,-C~ cycloheteroallcyl~ rcfen to saturat~d alicyclic hydrocarbon radical~ having thc indicated number of carbon atoms and additionally containing 1 or 2 hetero atoms in the ring sclectcd from the group consisting of N, O and S. E~arnples includc morpholino, pipcra~invl and pyrrolitinyl.

SUBSmUTE SHEET
- `'"'' ~' ' ., .. ;.' ~ .

wo 92/17185 ~cr/us42/02239 21~X~

The term 'IC~-C2 aLI~enyl" designates unsaturated aliphatic hydrocarbon radicals, or olefinic groups, which contain one or two doub!e bonds and the indicated number of carbon a~oms, e.g. l-propen-l-yl. 1.3-pentadien-l-yl and the like.
The term "tC~-Cto aryloxy)CI-C~ alkyl'' includes a~lo~yalkyl radicals such as phenoxymethyl, i.e. the aryl portion contains 6 to 10 carbon atoms, e.g. phenyl or naphthyl, while the aL~cyl portion conrains 1 to 8 carbon atoms, e.g. methyl or ethyl.
The terrn "C,-C7 cycloalkyl-CrH"-" includes cycloal~yl and cycl~kyl-allcylene- raticals conra~ning the indicated numb of carbon a~oms and bearing 0 to 2 C,-C, aL~yl groups as ring substituents.
Illustrative radicals include cyclopentyl, cyclohe~yl, cyclohe~ylmemyl, 1-methylcyclohe~-l-yl, ',2,3,3-tet~a nethylcyclopro~l-yl and the like.
The term "phenyl-CrH,r-" includes phenyl and phenyl-alkylene-radical~ containing the indicated number of carbon atoms, e.g. benzyl, any of which can bear 0 to 3 substituents as defined above. The substituents can be seleeted from Cl-C, allcyl, which can be st~aight or branched, e.g.
methyl, ethyl, propyl, isopropyl; C,-C, all~o~y, which can be straight or branched, e.g. metho~cy, etho~cy; halo, which includu bromo, chloro. iodo tO and fluoro; tnfluoromethyl; C2-C, diallcylamino, e.g. dimethylam~no and diethylamino; and C2-C~ alkanoylamino, e.g. acetamido and propionamido.
Substituted phenyl-C,H2,- Qdicals include such radicals p-tolyl, 2,4,6-trimethylphenyl and m-trifluoromethylbenzyl.
The word ~allcylene" when used in conjunction with the Z term '5 herein refers to bivalent radicals of the type -(C~)~- where n is 1, 2 or 3, and the co~onding bsanehed-chain group~. When it is part of the Z
terrn, the allcylene grouping can on~y be unsubstituted methylene if uhe drug residue i~ sufficiently hindered; otherwise, it should be substi~uted methylene or unsubstituted or subs~uted C2-Cj allcylene.
The term ~C,-C, cycloallcylene'' as used in conjunction with the Z
terrn dcsignatet radicalt of the type SUBSmUTE SHEET

... .
}

WO 92/~7185 2 1 ~ g 0 4 1 Pcr/lJss2~02239 -3~
CH--~H
(CH,~,,, wnere m is l to 6 and ~he corresponding branched-chain gtOUpS.
The expression "non-to~ic pharrnaceutically acceptable salts" as used herein generally includes the non-to~cic salts of compounds of fonnula (I) formed with non-toxic, pharmaceuucally acceptable inorganic or organic acids. For e~arnple, thc salts include those deri~ed &om inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfarnic, phosphoric, nitric and the lilce; and ~he salts prcpared &rom organic acids such as acetic, 10 propionic, succLnic, glucolic, stearic, lactic, malic, tanaric, citric. ascorbic.
pamoic, maleic, hydroxymaleic, phenylace~c; glutamic, benzoic, salicyclic.
sulfanilic, fumaric, methanesulfonic, tolucncsulfonic and the like.
The expression "hydroxyl protecting groupl as used herein is intended to designate a group (" which is inserted in place of a hydrogen I5 atom of an OH group or groups in order to protect the OH group(s) dunng synthesis and/or to improve lipoidal characteristics and prevent premature metabolism of the OH group(s) prior to the compount's reaching the desired site in the body. Thc e~prcssion ~protected hydroxy substituent"
designates an OY group wherein Y is a "hydro~yl protecting group" as '0 defined above.
Typical hydroxyl protecting groups contemplated by the presem in~cntion are acyl groups and carbonatcs. When the hytro~yl pro~ecting group is acyl ~i.e., when it is an organic radical terived from a carboxylic acid by remo ~al of the hydro~yl group), it casl be selected from the same 'S O
group of ladicals as those encompassed by the -C-R, por~ion of forrnula (I) hereinabove. Thus, the hydro~yl protec~ng group preferably rcpresen~s an acyl radical selected from the group consisthg of al~canoyl having 2 to 8 carbon atoms; all~noyl ha~ing one or two double bonds and 3 to 8 carbon 30 atoms;

SUBSmUTE SHEET

.~

wo 92/17185 PCr/US92/02239 21~)41 3~
p cycloallcyl-C,H,r-C-where~n the cycloaLkyl por~on contains 3 to 7 ring a~oms and r Is zero, one, two or three; phenoxyacetyl; pyridin~arbonyl; and O
phenyl-C,H~r-C-whercin r is zero, one, two or three and phenyl is unsubstituted or issubstituted by 1 to 3 al3cyl each having 1 to 4 carbon atoms, al~oxy having 1 to 4 carbon atoms. halo, trifluoromethyl, diaLIcylarl~ino having, to 3 10 carbon atoms ot _llcanoylamiino having 2 to 6 carbon atoms.
Whcn thc acyl group is all~anoyl, thcre are included both unbranched and btanched alkanoyl, for e~arnple, acetyl, propionyl, butyryl.
isobutytyl, valeryl, isovaletyl, 2-mcthylbutanoyl, pivalyl (pivaloyl), 3-methylpentanoyl, 3,3-dimethylbutanoyl, 2,2-dimethylpentanoyl, hc~anoyl lS and the li~e. Pivalyl, isobutyryl, iso~alcryl and he~anoyl are espccially Il prefe~red, both at -C-Rl grouphgs and as hydro~yl protective groups.
When the acyl gmup is allcenoyl, there are included, for c~amplc, crotonyl, 2,S-he~tadienoyl and 3,6-octadienoyl.
'0 When the acyl group is cycloallcyl-C,H,r-C-, there are included cycloallcanecarbonyl and cycloal~caneal~anoyl groups wherein ~he cycloalltane pomon can optionally bear 1 or 2 allcyl groups as 'S substituents, e.g. cyclopropanecarbonyl, l-methylcyclopropanecarbonyl, cvclop~evl, ~-methylcyclopropaneacetyl, l-meshylcyclopropane-SUBSmUTE SHEET

:

WO 92/17185 PCI'/US92tO2239 ,~ 21~g~1 aceryl, cyclopropanepropionyl, ~-methylcyelopropanepropionyl, ~-isobutylcyclopropanepropionyl, cyclobutanecarbonyl, 3.3-dimethvl-~yclobutanecarbonyl, cyclobutaneaceryl, ~,'-dimethvl-3-ethylcvclo-butaneaceryl, cyclopentanecarbonyl. cyclohexaneacen~l. cvclohe~ane-carbonyl, cyclohcptanecarbonyl and cyclohcptanepropionyl.
When the acyl group is pyridinecarbonyl, there are included picollnoyl (2-pyridinecarbonyl), nicotinoyl (3-pyridine~arbonyl) and isonicotinoyl (4-pyridinecarbonyl).
When the acyl group is phenyl-Ct~.t-C-, there are included, for example, benzoyl, phenylacetyl, a-phenylpropionyl, ~-phenylpropionyl, p-toluyl, m-toluyl, o-toluyl, o-ethylbenzoyl, p-tert-butylbenzoyl, 3,4~imethylbeyl, 2-methyl-4-ethylbcnzoyl, 2,4,6-15 trimethylbenzoyl, m-mahylphenylacetyl, ~isobutylphenylacetyl, ~-(p ethylphenyl)propionyl, p-anisoyl, m-anisoyl, o-anisoyl, m-isopropoxy-benwyl, p-mctho%yphenyhceql, m-isobutoxyphenylaceql, m-diethyl-aminobenwyl, 3-metho%y4-etho%ybenzoyl, 3,4,5-trimetho%ybenzoyl, p-dibugl~ninobenzoyl, 3,4-dietho~yphenylacetyl, ~-(3,4,S-trimcthoxy-'O phenyl)propionyl, o-iodobenwyl, m-bromobenzoyl, p-chlorobenzoyl, p-fluorobenwyl, 2-bromo-4-chlorobenzoyl, 2,4,~trichlorobenzoyl, p-chlorophenylaceql, ~-(m-bromophenyl)propionyl, p-~fluoromethyl beDyl, 2,4-di(~ifluoromethyl)bcnwyl, m-trifluoromcthylphenylacetyl, ~-(3-methyl 1 chlo ophcnyl)propionyl, p~imcthylaminobenwyl, ~(N-methyl-~5 N-ethy!amino)benwyl, o-acc~midobenzoyl, m-propionamidobenzoyl, 3-chloro4-acetamitophenylacetyl, p-n-butoxybenwyl, 2,4,~
- tnetho%ybenzoyl, ,B-(p-trifluoromethylphenyl)propionyl, 2-methyl~-methoxybenzoyl, p-acetamidophenylpropionyl, and 3~hlor~-etho%ybcnzoyl.

SUBSmUTE SHEET

- .. ... , ....... .
.' ~ `.

.

wo 92/1718~ Pcr/us92/02239 2 ~ 1 3~

When the hydro~yl protect~slg group is a carbonate grouping, it has ~e structural formula Y -O-C-i.e., it is an organic radical which can be consideret to be derived from a carbonic acid by removal of the hydro~cyl group from the COOH portion.
Y' prefcrably rcpresen~s allcyl having 1 to 7 carbon atoms; aLl~enyl having one or two double bonds and 2 to 7 carbon atoms;

cycloallcyl-C~

10 wherein the cycloallcyl portion contains 3 to 7 ring atoms and r is zcro, one, two or three; pheno%y; 2-, 3-, or 4-pyridyl; or phenyl-C,H2,-wherein r is zao, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 allcyl each having 1 to 4 carbon atoms, ~o~y having 1 ~o 4 carbon atoms, halo, trifluoromethyl, diallcyl~nino having 2 to 8 carbon atoms or allcanoylamino ha~ing 2 to 6 carbon atoms. Most prefcrably, Y' is C,-Ct allcyl, particularly ethyl or isopropyl.
Sim~ ly, thc e~cprcssion "carbo~cyl protecting group~ as used herein is intendet to dcsignate a group ~ which is inscrted in place of a 20 hydrogcn atom of a COOH group or groups in order to protect the COOH
group(s) during synthesis andlor to improve lipoidal charac2eristics and prevent premature meta~olism of said COOH group or groups prior to the compount's reaching the desired site in the body. Typical of such carbo~cyl protecting groups W are the groups encompassed by Y' above, 'S espe~ally C, C, allcyl, particularly ethyl, isopropyl and t-butyl. While such - SUBSmUTE SHEET

. - .. .

.
~ . ~ . ` , .

Pcr/US92/02239 wo 92/17185 2 ~ ~ 8 0 ~
,, simple alkvl esters and the like are orten userul, o~her car~30~yl protectmg groups may be selecled. e.g. in order to achieve grea~er control over the ~ate of in VtVO hvdrolvsis of ~e ester back to the acid and thus enhance drug deliverv. To tha~ end. carbo~yl protecting groups W such as the ~ollowing may be used in piace or the hydrogen of the -COOH group:

-CH,-C= C-CH3, O O
C

-alk-OCO-alkyl or -alk-O-al3cyl, wherein alk is C,-C6 straight or branched alkylene and the al~yl radica~ is straight or branched and conta~ns 1 to 7 carbon atoms (e.g.

-CHOCOCH2CH3 and -CH,OCH3).

Other carbo~yl protccting groups W which can be used in place Ot the hydrogen of the -COOH group and which are especially useful herein 'O are the following:

C3-C12 cycloallcyl-Cp~I,p-wherei~ p is l l. '' or 3;

C~-C2t polycycloaLkyl-C?H2p-SlJBSmUTE SHEE~

wo 9~/17185 PC~/VS92/02239 2~ ~8~1 wherein p is defined as above:

C"-C., polycvcloaLkenyl-C H.p-wherein p is defined as above;

C3-C,2 cycloalkenyl-CpH,p-wherein p is defined as above;

-CH.-X,-R, wherein X, is S, SO or SO? and R, is Cl-c7 alkyl or C~-C,2 cycloalkyl:

wherein R, is defined as abovc;

-CH-X,-R~

whercin X, is dcfined as above, Rb is C~-c7 a~ /l and R, is Cl-c7 alkyl or 1~ whcrein R~ and R, talcen togethcr rcprescnt -(CH2)",,- whercin rn' is 3 or 4 and -(CH2)~"- is optionally subs~itutcd by one to threc Cl-C7 allcyl;
Rd -CH-OCOR.

whesein Rd is hydrogen or Cl-c7 allcvl and R~ is unsubstituted or SUBSmUTE SHEEI

. . .
'' . ' '' ~ ' ' ' ' .. ...

WO 92/17185 2 ~ ~ 8 ~ ~ 1 Pcr/us92/02239 -- 3~ --o subs~tu~d Ct-C,2 alkyl [e.g. -CH.OC-C(C~ , C,-C,z ~ycloalhl -C?H.~-wher~n p it defined as ab~ve, C,-C12 cycloo~enyl-C~H,p- wherc~n p l5 defined a~ fe or C,-CO alkenyl, ~hc subsn~ucnu beLng sclected from the group consisting ot halo, C,-C7 al~oxy, Cl-C7 aLlcylthio, C,-C~
O O
Il 11 aL~ylsulfinyl, C1-C7 al~cylsulfonyl, -NHC-(C1-C7 al~cyl) and -OC-(C,-C.
alkyl), or R~, is unsub~tuted or subs~tutod phenyl or ba~yl, the subs~tuenu bcing selected from ~he group consis~n~ of Cl-C,, alkyl, C,-C.
aL~o~y, halo, carbamoyl, C2-C~ yc~rbonyl, C2-Ct alhnoylo~y, C,-C7 haloallcyl, mono(CI-C7 allcyl)amino, di(C,-C7 allcyl)anuno, mono(C,-G
allcyl)carb2moyl, di(Ct-C7 allcyl)sarb~noyl, C,-C, aLl~ylthio, C,-C, a~ 5Ulfirlyl and C,-C, allcylsulfonyl, or R, is C~-C2, polycycloalkyl-C~EI~;,-or C~,-Ct, polycycloallcctlyl-CpK ~,- wherein p is defined as ab,ove: :

IS R~
-CH-COOR, wherein R,l ~d R, a~ tefined as abovc; and -CH-CO~R~Rt 20 whc~ R~ i~ tcfinet a~ above and R~ and R~, which can bc thc same or diffescnt, arc e~ch hydsogen, C,-C~ allcyl, C,-CI2 cycloall~l-CpH,p-, C~ CI?
cyclo~ll~yl~2p-, phcnyl or ben~yl, or one of Rt ~d Rt ~ hydrogen, C,-C, ~llcyl, C~ cyclo~l~cyl-CpH,p-, C,~,2 cycloo,ll~yl-CpEI,p-, pheslyl or benzyl and the oth of Rt and Rs is C,,-C2, polycycloallql-CpH p- or C"-2a C2~ polycycloal~yl~ I.p-, or R~ and R~ arc com~ined tuch tha~ -~R~
rcprcxnU thc re~iduc of a sam~d monocyclic soconda~y an~ine.

SLlBSmUTE SHEE I

wo 92/17185 PC~/IJS92/02239 2 ~

WhCn the carbo~yl pr~tecnng group is C,-C,2 cycloallcyl-Cj,H,;,- or othenvise contains a C,-CI2 .ycloaLlcyl group, the cycloaLl~yl groups cont un 3 to 8 ring atoms and may optionaUy bear one or more, preferably one to t-our, al~yl substituents. Exemplary such cycloallcyl groups are S ;yclopropyl, 2-methylcyclopropyl, 3-ethylcyelopropyl, 2-butylcyclopropyl, 3-pentylcyelopropyl, '-he~yleyelopropyl, cyclobutyl, '-methylcyclobutvl.
',3-dimethyleyclobutyl, 3-butylcyclobutyl, ~-he~yleyclobutyl, ',3,3-tnmethyleyeloburyl, 3,3,4,4-ter~amethyleyelobuql, cyelopentyl, '-methyleyclopentyl, 3-ethylcyclopentyl, 4-butylcyelopen~yl, 5-methyleyelopenql, 3-pentyleyelopentyl, 4-he~yleyelopentyl, 2,3~imethyl-cyclopenql, 2,'.S,S-tetramethylcyclopertyl, _,3,4-tnmethyleyclopentyl.
~,-1~imethyl-3-ethyleyelopentyl, ',',3,4,4-pentameshyleyclopenryl. '.3-dimethyl-3-propyleyelopentyl, cyelohe~cyl, ',6~imethylcyclohe~yl. 3.3.5~5-tetsamethyleyelohe~yl, 2-meshyleyclohe~yl, 2-ethyleyelohe~yl, 4-propyl-IS cyelohe~yl, 5-butyleyelohe~yl, 2,3~imethyleyelohe~yl, 2,~-dimethyleyclo-hexyl, 2,S~imethyleyelohe~yl, 2,3,4-trimethyleyelohe~tyl, ',3~imethyl-5-ethyleyelohe~yl, 2,S-dimethyl-~propyleyelohe~yl, 2,4~imethyl-3-butyleyelohe~yl. 2,2,4,4-tethlmethyleyelohe~yl, 3,3,6,6-tetramethylcycl~
he~yl, 3,3,4,S,S-pentamethyleyelohe~yl, 3,3,4,5,S,6-he~amethyleyelohe~yl.
'0 3,3,S-tnmethyl~ethyleyelohe~yl, 3,4,4-trimethyl-5-propyleyelohe~yl, cyelohepql, 3-methyleyeloheptyl, 5-propyleyeloheptyl, 6-buryleyeloheptyl.
7-methyleyelohepql, eyelooetyl, 2-methyleyelooctyl, 3-ethyleyeloocsyl.
3,3,4-trimethyleyelooetyl, 3.3,S,S-tes~amethyleyelooetyl and the like.
When the e~bo~yl proteeting group is C,-Ct2 eyelo~ nyl-C?H.;,-'S or other~ise eon~isu a C~-C,2 cyclo~nyl group, the corrcsponding unsn~tod r~d;icals such as cyclopentenyl and cyclohc~enyl and thc Likc are eontempl~.
Ihe polyeyelo~llcyl-C~H ?- radieals whieh ean serve as earbo~yl proteeting gsoups, or as porsions of carbo~yl proteethg groups, are bndged 30 or fused S~D~d alicyclic hydrocarbon systcms consis~ng of two or morc nng~ ionally b~ing one or more aL~I subs~ucnt~ and ha~ing a total ~UBSmuTE SHEE l ,: . ' ' . ' . . . ' . ` . , .
.. ~ ~ - .

W092/17]85 2la30~l ,,,,,PCr/us92tO2~39 . .
~1-ot 6 to 28 carbon atoms in the ring portion. The corr~sponding bridged or ~used unsatusated alicyclic hydrocarbon systems are intended by the terrn "C6-C2s polycvcloalkenyl-CpH,p-'. Such polycycloaL~cyl and polycycloallcenyl radicals are e~templified by adamantyl (especially 1- or '-adamantyl), adamantylmethyl (especially l-adamantylmethyl), adarnantylethyl (especially 1-adamantylethyl), bomyl, norbonyl, (e.g. exo-norbomyl or ~g-norbomyl), norbomenyl (e.g. 5-norbomen-2-yl), norbomylmethyl (e.g. 2-norbomylmethyl) and norbomylethyl (e.g. '-norbomylethyl), and by radicals of the type -CpH.p-(sterol residue) wherein p is defined as above and the sterol ridue is the portion of a steroidal aleohol which remains after removal of a hydrogen atom from a hydro~y group therein. The sterol residue is preferably that of a pharmaeologieally inaetive steroid, e.g. cholesterol, a bile aeid (cholie acid 15 or related eompound) or the lilce. In the ease of polyeyelie radieals, p is prefe~bly 0, 1 or 2.

When the earbo~yl proteeting group is -CH-CONR~ wherein -NR,~I repraents the residue of a saturated monoeyelie Yeondary amine, 'O sueh monoeyeles prefesably have 5 to 7 ring atoms optionally containing another hetero atom (-~, -S- or -N-) in addition to the hdieated nitrogen atom, and opdon~lly bear one or more substituents sueh as phenyl, benzyl and methyl. Dlustrative of residues of saturated monoeyelie socondary amhes whieh are eneompa~set by the -NRfR~ tenn arc morpholino, 1-'5 pyrrolidinyl, 4 benzyl-l-pipe~azinyl, perhydro-1,2,4-o~cathiazin-4-yl, 1- or 1-piperazinyl, 4-methyl-1-pipazinyl, piperidho, he~amethyleneimino. 4-phenylpiperidino, 2-methyl-1-py~azolidinyl, 1- or 2-py~azolidinyl, 3-methyl-I-imidazolidinyl, 1- or 3-imidazolidinyl, ~-benzylpiperidino and 4-phenyl-1-pipa~nyl.

SU8SmUTE SHEE~' wo 92/17185 Pcr/us92/02~3s 2~ ûP~l t~
As yet another altematlve, the carboxyl group can be protec~ed bv ;onver~ng it tO an amide, i.e. the -COOH group is converted to a -CONRfR8 group wherein R, and R8 are as dermed and exemplified above.
Such arnide groups are also intended to be encompassed bv the expresslon "carboxvl pro~ecung group'' as used herem.
Selection of an appropna~e carboxyl protecting group will depend upon thc reason for protection and the ultimate use of the protected product. For e~amplc, if the protecting group is intended to be present in a pharmaceutically useful end product, it will be selected from those 10 ?rotccting groups describcd hcreinabovc which offer low to~icity and the desired degree of lipophilicity and rate ot ~n vivo cleavage. On ~he other hand, if the protecting group is used solcly for protection during synthesis, then only the usual synthetic requirements will gcnerally apply.
The e~pression "amino protecting group" as used herein is intended to designate a group (T) which is inserted in place of a hydrogen atom of an amino group or groups in order to pro~ect the amino group(s) dunng synthesis and/or to improve Lipoidal characteristics and prevcnt premature mctabolism of said amino group or groups prior to thc compound's reaching the desired site in the body.
'O As with the carbo~tyl protecting groups, selection of a suitable amino protecting group will depend upon the reason for protection and the ultimate use of the protected produa. When the protecting group is used solely for protection during synthis, then a conventional amino protecting group may be employed. When the amino protecting group is intended to 'S be present h a phannaceutically useful end product, then it will be selected from arnong arnino protecthg groups which offer low to~ciciq and the desired tegsee of Lipophiliciq and rate of ~ vivo clcavagc. Especially suitable for in, vivo use as arnino protecting groups T are activated carbamatu, i.e. the protecting group T has the structure SUBSmUTE SHEET

.. ~` , . . ` .

. . . ~ . .

. ~' , .

wo 92/17t85 2 1~ Pcrt~s92/02~3s I h -COCH-OCR
~1 11 O O

wherein Rh is hydrogen. Cl-C. alkyl or phenyl and Ri can be seiected trom the groups indicatcd as suitable carboxyl protec~ing groups W hereinabove.
Again, ~he bulkier groups are preferred for use ia vivo, and ~ is pre~-erably a polycycloalkyl or polycycloallccnyl~ontaining group, such as adarnantyl or a sterol residue, especially a cholesterol or bile acid residue.
rhc drugs which can be deriva~zed in accord with the present invenuon must contain at least one funcuonal group capable of bonding ~o ~he phosphorus atom in ~he mL~ed phosphate carrier moiety, direc~ly or through a bridging group. Drugs which are capablc of dire~t bonding are generally preferred becausc directly-bonded dcrivatives are more readily synthcsized and their !n vivo cleavage to thc active drug species is likewise 15 less complat. ~en a lin}~ng or bndging group is required, such must be chosen judiciously so that ~, vivo cleavagc will o cur in thc desired sequence. The mi~ed phosphatc derivatives of fonnula (I) are designed to be cleavcd Ul vivo in stagcs aftcr they have rcached the desired site of action. Thc first ckavage, by esterase, provides a negatively charged 2û "locked-in" intcrrnodiatc of the type [D~P-O';
OR, cleavage of thc terrn~nal cstcr grouping in (I) ~us affords an inherently 2S unstablc intcrmediate of thc typc 1l l 2 [D]-l ~-CHOH
ORt SUE~ST~TUTE SHEET

. ~ :

W O 92/1718~ PC~r/US92/02239 2 ~
~hich immediatcly and sponrancousiy releases R,CHO and the negativelv ;harged ~locked in" intermediate depicted above. With tlme, a second ~ieavage occurs; this cleavage is catalvzed bv means of alkaline ?hosphatase, releasing the onginal drug (D-oH in the case of hvdroxv-linked drugs, D-SH in the case of mercapto-linked drugs or, in the case or other drug classes. a drug-bridging group entit,v which will readilv release ~he original drug), along with RIOPO23. In the selected instances in which thc drug is of the nucleoside type, such as is the case of zidovudine and numerous oth antiretroviral agcnts, it is known that the drug is activated 10 ~ vivo by phosphorylation; such activation may occur in the present s,vstem bv enzymatic conversion of the "locked-in" in~errnediate with phospholcinase to the active triphosphate and/or by phosphorylation ot the drug itself after its release from the "locked-in'' intermediate as descnbed above. In either case, the onginal nucleoside-type drug will bc convened.
15 via the derivatives of this invention, to the active phosphorylated species according to the sequence:

SUBSmUTE SHEEl ~ .

WO 9'/17185 Pcr/US92/~)2239 2~a~
.

0~ O~H-OCR, D-O-H cnemical denva~ion D-O-P
onFmal / OR, (la) nucleosidc-~ypc drug /folm administercd in ~ivo cs~erax-calalyzed hydn)lysis L~ .

~D O l/ 1 In vo phosphorylation (~ l L OR~ bR, bH OH
nega~vely charged active phosphorylatcd "locked-in" inrermediate specics in nvo alhline /u- nvo phosphatase- / phosphoT~lation \ catalyzcd \~ydrolysis "' ~/
D-OH

S~lBSmUTE SHEE~

.
.
. . . .....
:, wo 92/17185 Pcr/US92/02Z39 21 U~O~l ~
It is apparent from the foregoing that, in the case ot nucleoside-tvpe drugs which are acnvated bv phosphorylation. the instant invention provides denvatives which need only a rwo-step in vtvo phosphorvlauon to ~rrive at the active tri-phosphorylated species. while the ori~inal drug requires a three-step acuvauon in vivo to the triphosphate.
In the case or drugs having a reactive hydro~yl or mercapto tunctlon directly bonded to the phosphorus atom, the cleavage to forrn the negatively charged "locked-in" interrnediates is much faster than the cleavage of the drug itself from the remainder of the ncgatively charged ~0 R?
intermediate, no matter wha~ the identity of the -OCH- grouping in rormula (Ia) or (Tb). The same is true for the case of imude-type and amide-tvpe drugs. Thus, R? in structures (Id) and (Ie), like R? in structures (Ia) and (Fb), can be any of the groups defined as R, values with formula (I) hereinabove. The derivatives of formulas (Id) and (Ie), like those of forrnulas (la) and (Ib), are thus first cleaved by esterase to give the negatively charged intermediate; subsequent cleavage by al~aline phosphatase in the case of the amides and imides giva an unstable interrnediate which rapidly is transforrned hto the original drug. On the 'O other hand, in the case of drugs linlced via an~lste or carboxylic acid functions, the identity of the R2 groups must be carefully controlled so that thc enzymatic cleavages occur in the proper order. It is apparent from a study of structures (Ic) and (Tf) hereinabove, that cach of these structures contains more than one bond susceptible to cleavage by esterase; if these 'S estcrase-cleavable bonts do not clcavc in the proper o sequcnce, i.e. if the bond linlcing R3C- to the rest of the molecule does no~
cleave before the carbo~cyl bond linlcing the drug to the phosphonate moiet~y, then the negatively charged "loclced-in" intermcdiate will not be forrned and targeted drug delivery will not occur. Bv utilizing an SUBSmUTE SHEET

- . . . . . . , ~ .

,. .. , ~ , . , . ~...... ,., .. " , .....
. . ...... .
., , ~ ,.~, ~ , .

wo 92/17185 21 ~ 8 0 4 1 Pcr/us92/0223s ~7-R, -OCH.- linkage for -OCH- in formulas (Ic) and (If), that lirkage becomes parucularly susceptible to ester ce. Nevertheless, judicious selection ot the -O-Z- lin ~age in forrnula (Ic) and the -OCH- linkage in forrnula (If) R", is required. For e~ampk, when the drug residue is sterically hindered.
-O-Z- can be -OCH2- in forrnu~a (Ic), because that bond will be less O
susceptible to esterase than the bond linking R7-C- to the rcst of the0 molecule, due to s~eric considerations. Likewise, -OCH- can be -OCH,-R~.
in forrnula (~f) when the drug residue is hindered. On the other hand.
when structurally simple drugs which are not bullcy/sterically hindered are derivatizcd, it may be required that -O-Z- cannot be -OCH2- in formulaS (Ic) and -OCH- cannot be -OCH2- in formula (If). In this way, R"2 the compounds are designed so that the bonds will clea ~e in the proper sequence.
From the foregoing, it will be apparent that many different drugs 'O can be deri~zed 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 memben for deri~ratization according to this invention is not intended to be c~hau~ti~e, but merdy il1ustrative.
'S Drug~ cont~ining a rcactivc hydrol~yl or mercapto function for use herein include, but are not limited to, steroid sc~ honnona, anti~rirals.
tranquilizcn, anticon~,rulsants, antineoplastics (anticancertantitumor agents).
hypotensiva, antidepressants, narcotic analgesics, narcotic anugonists and agonisttantagonists, CNS anticholinergics, stimulants, anesthetics, 30 antiinflammatoq steroids, nonsteroidal antiinflammatory agentstanalgesics, $UBSmUTE SHEET

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wO 92/1718S Pcr/uss2/o2239 2 1 ~
antibiotics and CNS prostagiandins. Preferred drugs or this rype are antivirals, antincoplastics and steroids.
.~ore specifically, arnong the steroid se~ hormones therc are ;ncluded: male se% hormones/androgcns such as testosterone and methvl estosterone: and female se~ hormoncs. including cstrogens. both - semisynthetic and natural, such as mestranol. quinestrol, ethinyl estradiol.
estradiol, estrone, estriol, estradiol 3-methyl ethcr and estradiol benzoate.
as well as progestins, such as norgestrcl, norethindrone, ethisterone, dimethisterone, allylestrenol, cingcstol, ethynerane, Iynestrenol, norgesterane, norvinisterone, ethynodiol, oxogestonc, tigcstol and norethynodrel. Typically, the rni%ed phosphate moiety uill be banded ~o the steroid via a hydro%yl in the 3- or 17-position, with the 17-pasiuon bcing generally preferred.
Among the antivirals, there are included those of the nucleoside lS type, glycosides, phenyl glucoside deriva~ives and others. rhose of the nucleoside type (i.e. a purine or pyrimidine base-type structure, including analogs of purinet and pyrimidines, bearing a singly or multiply hydro%ylated subs~ituent, which may be a natud or unnatud sugar.
hydro~cy-beanng aLlcyl group or similar substituent) are preferred.
'O ~emplary nucleoside-type anti~rirals include zidovudine (AZI;
- ~idothymidine), ribavirin, (S)-9-(2,3-dihydro%ypropyl)adenine, 6-azauridine, acyclovir (ACV), 5,6-dichloro-l-,B-D-ribofuranosylbennmidazole, 5,7-dimethyl-2-,B-D-ribofuranosyl-s-triazole (1,5-a) pyrimidinc, 3-deazauridine, 3~eazaguanosine, DHPG (ganciclovir).
'S ~azauridine, ido~uritine, dideo~cycytidine (DDC), trifluridinc (trifluorothymidine), diteo~yinosine, dideo~cydehyd othymidine, dideo~yatenosine, BVDU, FIAU, FMAU, FIAC, Ara-T, FEAU, cyclaradine, 6-deo~yacyclo~ir, 3-deazaaristeromycin, neplanocin A, buciclovir (I)HBG), selenazofurin, 3-deazaadenosine, cytarabine (cytosine arabinoside; Ara~), 5-FUDR, vidarabine (Ara-A), tiazofurin, 3'-fluoro-_',3'-dideo~ythymidine (FddThd), 1-(2,3-dideo%y-B-D-glycer~opent-2-SUBSmUTE SHEET

.

:. . .,` .. ~
~ ~ . i . .

WO 92il7185 2 1 O ~ 0 4 1 Pcr/~!s92~02239 . :
~9 enofuranosyl)thyminc (D4T or d4T), 3'-fluoro-2',3'-dideoxy-5-chlorouridine (FddClUrd), 5-(2-chloroethyl)-2'-deo~cyundine (CEDU), 5-~thyl-2'-deo~yuridine (EDU), S-(l-hydro~y-2-chloroethyl~-2'-deoxvundine.
5-(1-metho~y-2-bromoethyl)-2'-deo~cyuridine, S-(1-hydro~sy-2-bromo-2-(ethoxycarbonyl)ethyl)-2'-deoxyundine. S-(l-hydro~y-~-iodo-2-(etho~cycarbonvl)ethyl)-2'-deo~yuridine. 3'-azido-2',3'-dideo~yundine (AZU), 3'-azido-2',3'-dideoxy-5-bromouridine, 3'-azido-2',3'-dideoxy-5-iodouridine, 3'-azido-2',3'^dideo~y-5-methylcytidincand 3'-fluoro-2'.3'-dideoxyuridine (FddUrd). These and numerous other nucleoside-type 10 anuvirals suiuble for derivatization in accord with thc present invention have been descnbed in the literature. See, for example, Van Aerschot et al. J. Med. Chem. 1989, 32, 1743-1749; Mansuri et al, J. M~em.
1989, 32, 461-466; Kumar et al, J. ~h~m. 1989, 32, 941-944; Lin et al, J. Med~Chem. 1989, 32, 1891-1895; Kim et al, J. Med~ Chem. 1987, 30, 862-866; Lin et al, L M~g. Chem. 1987, 30, 440444; Herdewijn et al, J. M~Che~n. 1988, 31, 2040-2048; Turk et al, Antim~Aeent~
and ChcmQ~h~2y~ Apr. 1987, Vol. 31, No. 4, 544-SS0; F~ion, in IQ~
in ~i~ioaL~, 4th SCI-RSC Medicina~ Chem~ Symposium, ed. P. R. L~eming, Royal Society of Chemistry, London, 1988, pp. 163-'O 171; Roberts et al, in Topicjs in Med1uD~s~em~y~ 4th S5~
Me~ Ch= Symposium, ed. P. R. Leeming, Royal Society ot Chemistry, London, 1988, pp. 172-188; Kelley, in To~ics in Medicinal i5~, 4th SC~SC Med~a~ Chem~y Symposium, ed. P. R.
r eeming, Royal Society of Chemistry, London, 1988, pp. 189-212;
'S Harnden et al, in Topi~ in MedicjnaL~ DL, 4th SCI-R~C Medicinal Chcmis~y5ym~m, ed. P. R. Leeming, Royal Society of Chemistry, London: 1988, pp. 213-244; Reist et al. in ~ucleo~ An Anti~j~ A~, ACS Symposium Series 401, ed. John C. Mamn, American Chemical Society, Washington. D.C., 1988, Chapter 2, pp. 17-30 34; DeClercq, in A~roach~ to Antiviral A~ents, ed. MichaelR. Harnden.VCH, Great B itain, 198S, Chapter 3, pp. 57-99; Holy, in ~rQafh~ to SUBSmUTE SHEET

.
- , -.

WO 92/1718S PCI'/US92/02239 2 1 ~
-s~
~ , ed. Michael R. ~arndcn, VCH, Great Bntain, 198S, Chapter 4, pp. 101-134; and Hovi, in Anti~r I Agents: e Develo~men~
and Assessment of Antiviral ChemotheraDv, Volume 1, ed. Hugh J. Field.
CRC Prs, Inc., aoca Raton, Flonda, 1988. Chapter 1, pp. 1-.1.
I`ypically, the mixed phosphate moicry will be bonded to thc nucleosite-type anti~iral via a primary hydro~yl in the S'-position or co~sponding position when the antiviral doe~ not have a S'-hydroxyl.
~on-nucleoside ~nti drals for possible deri~tizauon herein include 10 hydro~y~ontiining glycosides such as 2-deo~y-D-glucose and 2-deoxy-~-nuoto-D-mannose, phenyl glucosidcs such as phenyl-6-chlor~6 deoxy-3-D-glucopyranosidc and benzimid;~ole analog type an~ivi~ls such as uhc svn and an~i isomers of 6tt(hydro~yin~ino)phenyllme~hyl]-1-~(1-methylethyl)sulfonyl]- lH-benzimida~ol-2-amine.
lS Among the tranquilizers for derivatization hetn, thcre can be mentioned hydro~y-contiining benzodhzcpine t~Lnquilizcrs, for e~amp!e o~azc~n, lorazep~n and tcmazcpam; tTanquilizcrs of the butyrophenone group, such ~ h~lopetidol; tranquilkm of the diphcnylmcthanc group, for e~nple hytro~yzinc; phcnothiazinc-typc tranquilizcn, for exarnple 'O acctophcn~inc, carphcnazinc, fluphcnazine, perphcnazine and pipaace~e; and tranquilizcr analoss of phenothi~ina, e.g.
clopenthi~ol.
Among thc hydro~y-containing anticonwlsants, thcre can be mcn~iooed, for c~mplc, thc mctabolita of ~alproic acid, i.c. S-hydroxy-2-'5 n-propylpcntanoic acid, 4-hydro~cy-2-n-pr~pylpcntanoic acid and 3-hytroxy-2-n-propylpcnt~oic acid.
Among thc antineoplastics, i.e. antic; ncer andlor antitumor agcnts.
thcrc can bc mcntioned a iUust~ative urca dcnvative~, hormon~l antincopla~tic~, podophyllotox;in~ (e.g. teniposide, etopo~ite), antibiotic-30 t~fpC antibiotic~, nitrosourca-typc al~tylating ascnu ~d, cspecially, punnc ant pyrimi~i~ antagoni~u. The punne ant pyri~nidL~c antagonist-typc SUBSmUTE SHEET

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- ~ .

wo 92/17185 Pcr/US92/02239 2 ~ q l , . . .

antineoplastics include simple purine and pyrimidine base-type structures.
e.g. thioguanine and 6-mercap~opurine, as well as those of the nucleoside-~pe, e.g. Ara-AC, pentostatin, dihydro-5-azacytidine, tiazofurin, sangivamycin, Ara-A (vidarabine), ~MMPR, 5-FUDR (flo~undine), cytarabine (Ara-C; cytosine arabinoside), 5-azacytidine (azaci~idine), uridine, thymidine, idoxundine, 3-d~uridine, cyclocytidine, dihydro-5-azacytidine, triciribine and fludrabine. Many nucleoside-type compounds have utility both as antineoplastics and as anti~i~al agents. Such are typically derivatized as described hereinabove with reference to the 10 nucleoside-type an~virals.
Among the anesthetics. thae can be mentioned pentothal thiopental) .
Among the antibiotics, there can be mentioned lincomycin tvpe antibiotics such a~ clindamycin and lincomycin.
Among the narcotic analgesics, there can be mentioned those of the meperidine rype such as meptaDnol, profadol and myfadol; and those which can be considered morphine denvatives. The morphine derivatives include those of the morphine xri, such as hydromorphone, oxymorphone, apomorphine, Ievorphanol, morphine and metopon; those Ot 'O the benzomorphan series, such as pentazocine, cyclazocine and phenaweine; and those of the codeine series, such as codeine, oxycodone, drocode and pholcodine.
The narcotie antagonists and mi%ed agonist1antagonists include such compounds as nalbuphine, nalmone, nalorphine, buprenorphine, '5 butorphanol, le~allorphan, naltre%one, naltnefene, alazocine, oxilorphan and nalme%one.
;rhe antiinflammatory steroids include such compounds as conisone.
hydroeonisone, be~amethasone, de~amethasone, flumethasone, fluprednisolone, methyl prednisolone, meprednisone, prednisolone.
30 prednisone, triamcinolone, tnameinolone acetonide, cortodo~cone, - SUBSmUTE SHEET

. ~ ` , . `

. ` ` : , ,.` ::

W O 92/17185 PC~r~US92/02239 2 ~ ;2-:ludrocortisonc, Qurandrenolone acetonide (flurandrenolidc) and ?aramethasone.
Among the nonsteroidal antiinflarnmatory agentslnon-narcotic malgesics, there can bc menQoned, for exarnple. cloni~enl, sermatacm and naproxol.
It will be apparent from the definition of R, in formula (I), that when drugs containing a reactivc hydro~yl function are selected for denvat2zation in accord with thc prescnt invenuon, both ~D] and OR, is formula (I) can be drug residues. While virtually any of the hydroxyl-containing drugs disclosed above could be used to prepare a compound o~
~ormula (I) in which [D] and OR, are the same or different drug residues.
specific uri}ity classes and specific hydroxyl-conta~ing drugs within those classes lend themselves es~pecially to this type of derivatization. Thus. the nucleoside-typc drugs, which are especially useful as antivirals and 15 antineoplastics, and are known to be activated in vivo by phosphorylation, are particularly desirable targets for this type of derivatization; the bioavailabiliq of drugs of this type may be enhanced by providing two identical drug residues in the compound of forrnula (1), in essence proviting for faily rapid release of the first drug resitue and its conversion ~0 ~o active species, followed by a sustained release of the second drug resitue ant its activation. Of pamcular interest are compounds of the invention in which both rDI ant -OR, represent AZI (zitowdine) residues or in which both represent DDl (diteo~yinosine) rcsidues.
Moreover, the possibiliq of incluting two tiffcrent drug resitues ~5 withh a systcm for targeted drug dclivery is of pamcular interest when it is desired to deliv two d ug~ to the sa ne target organ, espocially whcn the drugs may have a syncrgistic, rathcr than a simply additive, effect when co-ata~inistered. Of pareicular interest in this coMection are combinauons of two antineophstics or n,vo antivirals. cspecially two nucleoside~
30 antivi als. Nevcrtheless, cven whcn thc combined cffect is no morc than atditive, it may be convenient to inco~poRte residues of two different SUBSmUTE SHEET

: , : ` ~ ~ ` ` . .
~ . .. ;

wo 92/17185 2 ~ 0 3 a ~ ~ PCI/l,'S92/02239 5~ , ' -::
S drugs in the same molecule, as may be the case for cer~in antineoplastic-antineoplastic or antiviral-antivi~al combinations, antineoplastic-antivi~al combinations, antibiotic-antiinflammatory combinations and estrogen-progestin combinations. Still further, when -ORI represents a drug residue in forrnula (I), it may be a substance which functions wholly or partially as an enhancer or activator when used in combination with the drug whose residue is represented by [Dl, or to prevent deactivation thereof, e.g. an enzyme inhibitor for use with an antiviral agent, or it may function as 2 transport facilitator, in which case it may not be a ~drug~ residue in its normal sense but simply a protective residue which functions to enhance transport or delivery of the drug whose ~s~due is represented by [D], - principally by improving lipophiliciq. It must, however, bc a group which is enzymarically much less sensitive to clea~rage ~n vivo than the acylo~cyalkyl group -OCH(R2)OCOR3. It is not an acylo~yalkyl group in any event. Preferred protective residua are discussed in more detail hereinbelow.
As par~cular pairs of non-identical hydro~cy-containing drugs to be combined in a single compound of formula (1) as [D] and ORI residues, an estrogen such as estradiol may be pa;red with a progestin such as norethindrone, or norgestrel, for contraccptive use or other use known for ~5 an estrogenlprogestin combination.
Of special interest as pairs of hydro~y-containing drugs whose residues may be combined in a single compound of formula (I) are combinadons of antivi~l drugs with enzyme inhibitors and combinations of two andviral agents. The rationale for such combination in a single molecule includet the fact that the and~rirals and antivi~alslenzyme-inhibitors have themselves been co-administered. See, for e~ample, AntiviraI A~ents: The DeveloDment and Assessment of An~iviral Chemotherapy, Volume L ed. Hugh J. Field, CRC Press, Inc., Boca Raton, Florida, 1988, Chapter 3, pp. 29-84.

SUBSTrrUTE SHEET

. : ~ ~ ., .. ` .

,~, 21~8~1 Adenosine-containing nucleoside antivi~als are susceptible to adenosine dearninase metabolism. Deamination appcars to substantiallv decrease acti~ity. 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 uhe widespread 8U8SmUTE SHEET

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PCr/US92/02239 WO 92/1718~ 2 ~

adenosinc deaminase enzyme. Antiviral drugs susccptiblc to such inactivation includc vidarabine (adenine arabinoside or Ara-A), 3-deo~yadenosine (3-dA, cordycepin) and 2',3'^dideoxyadenosine.
Adcnosine deaminasc inhibitors include coformycin, 2'~eoxycoforrnvcin.
EHNA [crythro^9-(2-hydroxy-3-nonyl)adcnine~, acyclo-coformycin. DHPA
[9-(2,3-dihydroxypropyl)adcninc~ and N~-methyldeoxyadenosinc.
Combination of such an antiviral drug and such an cnzyme inhibitor in a single moleculc of formula (I) may be of parncular use in combating DNA
viruses such as vaccinia virus, varicclla-zoster, HSV-l, HSV-2, 10 adcnoviruses, ctc.
2'-Deo~ycytidinc and many cytidine anabgs arc substratcs for cytidinc^deoxycytitine deaminase, which is widely occurring. Dcarnination by cytidine-deoxycytidine deaminase may lead to cnhanced cytotoxicity and/or reduccd activiq. Antiviral nucleosida susceptiblc to this enzyme lS include thc S-ioto- and 5-bromo-2'^deoxycytidines, Ara-C and FIAC [1-(2'-deoxy-2'-fluoro-B-D-arabinofuranosyl)-5-iodocytosinc~, while the enzyme inhibiton includes tet~ahydrouritine (I~IIJ) and 2'-deo~cyte~ahydrouridine (2-d'IHU). DNA v~usu such as HSV-1 and -2, VZV ant HCMV may be particubrly susseptible to such combination in 'O formula (I).
Thymidine, uridine and many pyrimidine nucleoside analogs are subject to cleavage by phosphorylascs. By inhibiting phosphorylysis, it may be possi;ble to incrase drug half-life and enhance plasma levcls of drug. Anti~ susceptible to clea~rage of this sort include ido~curidinc '5 (rUdR or S-iodo-2'-teoxyuritine), 5-ethyl-2'-teo~yuritine (EtUtR), trifluridine ( I~:T or S-trifluoromethyl-2'-deoxyuridinc), 5-E-(2-bromonnyl)- 2'-teoxyuridine (BVDU) and S-(2-chloroethyl)-2'-deoxyundine (CEDU). Thymidine and uridine phosphorylase inhibitors indude S-benzyl acycloundine, 2'-deo~yglucosyl thymine and 5-methyl 30 acyclouridine. Agam, combination of antiviral and inhibitor in a single SUBS~lTllTE SHEET

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wo 9~/17185 Pcr/US92/02239 compound of formula (I) may be of pamcular interest in treating inflecuons causod by DNA viru~cs.
Selection of two differen~ antiviral agents for incorporanon of their ~esidues into formula (I) may be made, by wav of illustration. from among viNs-speeific agents which act on or via DNA polymaase, from combina~ons of those specific agents with less specific agents, from a-T ong less speeifie agents and from among agents active against RNA viruses.
Thus, two DNA virus-speeifie agents such as acyelovir (ACV), 5-E-(2-bromovinyl)-2'-deoxyuridine (BVDU), 9-(2-hydro~y-l-(hydro~yme2hyl)ethoxymethyl)guanine (DHPG), spongothymidine (Ara-T) and 5-ethyl-2'-deo~yuridine (EtUdR) may be sele~ed. e.g. residues of ACV and BVDU, DHPG and BVDU, ACV and DH~G, Ara-T and ACV, and Ara-T and EtUdR eombinations as the ~Dl and OR, moieties.
Combinations of DNA- speeific with less specifie nucleosides include, for e~ample, selection of a specific agent such as ACV, EtUdR.
MMUtR (S-metho~ymethyl-2'-deo~yuridine), BVDU or Ara-T, together with a less specifie agent such as Ara-A, IUdR, lFr, FUdR, FMAU, FIAC or AR-C. Illustrative of such eombination~ a~ ~D3 and -ORI are the residues of ACV/Ara-A, ACV/FIAC, ACV/IUdR, ACV/TFT and 'O ACV/FUdR. Thoo~tieally, such eombinations are of interest because ot blockade of in~dqr~ or convergent pathways. Combinations utilizing a TFT residue as the less specific agent are of particular interest because itxlf ha~ pro~red synergistic w~th numerous more spocifie andvi~l agents.
'S Two agents, eaeh with little anti~rira~ spo~ficity (e.g. Ara-A, IUdR, r~, FUdR, FMAU, FIAC, Ara-C) can also be selocted for deri~atization in aecord with the present invention. Such combination may lead to low doses and thus to lower to~icity. Lilcely combinations of residues inelude those of Ara-A with ~UdR, Ara-A with Ara-C, IUdR with FUdR, Ara-A
with ~IAC, Ara-A with FMAU, Ara-A with TFr. Moreover,.choiee of onc of thcsc agent~ for derivatization may be combined with a choice of a SUBSTlTUTE SHEET

. . .
..... ,.. . . ,.. - .-.. , ~ . .... . , `.~ , wo 92/17185 2 ~ O ~ ~ ~ 1 Pcr/US92/02239 selective inhibitor such as 5 ' -amino-5 ' ~eo~ythymidine (5 ' -AdThd) or with a selective protector such as deo~ythymidine (dThd). An objective of selective inhibition may bc to inhibit enzyma responsible for undesired activation of the antiviral drug in uninfected cclls, while an objective of selective protection may be to provide a compctitive substrate for enzymes which are responsible for cellular to~icity.
RNA virus-speeific agents whosc residuu can be combined as [D]
and -ORI in a compount of the prescnt invcntion inelude selenazofurin, ribavirin, 3-deazaguanosine, 3~eazauridine, tiazofunn, 2-deo~y-D-glucose, 10 6-mercapto-9-tetrahydro-2-furylpurinc (~MPI~:), zidovudine (AZI~, dideo~yinosine (DDI), dideo%yadenosine, DDC, D4T and the like.
Selection of two such agents from thc group eonsisting of ribavirin, selenazofurin and dazofurin for derivatizadon hcrcin is of partieular interest. Also of partieular intcrest arc eompounds of fonnula ~I) in which lS both tD] and -OR~ arc scleeted from thc group eonsisdng of residues of AZT, DDI, D4T, DDC and dideo~cyadcnosinc, espocially when one of [D]
and -ORI is an AZT rcsidue.
Other espeeially intcrcsdng eompounds of the invention in which both ~ and -ORl rcprcsent diffcrent trug resitucs arc thosc in which one 20 of ~D] and -OR~ is a highly aetive trug rcsitue, c.g. an AZT residue or residuc of othcr nueleoside-typc antiviral, and thc othcr of tD] and -ORI is a relatively innoeuous or inaetivc csscndally nonto~cie lipophilie aleohol residuc sueh as that of a naturally occurring stcrol lilcc cholcstcrol or hytroeortisonc or androstan-17-ol or androstanolonc (3-hydro~cy-~5-17-'5 one), or a long chain aliphatde aleohol (typieally a C9-C22 fatty aleohol, sueh as stcaryl aleohol, myristyl aleohol, lauryl aleohol, eetyl aleohol or deeyl aleohol) or polyearboeyelie aleohol (e.g., adamantanemethanol) used to enhanee delivery of the andviral agcnt via improved lipophilieity.
Indecd, thc Rl group ean be many of thc groups dcfined as earbo~yl 30 protceting groups hcreinabove, from simple aL4yl grwps sueh as ethyl to carboeylie and polyearboeyelie groups (cycloallcyl CpH2p-, polycycloalkyl-SUBSllTUTE SHEET

, ~
~ `; ~;, ;- , - .
.` , ., `

WO 92/17185 Pcr/us92/o2239 21080~1 - 58 -CpH,p- and so fonh, especially the polvcycloalkyl-CpH~p- groups as defined and exemplified hereinabove), just so long as it is enzymatically much less sensitive to cleavage i~ vivo than the -OCH~R~)OCOR~ 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 -ORI is of particular interest when the drug is hydrophilic (e.g. a nucleoside); on the other hand, when the drug is lipophilic, Rl can easily be one of the smaller, more simple residu (e.g. methyl) as there is no need to enhance lipophilicity. The final compound of formula (r) will optimally have a log 10 P of between about l and 5, prcfesably betwecn about 2 and 3, and this can be controlled by appropriatc sclection of -ORI for a given drug residue [D].
It should bc understood that in all of thc situations discussed above in which both [D~ and -ORI rcprescnt drug rcsiduu, such residues may lS bear appropriate protecting groups at either or both locations, just as the drug residues in thc othcr compounds of thc hvcntion may optionally bear protecting groups.
Drugs containing a rcactivc amidc or imidc function for derivatization hcrein includc, but arc not limitcd to, tranquilizers, sedatives,20 anticonvulsants/anticpilcptics, hypnotics, anthcoplastics, antivirals, antibioticslantibac.tcrial agcnt5, barbituratc antagonists, stimulants, antihypcnensiv ant antidcprcssant/psychotropie drugs.
Morc specifieally, thcrc ean bc mcntioncd hydantoh-typc tranquilizcrs and andconvulsants/anticpilcptia, for c%amplc, phenytoin, 25 mephcnytoin and cthotoin; barbituratc sedativa/anticonvulsants/
antepileptics, c.g. phcnobarbital, amobarbital and butalbital; gultarimidc or piperidine dcrivadva which arc scdativa and hypnotics, for examplc, glutethimidc, mcthyprylon and arninoglutcthimidc (also an anticonvulsant);
benzodiazepine-typc tranquilizcn, such as nit~azcpaun, bromazcpam, 30 demoxepasn, oxazcparn; antidcprcssants/psychotropics, e.g. sulpiridc;

SVBST~TtJTE SHEET

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W O 92/17185 P ~ /US92102239 2 ~
_ 59 _ GABAergic agents/antiepileptics, for e~arnple progabidc; valproic acid derivative-type anticonvulsants, c.g. valprornidc; barbituratc antagonists, for c~ample, bemegnde; tetracycline-type antibiotics, such as demeclocyclinc, o~ytetracyclinc, chlortetracycline, tetracycline.
5 methacyclinc, minocycline ant do~ycyclinc: nonsteroidal antiinflamls~ory/analgc~c agenu, e.g. tcsic~n; and antineoplastics, for e%amplc all~latint agenu of the nitrogen mustard-~e, e.g. uracil mustard.
spiromw~nc and cyclophosphamide, allcylatin~ agcnu of the nitrosourca type such ~ PCNU, punne/py~imidine antagonisu, e.g. S-FU(S-10 fluorouracil), and ~nou~ och an~neoplastics, such as sazo~ane andICRF- 1 87.Drup cont~ning a reactive carbo~yl function for dcriva~za~on in accord with the praent in~ention includc, but a~e not limited to, an~-convul~t~, ant~neoplastia, antibiotics/antibact.erial~, diagno~tics and IS non~roid~l antiinfl~nmatory agcntslnon-narcotic analgesics.

SuBSmuTE SHEET

, ~ :

WO 92/17185 PCl/US92/02239 2~ 9~8~41 More specifically, there can be men~ione~ iconvulsants, e.g.
valproic acid; antineopias~ics. for exarnple, nitrogen mus~ard-type alkylaung agents such as chlorambucU and folic acid antagonists such as methotrexate and dichloromethotrexate; penicillin-type antibiotics such as amo~icillin, phenoxymethylpenicillin (penicillin V), benzylpenicillin, dicloxacillin.
carbenicillin, o%aci~lin, clo%acUlin, heucillin, methicillin, nafcillin, ticarcillin and epicUlin; cephalosporin-type antibiotics, e.g. ccphalothin.
cefo%itin, cef~olin and cephapirin; miscellaneous other antibiotics, e.g.
oxolinie aeit; nonsteroital antiinflarnmatories/non-narcotic analgesics.
10 including propionie, aeetie, fenamie and biphenylearboxylic acid derivath~, for example, ibuprofen, napro%en, f!urbiprofen, zomepi~c.
sulindae, indomahaein, ketoprofen, fenbufen, fenoprofen, indoproxen, fluprofen, buc10%ie acid, tolme~in, alelofenae, fenelone aeid, ibufenac, flufenisal, pirprofen, flufenamie aeid, mefenamie acid, clonLlcin, IS meelofenamie aeid, aunixin, dielofenae, carprofen, etodolac, fendosal, prodolie aeid, tifluni~l and fluti~n; and diagnosties sueh as diohippuric acid and iothalunie aeid.
Drugs eont~ng a reaeti~re amino funetion for use in a~cord with the p~esent in~ention inelude, but are not limited to, GABAergies1anti-'0 epilepda, anf~neoplastia, eerebral stimulants, appetite suppressants. MA0 inhibiton, tncyclie antideptessants, decongcstants, nareotie analgesics.
anti~l~, nc~t~nsmittcn, small peptid, dopuninergie agents and antibiotia. Illu~ati~e drugs of this struetud type inc~ude ansiepileptics sueh u G~ G~B~ and r-aeetylenie G~B~; nitrogen mustard-2S Iy~pe ~non~ such u mdphabn; antibiotic-qpc antineopl~stics, c.g.
daunorubicin (d~u~omycin), do~orubicin (adriamycin), dac~nomych and mitomycin C; nitrosourea-type antineopbstics such a5 abnoshe;
misccllaneou~ other antineopl~stics, e.g. bactobolin, DON and acivich:
sympa~hedc stimulants/appedte supprcssants. such a~ methamphetamine.
30 phcntcrmine, pbalr~ne, dc~troamphaan~ine, lev~nphet~nine, amphetanDnc, phcnahyl~ninc, methyl phenidate, aletamine, cypalaminc, SUBSmUTE SHEET

- ' , , ~, ~ .,, ........... : : . .
,.; i ' .

WO92/17185 21 ~ 1 PCr/US92/~2239 , ~

fcncarnfamin and c~yptan~ine; MAO inhibitors, e.g, tranylcyprominc;
tricyclic antidepressants. e.g. protnptyline, desipram~ne, nortriptyline, octripqline and maprotiline; ccreb~al stimulants, e.g. amedalin, bupropion.
cartazolate, daledalin, difluanine and niso~etine; antivirals such as glucosan~ine, 6-am~no~deo~ty-D-glucose, amantadine and rimantadine:
arnino acids/neutrotransrnitters, e.g. tryptophan; small peptid, typically conta~ning 2-20 amino acid units, e.g. the enkc,phalins (Icu~-enkephalin, met~-enl~ephalin), cndorphins and LHRH analog-; catecholarnine neurotran~mit~ters, e.g. norepinephrine, epinephrine ant dopamine; other 10 neurot~nsmitters, e.g. serotoni.n, and relatod compounds such as tryptarnine; penicilUn-type antibiotics such as ampicillin; cephalosponn-type andbiotda, e.g. cephale~in; and sympatholytic apnu such as guanethidine and debnsoquin.
Also illustradve of the drug species contemplated by this invcntion lS are pharmacologic~lly ~ e metabolites of drugs. Such metaboUtes are typified by hydro~tylated metabolites of tricyclic anddep~nu, such as the E- ant Z-isomers of l~hydroxyno tripqline, 2-hytro~yimipramine, 2-hydro~cydesipsminc and 8-hydro~ychloripnmine; hydro~ylated metabolites of phenothi~ne tnnquiliz~, e.g. 7-hydro~ychlorprom~ne; and ~0 desmethyl metabolites of N-methyl b~li~ e tran~uilizen, e.g.
desmethyldiaz~m. Oth ac~ve metabolitu for use he~in will be apparent to thosc sl~lled in the art, e.g. SL 7S102, which is an active metabolite of p~:gabide, a GABA agonist, ant hydro~y-CCNU, which is an activc maabolite of CCNU, an andcancer nitrosourea. Typically, these 2S ph~cologieally aaive metabolitu have been identified as such in the scientific litc but hvc not been atn~inis~ ~ tmgs themxlves. In many ca~es, the acdve metabolites are believed to be companble in activity to their parent drugs; froquently, however, the metabolit have not been administaed ~ 5~ because they arc not thcmschru able to penetrate 30 biological membRna such as the blood-brain ba~Ti.

SUBSmUTE SHEET

.

PCr/US92/0223g WO 92/1718~
2 1 ~

Diagnostic agenu, including radiopha~naceutical~. are encompasse~
by the e~pression "drug" or the likc as used hcrein. Any diagnostic agent which can be derivatizcd to afford a mixcd phosphate derivative of formula (r) which will penetrate biological membrane~, e.g. the BBB, and concentrate in the target organ, c.g. the brain, in its negatively charged forrn and can be detected ~herein i~ encompassed by this invention. nle diagnostic may be "cold~ and be detccted by X_RY (e.g. radiopaque agents or oth means such a~ ma~ spectrophotometry, Nb~ or other non-invasive techniqua (e.g. when the compound includa stable isotopes such as C13, N1S, 018, S33 and S34). n e diagnostic alternatively may be "hot~, i.e. radiolabelled, such a~ with radioactive iodine (I 123 1 I'S. I
131) and detected/imaged by radiation detectioniimaging means. T~pical 'cold~ diagnostict for derivation herein include o-iodohippuric acid, iothalamic acit, iowdol, iodamide and iopanoic acit. Typical lS ~adiohbellet diagno~tic~ include diohippuric acit (I 12S, I 131), diotyro~ine (I 12S, I 131), o-iodohippuric acit (I 131), iott~lsmic acid (I
12S, 1 131), thyro~ine (~ 12S, I 131), iotyrosinc (I 131) and iodomet~m;inol (I 123). rn thc case of diagno~tics, unlil~e the case of drug~ which arc for thc tra~nent of tiseasc, thc ~locl~ed-in~ ncgatively ch~rged fonn will bc the form that i~ imagcd or othe~ise detected, not ~hc original di~ostic itsdf. Morcovcr, any of the drug~ disclosed herein which arc intentod for thc treatmcnt or prevention of metical disorders but which can bc adiobbelled, e.g. with a Qdioisotope ~uch a~ iodine, or iabcllod with a stablc isotope, can thus bc con~re~et to a diagno~tic for 2S incorpo~don into thc mL~od phosphte of formula (I).
When the dmg selec od for deri~atiz;uion according to the pruent in~ention i~ to be linlced to the mu~ed phosphatc moiety ~a a secondary or temary hydro~yl, or via a hindered hydro~yl, it may bc desirablc to use a SUBSmUTE SHEET

, Pcr/uss2/0223s wo 92/17185 2 ~ a 4 1 -- c3 --briidging group -CH-~ as described above for linl~ing an~ide and imide groups to the phosphate. rather than a direce bond between the drug s hvdro~yl group and the phosphorus atom.
S The compounds of formula (I) can be prepared by a variety or syntheeic procedur tailored to the seructure of the particular drug to be denvatucd par~cularly to the nature of the reaceive funceional group to be linlted to the miseed phosphaee moieey the idenuq of the bridging group if any and the prcsence of other funceional group~ which may benefit from protecdon. In preferred embodimenes of the invendon the drug comains a reaceive hydro%yl group suscepdble to direce bonding to the phosphorus atom in the mLxcd phosphate moiery. ~t is ~so preferred for simpLicity s sabe that the xlected drug not require protectdon of other functional groups although such groups can be prote~d when necessary. n~e IS ILLUSTR~TIVE SYN~IIC MEl~IODS xt forth hereinafter describe various methods for the preps~tion of the compound~ of the invention.
while the E~ES which follow illustnte these ant alten~ative methods. These methot~ can be summarizod as follow~ for drugs in each of the myor structud c~ori wheran the definitions of the structural var~bla ~re as xt forth abo~e in conjuncdon with fonnulas (Ia) to (If):
The compounds of formulas (Ia) and (Ib) can be synthesizcd by nrst convemng the drug D-OH or D-SH respectively to the cor~esponding mi~od p~e die lter intennediate of the forrnula D~IP-OH or D-S-I OH
OR, OR, 2S rc~pocti~rely which can be accomplished by one of variety of methods; thcn by converdng the resultant intennediatc dcpicted above to the co~ mi~od trie ter of formula ~a) or (Ib) which al~o can be SUBS'rTrUTE SHEET

.,.

wo 92/17185 Pcr/US92/02239 21~0~1 accomplished by one of a vanety of method-t. rhe conversion to the diester is often advantageously effected by reacting the starting alcohol or ~hiol with a phosphorylating agent such as 2-chloromethyl 4-nitrophenylphosphorodichloridate and subsequen~ hydrolysis to give the corresponding diester of the type O
D-O-P OH ~_~ or D-S-P-OH
b~NO2 b~3No2 CH2CI CH2Cl which is then reacted with R,OH to afford thc desised intermediate Q
D~-OH or D-S- I -OH
OR, OR, (Alternative routes to that intermediate include reac~ng the stamng alcohol 10 or thiol with POCI3, then subjecting the resultant q O
D-~P-a or D-S- I -Cl a Cl to reaction with R,OH and subsequent hydrolysis; or reac~ng the stamng O
alcohol,or thiol with R,OPCI~.) That intermediate can then ~e ~eated with 15 aqueous sodium hydro~ide and aqueous silv nitrate to afford the corresponding silver salt, SlJBSmUTE SHEET

, .

wo 92/17185 ~ 1 Pcr/us92/o2239 . ~, , .... : .

D-O-P-OAg or D-S-I-OAg .
OR, ORI

respoctively. Reaction of the silvcr salt with R3C-OCH-I, e.g.

O
(CH,),CCOCH21, affords ~he corresponding compound of formula (Ia) or (Ib), respectively. A preferred alternative u) 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 thc fonnula R
D-O- I OH or D-S-j'-OH
OR, OR, prepared as described above, is reacted with cesium fluoride (or o equivalent cesiurn salt) and a compound of the formula R3C-OCH-I, e.g.

CH3(CH~),COCHtI, in a suitable organic solven~, c.g. dimethylformamide, acetoni~ile, ni~romethane, chloroform or dimcchylacctamide, to give the corresponding compound of formula (Ta) or (Ib), respoc~vely.

Whcn both D-O- and OR, in formula (la) represent rcsidues of 'O drugs having ruc~ve hydroxyl func~ons. an ad~rantageous synthe~c mcthod SUBSmU~E SHEET

.

wo 92/17185 Pcr/uss2/o223s V~ 1 66 -begins with reaction of 2-chlorophenyl phosphor~dichlondate with l-hydro~ybenzotri 7ole to a~ford . -chlorophenvl-O,O-bis~l-benzotn 70~ ]-phosphate of ~he formula ~ o l~ ~ 0--N ~
Cl ;~

according to the mcthod of van der Marel et al, ~ h~ I~, 2', 3887-3890 (1981) and Wressmann et al, ~uclei Acid Rcs. 1~. 8389-8405 (1983). When D-O- and -OR, are not identical, there follows a two-s~ep process in which, as the first step, 2-chlorophenyl-O,O-bis[1-benzotriazolyl]-phosphate is reacted with the first drug, D-OH, in the 10 presence of an acid scaveng, e.g. triethylarnine or other suitable amine, in an appropriate solvent, for e~arnplc, tetrahydrofuran/pyridine. In the seeond step, the intermediate thus obtained is reacted v~ith the sccond drug, R,OH, under the sarnc conditions as in the first step, to give the desired mi~ced phosphatc dicster internaediate of the formula o D-O-P--OH
l Rl U~hen D-~ and -O~, arc identical, the two steps ca~l be combined in a singk step u~ ng two cquivalents of D-QH to ghe thc corresponding dicster intcnnediatc. In either case, the diestcr intennediate can then be conve~ed to the compound of formula (I) ~y one of the methods descnbed SUBSmUTE SHEET

wo 92/1718~ 2 1 ~ 1 Pcr/us92/0223s ! ~

in the preccding pa~agraph, preferably by reaction with cc~suim fluoride and O O
Il 11 a compound of the formula RlC-OCH-I such as CH3(CH,),COCH,I, R.
or by reaction with sodium metho~ide and a compound of the fonnula o R3C-OC~-C1. As ye~ another alternative when D-O- and -OR, are identical, a one pot process utilizing 2~hlorophenyl phosphorodichloridate and l^hydro~ybcnzotriazolc yields 2-chlorophenyl-O,O-bis~1-benzotnazolyl]-phosphate as an unisolated precipitate, the rcaction susplsion then being reacted with two equivalents of D-OH without further addition of solvent to afford the intermediate ~o P--tO D ) 2 That htennediatc can bc isohtcd by colurnn chromatogTaphy (although the 2-chlorophcnyl moiety can bc casily hydrolyzcd on the column), ~hen subjected to depmtecnon with pyridhe-2-aldo%ime tnd 1,1,3,3-tetwnethylguanidine to givc the correspondhg dicscer intennediate. The dicstcr intermediatc can thcn bc converted to thc compound of fonnula ~1) as dcscribod immediately above.
Ihe compounds of formula (Ic) can be synthe~izod by reac~ng the drug D-COOH with chlommcthyl chlorosulfatc or similar compound of the type Cl;Z-SO3a to givc an intermediate of thc type D-COO-Z-C1, SUBSmUTE SHEET

wo 92/1718~ Pcr/US92/02239 21~8~1 68-O
which can be reacted with a silver or cesium salt of R,OP(OH)2, ~o arford a compound of the type l/OH
D-COO-Z-O-P

S That interrnediate, which contains.a lin~ng group bearing a reac~ive -OH, can then be reacted with ccsium floride or e~uivalent cesium salt O
and a compound of the formula ICH,OCRl in a suitable organic solven~ as discussed in the preceding paragraph, to give the corresponding compound l0 of formula (Ic).
The compounds of formulas (Id) and (Ie) can be synthesized by //o ~C O
reac~ing the drug, D NH or D-C-NH, respectively, with an C~ R, O
appropnate aldehyde of the type R2CHO, e.g. fonnaldehyde, chloral, acetaldehyte, furfural, benzaldehyde or the like, in the prcsence of a basic catalyst such as potassiwn car~onatc, to givc thc co~cspondhg 'O ~0 ~C R2 IR2 intenne.diate of the type D N-CH-OH or D-C-N-CH-OH. That ~O R~

SUBSmUTE SHEET

. -W O 92/~7185 2 ~ 1 PC~r/US92/02239 _ 69 interme~iate, which contains a lin~ng group bearing a reac~ve -OH, can ~,hen be reacted. analogously to the compounds of formula (la) and (Ib), first to give the int,-rmcdiate / ~ I 11/ 1~ 1 11/
D N-CH-OP or D-C-N-CH-O-P\ respecuvely, then C ORI R, OR, O

with cesium floridc or ,~4uivalent ccsium s,alt and a compound of ~he p formula R,C-OCH-I in a suitable organic solvent, as discussed hereinabove for the hydro%y-conta~ning trugs, to give the corr sponding compound of forrnula (Id) or (Ie), respectively. Drugs containing reactive 15 primary or secondary sulfonamide functions (D-S02NH or D-SO2NHR,) can 'oc denvatiud si nilarly to the primary or secondary car~o~arnide-cont~ning dmgs to gi~e analogous com~pounds of fonnula (I) and are witnin tne ambit of the presnt invention. The identi~y of thc R~ group in ~he secondary amidcs and sulfonamides, lilcc the R~ group in formula (If), 'O is im~material in that it is of course part of the drug residue itself and is left uncnanged 'oy dcrivatization in accord with tnis invention.
Thc compounds of formula (If) can 'oe synt'nesized by rea,cting tne drug, DN~" witn a 'naio(optionally substituted met'nyl)cnloroformate to give an inter~nediatc of the type ~5 D-~;l-CO-fH-halogen.
R, '~

SUBSmUTE SHEET

Wo 92/17185 Pcrlus92/o223s . .
2~3a~ 70 _ o which can uhen be reac~ed with a silver or cesium salt ot R,OP(OH)" ~o a~ford a compound ot the type O OH
Il 11 /
D-~-CO-CH-P
R, R" OR, That intermediatc, which contains a linking group bearing a reactive -OH, can thcn be reactcd with cesium rlonde or equivalent cesium sal~

!l and a compound of the formula ICH2OC'R~ in a suieable organic solven~ as discussed hcreinabo~,re, to give the corresponding compound of formula (If).
When required, the various protecting groups for hydroxyl, carbo~cyl and amino functions discussed above can be substitutcd for the hydro%yl, carboxyl and amino functions in the instan~ compounds or their prccursor molecula by methods well-known in thc an. Most frequen~ly, the protccsing group will first be introduccd Lnto the drug molecule by well-known mcthods and thc protccsed drug will thcn bc subjected to the processes described above for preparation of the instant compounds.
Methods for chcmical rcmoval of the protecting groups (when such are not to be resained in thc pharsnaccutically uscful end product) arc likewise well-known to thosc s~dlled in the art. Typically,- aminc protxting groups are 'O chcmically removed by acidolysis (acid hydrolysis) or hydrogenation.
dcpending on the particular prosec~ing group cmploycd. Hydro~cyl and carbo~yl pmtecsing groupg arc typicaLly removed chcmically by acid or basc hydrolysis. Protecsing groups which are incorporated into the phannaceutical end producs must be amenable to hydrolytic or metabolic 5 clcaYage in vo.

SVBSmUTE SHEET

v~o 92/17185 2 1 ~ Pcr/US92/022 Thc stamng matenals needed for the vanous proccsscs descnbed ~bove are commercially available or can be readily prepared by known methods.

ILLUSTRAllVE SY~'VETH012S

. ~ethods for l~eri~atuin~ -OH and -SH F~iQ~ in l~

~l~OD A
The drug containing a rcactive hydro1cyl or mcrcapto function is rcacted with a phosphorylating agcnt such as 2-chloromethyl~-nitrophenylphosphorodichloridate, followed by hydrolysis, followed by reaction with methanol, to afford the intermcdiate phosphate diester. The resultant intermediatc is then reacted with cesium fluoridc and (CH,)3CCOCH2I in an organic solvent such as dimcthylformarnidc to givc thc dcsircd compound of forrnula (la) or 15 (Ib). Thc rcprucntativc drugs dcpictcd below ("Starting Matcrial") mav be derivatizcd in this manner, first to the phosphatc dicstcr intennediatc ("In~ennediatc"), and then to the corresponding compound of formula (la) or (rb) (~Final Product").

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wo 92/17185 Pc~r/US92/02239 2 ~

In the pr~cess of MET~OD A descnbed above, the intcrrncdiates and final products shown are not always the only intermediates and final produc~s obta~ned in significant amounts; yet other intennediates and final products of forrnulas (la) and (rb) may be obtained which are encompassed by the present invention.
rhus, for e%arnple, when the drug containing a reactive hydroxyl or mercapto funcuon also contains a reactive imide or arnide function, in addition to the major product which is depicted above, therc may be isolated a minor product in which the hydro~y function is derivatized as 10 shown while the amide or imide function is acylo~yalkylated. The minor product will be produced in a larger amount if e~cess (CH~),CCOCH~I or analogous reagen~ is employed in the final step. In the case of zidovudine (AZT), the minor product rcsulting from METHOD A has the formula (CH~)ICCOCH~ C)~ O

k~ OCH 3 while the snajor product is that depicted with METEIOD A. Drugs such as tiazofunn, 5-FUDR (flo~uridine), ribavirin, 6-a~auridine, acyclovir, SVE~SmUTE SHEET

`

WO 92/1718' 2 ~ 1 PCI/US92/02239 3-deazaguanosine, ganaclovir ~D~G), 6-azauridine, ido~curidine, ~;ifluridine, dideo~yinosine ~DDI), dideoxvdehydrothymidine, BVDU, FIAU FMAU, FIAC. Ara-T, FEAU, selenazofurin and buciclovir (DHBG) may be acyloxyalkylatcd at the amide or imide nitrogen in a S similar manncr to zidovudinc; derivatives of this type are even more lipophilic than thc major products depicted hereinabove wherc the imide ot amide group is unreacted.
As another e~arnple, when the selected drug contains multiple reactive hydro~yl functions, a mixture of interrnediates and final products may again be obtained. In the unusual case in which all hydroxy groups are equally reactive, there is not e~tpected to be a predominant product (unless all would give the sarne product, e.g. ganciclovir), as each mono-substituted product will be ob~ained in approximately e~ual arnounts, while a lesser amount of muldply-subsdtuted product will also result. Generally lS speaking, however, one of the hydro~yl groups will bc more susceptible to substitution than the other(s), e.g. a pnmary hydroxyl will be more reactive than a secondary hydro~cyl, an unhindered hydro~yl will be more reacdve than a hindcscd one. Consequently, the major product will be a mono-substituted one in which the most reactive hydro~tyl has been derivatized, while oth mono-substituted ant multiply-substituted products rnay be obtiined a~ minor products. In this instance, too, O
control of the amount of (CH3),CCOCH~I or analogous reagent affects thc amount~ of the ~ariou~ products obtained. Drugs which rnay afford other 'S hydro~y-~ub~tituted (mono- or multiply-substituted) terivativ in addition to those tepicted for MEl~OD A include pentostatin (2'-deo~ycofor-mycin), .vidarabine (Ara-A), S-FUDR (flo~uridine), cytarabine (Ara-C), apomorphine, morphine, nalbuphine, nalorphine, buprenorphine, (S)-9-(2,3-dihydro~cypropyl)adenine, ganciclovir ~DHPG), ito~uridine, trifluritine, BVDU, F~U, FMAU, FIAC, Ara-T. FEAU, cyclaradine, buciclovir (D~G), eshinyl estra~liol, e~adiol, ethynodiol, cortisone, hydrocortisone, SUBSllTUTE SHEET
. ~ ., ., . . - ~ ., :- .
: .: .

Wo 92/17185 PCr/US92/02239 2 ~1 X~ 128 -betamethasone, de~arnethasone, flumethasonc, fluprednisolsnc, methylprednisolone, meprednisone, prednisolone, prednisone.
triamcinolone, tr arncinolone acetonide, cortodo~one, fludrocomsone, flurandrenolide, paramethasone and the li~e.
In thc special ins~ance in which thc selecr~d drug contains multiple reactivc hydro~yl funaions which arc positioned in such a manner thal thev may form an undesired cyclic product when subjected ~o the process or ~ET~OD A, a synthetic route other than that of MET~IOD A may be generally prefe~Tcd. Thus, in the case of nucleoside-type antivirals and 10 antineoplastics ha~ng hydro~yls at both the 2'- and 3'-positions as well as at the 5'-posi~on, a product which is derivatized only at the ~'-posi~ion (i.e. as depicted with METHOD A) is prcfcrred, and such product is most advanugeously produced by use of a transitory protecting group such as the acetonidc group described in MEl~OD F hcreinbelow. Drugs such as 15 dihydro-5-azacytidine, tiazofurin, ~MMPR, 5-azacytidine, ribaYirin, 3-deazaguanosu~e, ~azauridinc, 5,~dichor~1-,B-D-ribofuranosyl-benzimidazole, S ,7-dimethyl-2-,B-D-ribofuranosyl-s-triazole ( 1,5-a)pyrimidine, 3-deazauridinc, ~azauridhe, 3-da~aansteromyc~n, neplanocin A, scknazofunn and 3-deazaadcnoshe thus arc prefcrably ~0 subjected to MEI~OD F to afford the p~eferred 5'-derivatized products depicted with MEI~OD A.

The proccs of MEI~OD A is rcpeated, c~cept that an equivalen~
quantiq of benzyl alcohol is used in the prcpa~ation of the htennediate ~5 phospha~e diater in place of methanol. Whcn each of the representative star~ng mat~ s listed with MET~IOD A is subjected ~o this process, the intennediate phosphate diester dcriva~ve has the pastial formula SUBSmUTE SHEET

, , WO 92/1718C 21~3 3 0 ~1 PCI/US92/02239 O OH O OH
Il / 11 /
P" r instead of -P
OCH. ~ OCHl as depic~d in thc intermediate column, and the final product of formula (~a) or (Ib) is as depicted in ~:T~OD ~, exccpt that the O/ OCH~OCC(CH3), portion of the product is replaccd with O OCH20CC(CH3~3 OCH

in each instance.
.~Q~

The procas of ~fEI~OD A is repeated, except ~at in the final o step the (CH,)3CCOCH2I rcactant is replaced with an equivalent ~uantity o of C~I3(ÇH2)~COCH2I. Wherl each of the representative stamng materials ~isted with MEl~OD A is subjectod to this process, each of the intcrmed~atc phosphate diester derivatives is as depicted in the interrnediate column, whilc the corrcsponding final product of formula (Ia) or (Ib~
2S differ~ from that dcpictod in MEI~OD A in that the SV~SmUTE SHEET

wo 92/l 71 85 Pcr/us92/o~23s 2~a~ 9 -o O OCH!OCC(CHl)3 -p portion of each produc~ is rcplaced with O ~OCH20C(CH,),CH3 p ~2 lllc process of MEl~IOD A is repeated, e3ccept that in the final step thc (CH3),CCOCH2I reactant is replace~ with an cquivalent quantity lS of CH3(CH2),COCHI. Whcn cach of the represcntativc stamng matenals listed with METElOD A is subjected to this proccss, each of the intermetiat~ phospha~ diestcr derivativcs is as dcpicted in the interrnediate column, whilc thc corresponding final product of formula (la~ or (Ib) diffcrs from that dcpictcd in MEl~OD A in tha~ thc ~0 0 O / OCH,OCC(CH3~3 OCH, SVBSmUTE SHEET

` ., : . :
.. .. ~, .~, .

WO 92/171~ i 2 ~ ~ ~ 9 ~ ~ PCr/~1S92/02239 .i, .
por~ion of each product is replaced with CH[3 O OCHOC(CH~)~CH?
_p O

- This is a modification of the basic method described ~ .~IETHODS
A-D for drugs containing multiple hydroxyl substituents, pamcularly for the nucleoside-type antivirals and antineoplastics. The drug selected as the 10 stamng material contains one primary hydroxyl substituent and one or more secondiary hydroxyl substituents. When the drug is a nucleoside-type containing a ribofuranosyl grouping, the primary hydroxyl is in the 5'-position, while the secondary hydroxyl(s) istare in the 2'- and/or 3'-position(s). Drugs of this type are e~emplified by, but not limited to, 15 vidarabine, cytarabine, riba~rin, 3-deazaguanosine, ido~uridine, BVDU, FIAU, FMAU and the Li~e.
The selected nucleoside st,~ing material as described above is reacted wi~ 4,4'-dimethoxytrityl chloride to give the 5'-(4,4'-dimethoxytrityl)ether dcrivative. The 2'- and/or 3'-hydroxy group is then 20 esterified by reaction with a variesy of acid anhydrid such as pivaloyl, benzoyl, isobutyryl or acetyl to give the 2'- andtor 3'~ster groupings. The resultant compound is then tireated w~th acetic acid to regenerate the 5'-hydro~y.moieq. nle 2'- and/or 3'-protected compound with a free 5'-hydro~cy group is thereafter utilizod as the starnng materi~ in the process of any of MEI~ODS A-D to give the compound of the invention with a mixed phosphatc moiety at the 5'-position and protccted ester grouping(s) at the 2'- and/or 3'-position~s).

SUBSmUTE SHEET

~ . , . .. ~ , ..."
.
.~..
. ~ . .
...
, ~ .

WO 92/1718~ PCI`/US92/02239 2 ~ 132 -~IE,TIIOD F

A stamng matenal with multiple hvdro~yl substltuents is selected as descnbed in the first paragraph of M~T~IOD E, e~ccpt that the se!e~te~
compound must contain hydro~yls at both the 2'- and 3'-positions as well as the 5'-position, e.g. ribavirin, 3-deazaguanosine or thc like. Reactlon with acetone gives the 2',3'-0-acetonide. That protectcd intermediate can then bc uscd as thc st~g material in the process of any of .~'~IODS
A-D, followed by, if desired, removal of the acetonide protecting group with formic acid, to give the sarne compound of the invention as depicte~
lû as the final product of METHOD A.

ME,T~IOD G

This is a variation of MEl~IODS A-D used when thc drug also contains one or more -COOH function(s) which islarc to be protected.
The drug, e.g. a valproic acid metabolite such as 5-hydroxy-2-n-15 propylpentanoic acid, sermatacin or the like, is first converted to the corresponding ethyl, ~-butyl or similar estcr grouping by well-~nown esterification methods. That ester is then used as the star~ng material and MEl~IOD A, B, C or D is repeated to give the desired compound of the invention.
~0 ~T~,O~,~

The process of MEl~OD A is modified to produce compounds in which there are two residues of hydro~yl-contair~ng drugs. Thus, the first drug co~taining a reactivc hydro~yl function is reacted with '-chlorophenyl-O,O-bis~1-benzotriazolyl]phospha~e in ~S tet~ahydrofuTan/pyTidine in the presence of an acid scavenger, then the second dnug contais~ing a reac~ve hydroxyl function is reacted with the resultant intennedi~ate in te~ahydrofuran~pyridine in the presence of an acid SUE~STl~UTE SHEET

`

. ~ .

W O 92/17185 PC~r/VS92/02239 2l0~a~ l - 1~3 scavenger, ~o atford the des~ed intermediatc phosphate di~stcr. That intermedia~e is then reac~ed wtih cesium fluoride and o (CH3)3CCOCH,I in an organic solvent such as dimethylforrnarnide as set fonh in METHOD A. llle representative drugs depicted in the two - columns headed "S aning Matenal #1~ and ~Star~ing Material #2~ mav be conver~ed in this manner, first to the dcpicted intcrmediate (~Lntermedia~e") and thcn to the corresponding compound of formula (Ia) (~Final Product").
It is understood that when "Starung Material ~1~ and ~Star~ng Material #2 are identical, then thc diester intennediate can be obtained in one step by reacung 2 e~uivalents of drug with 2-chlorophcnyl-O,O-bis~l-benzomazolyl]phosphate (forrned in ~ by reaction of 1-hydro~ybenzotriazole and anhydrous pyridinc) and decomposing the product to remove the 2-chlorophenyl group. The diester intermediate can lS then bc converted to the triester of formula (Ia) as descri~ed hereinabove.
O
e.g., by use of cesium Quoride and (CH,)3CCOCH2I or by u~e of sodium O
metho~ide and (CH3),CCOCH2Cl.

SUBSllTl)TE SHEET

.. ' - .. ,.;

WO 92tl718~ PCr/U~;92/0223~
. .
2 3 ~ 134 -Stamne ~a~al #l S~r~ Ma~nal *2 o HNJ~CH 3 H J~CH 3 k~CH 20M k~CH ,OH

~idovudine (AZT~ ~idovudine (AZT) Intermediatc 11N~Ch~

k~C H 2-- I~-O H

N3 _ 1 Final Pr~uct o H N J~ C H 3 O o k~CH,O --~ P-OCH2occ~cH3) 3 _ ~2 SUBSmUTE SHEET
- . ' - : ~

.,,: .,... ; ., , ~ ::

WO 92/1718~ 2 ~ O ~ Pcr/vs92/o223s -- 1 ~ 5 -- .

S~mn~ Matcrial #l Star~e Matenal #2 q dideoxyinosine ( D D I ) didec~xyinosine ~ D D I ) Lnte~çs~

O _ ~q~ O
k~C H 20 ~ O H

Final P~duct ~H20-- I~-OCH 20CC~CH 21 ~

SUBSmU~E SHEET
-.. .. .

.. ..

..

Wo 92/17185 PCr/US92/02239 2 ~ ~ $3 '~ 3 6 -Slall20~, Ma~l #I Stamn~ Matenal #2 Jl c o ~_~CII~OH N k~C H 01`1 zidovudine (AZT) ciideoxyinosine ( DD I ) ,Ln~ermçdiate HNJ~CH 3 ~C H 2 _ 1~ O C

Final ~

o ~ N--~-- o ~CIt20-; -0~

OCH~OCIC(CH3~ 3 SUBSmU~E SHEET

~ ~ .
~. . , - , . -. ' ~ . .

wo 9~/17185 Pcr/us92/o223s 210sa~1 Sramn~ Ma~#l Sta~ Matmal #2 HN~CH, O ~ H N ~CH;

¦, ~CH20H

HO

zidovudine (AZT) . D4T(d4T) Lntermed~e o H ~ c H 3 o HlJ~ C H~
o ~lCH20 ~ ~

Fin~

H ~ JL3, C H 3 H N ~C 3 k~CH 0 ~ ---O ~--~/
N3 OCH b' ~CH3~3 SUBSlTrUTE SHEET

.

2 ~ 138 -Star~ Ma~cnal #I S~ .Ua~al #2 ~,~CH ~H ~
o~ ~ o1~
~CH Otl ~idovudine (AZT) dldeoxycytidine ( DDC ) ,'J H 2 ¦--o ~C H O _ p ~ O C H 2 --t'lOH 1, \
'~ 3 Final P~duçt o ~IN--~CH 3 ~CH_O-- --OcH ~3 OCII 20CC~CH 3~ 3 SUBSmUTE SHEET

WO 92/17~85 PCl/lJS92/02239 2la~0~l Star~z~ Ma~al ~IStamn~ Matcnal #2 U

~ 3 zidovudine (AZT~ dideoxyadenosine Intcrmç~ase ~N~H ~ ~N
ko~C~2~ C~z ~/ OH ~ ~.
3 _/

"H2 ~IN~CH 3 k~CH:O -!- oc~

~3 OCH OCC~CH~) 3 SUBSmUTE SHEET

. :

21~0`~1 -- 1~0 --Sta~ ~l #I Sta,~nL.Ua~cnal ~
o H ~CH; ~ ~CH;

~CH OH HO~J C H3 2idovudine ( AZT ~
cholesterol In~pte ~Ch~ CH~

¦-- ~ H20---- P _O
~ ~ 1 Fin~ Pr~ya HlC
}

k~CH 2--~ -N3 0cH2occ~cH3~3 SUBSmUTE SHEET

- .

WO 92/1718~ 2 1 ~ PCI~/US92102239 Su~n~ Ma~ia~ #I Stamn~ Ma~al #~

~CONH. H NCO
~Se o CH.OH ~ ~
~CH ~OH

OH OH
HO OH

ribavirin selena~ofurln Intenncdia~

N~CoNH 2 N ~ H 2N CO~
k~Ch~O~ OC~S-OH OH
OH OH

Final PT~

H 2NCO~
k~C!IO---OC~,S~

OH OH
OH OH
OCH 20CC tCH 3~ 3 5UI~STITUTE SHEET

WO 9'/17185 PCl/US92/02239 2 ~ ~ ~ .3 ~ 2 -S~amn~.~la~nal #I S~LMatcr-al #2 _~CONH, H ~!
~,~,,`1 ~
S
GC H ~O H ~, ~
¦ O CH,OH

OH OH \~
OH OH

ribavirin tia20furin In~ermed~e ,~ H 2N C

o CH O~ OCH N~5 O H !~ ~i O H O H \l OH OH

Final P~dUl ,~ H 2N C ~_ k~C H 2 ~ O C~ S

OH OH

SUElSmUTE SHE~ET
.. ~, , .

, .
. .' ':` . ' ``~: `

WO 9~/17185 2 1 ~ ~ 3 ~ ~ PCr/US92/0223s ,-Star~n~ Ma~ ~1 S~Matcnal #2 C o C
.~se ~s o ~CH OH
H O

HO OH \~
OH OH
selena20furin tia20furin Intcrmedi~e H2NC~

~CIl ~0--=--OC H

OH OH

Final P~duct ~ H 2 NC~
~ ~CIl~O~ OC~

OH OH
2 o 3 3 SUE~SmUTE SHEET

wo 9~/ 1 7 1 85 Pcr/us92/o223s 2 1 i) ~

Staron~ Ma~ #IS~n~ Matcnal #2 N H~

N/~
N CH,OH \a~

~CH 20H
OH
OH

vidarabine (Ara-A) 2'-deoxycoformycin ( 2'-dCF) Interme~

"H2 OH
H- N/~;

H 20--~--'L~ ,1 O H 1\~
OH

H2 ~OH

1120 --C~

OH
OCH,OC~C~CH3 SUBSmUTE SHEET

.
,.. ;~ ~ .
`

Wo 92/1718~ PCr/US92/0223s Su~n~ Ma~nal #l ~a~L~

N ~CH~OH HN~/~HN\~

OH HO~o vidarabino (Ara-A) acyclo-coformycin Ln~ . .

H~O H

N k~CHzO~ ~O ¦
OH
OH

F~l Product ~1~0H
B~

~CH 20--i o ~1 Oh OCH 2 ~C~C ~ CH 31 3 SUBSmlJTE SHEET

' ;.

W~ 92/17185 PClt~'S92/02239 2~ 146-Star~ Maten~ #I S~ Malcnal ~2 `~ H H OH

0~ 0~ ~ ~
k~--OH HO~

OH OH

,-ioao- 2' -deoxycytidine 2' -deoxytetrahydrourldine ( ICdR; ICDR) ( 2' -dTHU ) atc N6~l HNX
OJ~ N~J O1NJ
~0 ~ o~

OH OH

Fina~ duct N ~ I H N ~

~- -K:~
OH OH
CH 2Cc tCH 3~ 3 SUBSmUTE SHEEl' ... . ` j . . `, WO 9~/171~ PCr/US92/02~39 21~41 ~ 7 -- :;

star~n~ .Uat~rial #! s~ Matcnal #2 NH
H ~ OH

01~
~C H ~ O H H O~

OH
OH

FIAC
2'-deoxytetrahydrouridine ( 2'-dTHU) Lntem~odiate ~H2 HXOH

ol~ O o 1 N ~
~ O-- P--0_~

Final Product HN~
~-o_l o~

OH OH
OCH OC~ C ( CH 3~ 3 SUE~SmUTE SHEET

.
. :~

...

2 ~ 8 _ Star~a~al #I Starnne Mucnal ~2 NH
H ~,~ O H

0~ N~3 O~
~C H ,O H H O '~

OH OH OH

cytarabine (Ara-C) tetrahydrouridine (THU) Int~rme~iatc ~2 H~ OH
~3 H N ~

~ --l,.--~ .
OH
OH OH

Final Pn~duc~
I'~IH

N ~3 H N ~:1 ~0~ 0~

OH OH
OCH,O~C~C~CHI) 3 SUBSmUTE SHEET

: , - `: , .':

WO92/17185 21 0 8 Pcr/uss2/o223g -- 149 ~

Staria~Ma~l #l St~M~tenal #2 o ~o o~f~``

HO ~ o~¦
OH

idoxuridine (lUDR:lUdR) ;-benzyl acyclouridine In~iate NH o~3 N O O
~ --I --O ~o~

OH

Final P~duct ~N~O o HN~3 k~o~ -I~o~

OH
~l i 2Cc ~ CH 3~ 3 SUBSmUTE S~IEET

WO 92/17185 PCr/US92/02239 2 1 Q ~

~Lkl~ Staron~ Matcnal #2 o o H N ~ C F ~
o N O
k~'H 20H HO~

trifluridine (TFT) 2'-deoxyglucosyl thymine Intcrmaliate O ~ l k~ 1H
OH
OH

Final P~

HNJ~CF3 o o~
OH
OcHzolclctcH3~ 3 SUE~Sl~UTE SHEET

, . . - . ~.

; ,,.. ~. .
, . .

Wo92/l,l8~ 2 1 ~ PCI/US92/0223~

S~ ~#l Stamn~ M~terial #2 HN ~ CH~CH~3r H N ~ CH, O `~
H,OH

OH

BVDU 5-methyl acyclouridine te ,,~di~

N~fH~CHBr O~

k~o~ o~OI , Final Produ~
o 11 olJ~f o k~o-l'l ~o~

O~ OCH 20bC t C~ 3~ 3 SUBSmUTE SHEET

... ~

WO 92/17185 PC~/US92/02239 2 1 0 ~3 ~ 152 -S~L#I SSaS~nQ Matcrial #2 o o H ~ H N J~C HSC H ~ r H_N N \ O
CH20CH,CH .OH j~O~CH OH
~1 OH

acyclovir ( ACV ) BVDU

Inte=c H~ CH 20CH 2CH O--P OCH ~
OH ~/

OH

Fj~l Pn~dUCt H Nl~N~ O HNJ~cH~CHE~r C H IOCH C H O--i'--o c~ Ol ,.

~ ' ~CH3~3CCOCH,O OH

SUBSmUTE SHEET

. . - . . .... .~ -. ......... . , . .. ,.. . " .. ,..... .. --. , . ~

- ; . ., , WO92/17~8~ 3~3-5 ~1. PCI/US92/02239 H N ~ C H----C H B r O CH OH
CH.OCHCH,OH / \
CH ~OH \~
OH

gancic~ovir ( DHPG ) B VDU

Ln~ate H N J~ q H N~N~ILN O
2 I H N ~CH C H 9, '~/1 OH

Fislal P~

HNJ~q H2N~ t HN~H c~

CH2ocHcH2o P OCH2 CH2OH ¦ 1~ o~¦
(CH ) CCOCH O
o OH

SUBSmlJTE SI~EET

.

Wo 9~/17185 PCr/US92/0223s 2 1 ~
-- 15~--S~n~ M~al #l StarQn~ Matcnal o HN J~CH 3 O
O ~ N ~ H HJ~
L, CH2H H,NN ~ \
' CH 20CH .CH ,OH
OH

Ara-T
acyclov i r ( A C V

Intermed~

Il o ~CH~O--~ OCH CHzOCH, OH

Final P~duct o U o ~ I OCH CH OCH N ~H
OCH ofi c ( CH 3~ 3 OH O

- SUE~SmUTE SHFET

~: `

WO 92/17185 2 ~ PCr/US92/0223s . , . , ` : :

S~l Stamne Matenal #2 O .`~ H, ~N ~ N CH ON

OH

acyclovir (ACV~ vidarabine (Ara-A) Intermedia#

H2N 1 ~ CH20CH2CH,0 _ P
C~

OH

F~nal E~Çt C H ~OC H ~ C H .O--P--OC H ~`~ J
I ~0~

(CH3)3CIClOCH ~ OH

SUE~SmUTE SHEET

' .
~: -WO 92J17185 PCI'/US92/0'2239 . ~

2 1~ 156 -Sta~ #I Sta~l~; Ma~lal #2 O O

1-1 N 1 `I \ ~
- CH OCH.CH OH ~~ H20H

OH

acyclovir (ACV) trifluridine ~TFT; trifluorothymidine~

.

~I,Nl~ CrzOCHlC~O--D--oc~J~

OH

Fin~l Pnxlu~
o H,N ~1~ \ HNJ~ CF3 C H OC H C H O--P--O `C H 2 O
OH

SUBSmUTE SHEET

.

.,~........... . ~ . : `

W O 92/17185 Pc~r/us92/o2239 2~ ~g~

S ~ ~ M~uon~ #I S ~ Y Ma~nal #~

H N~ ~\
CH OCH CH ,OH

0~

acyclovir (ACV) FUdR ( ~-FUDR; floxuridine) Lntes~ediate H ~Nl N~ \ o ~F
CH.OCH,CH O-- P _OC~

OH

Fhal Product o H ~,N ~ \ O oi~
c H o c H H o _ I o f H, o ; ), C ICI O C H 0 ~ ~I
~1 OH

SlJE~SmUTE SHEET

.
~ .
, .

W o 9~t17185 Pc~r/us92/02239 , 2 ~ ~ ~ a ~ 158 S~nin,~L~aion~ #l So~nin~ Mauon~ #n .~

, CH.OH
~CH~OH

OH
OH

vidarabine (Ara-A) cytarabine (Ara-C) Ln~nDKxia~

N~

k~' ' ,--F --oC~3 0~
OH

Fin~ Produa H20_ ¦ _ OH
( CH3J 3CCOC H2 OH
o SUB5TI~UTE SHEET

":

~ 21~4~

S~ Mta~ial #I S~a~t~ Ua~e~al #2 o o `~ ~0 oi~
k~C H O H ~C H O H

CH OH

lUdR (idoxuridine IUDR) FUdR tS-FUDR; floxuridine) ~N ~ 0 0 ~ F
k~CH20 P--OC~ ' Final Ps~duct ~N ~O O ~F
k~CH O--i _OC~

o W O 92/1~185 PC~r/US92/02239 !

2 ~ 160 -SLanm;L~bloe~ #I SLaninc Maten~ #2 ~H~ O
HN J~ 3 ~CH 20H ~CH ,OH

OH

v ida ra~ine ( A ra-A ) FMA U

Lntermççiate CH O--~--OC J~J~

OH

Funal Prodwu~
NH2 o O~CH2--1 OCH2 OH
OH
( CH3) 3C ICIOCH O

SUBSmUTE SHEET

.: :., :.. ,.. ,: . ;

WO 92/171X~ 2 1 ~ PCT/US92/02~3s -- 161 -- .

Star~F .Uatcnal # I Star~ .Uatenal #2 NH~ O

01 N~
~C H O H ~ ~C H O H

vidarabine (Ara-A) trifluridine ( TFT; trifluorothymldine I

Intermediate N ~q ~ C F 3 ~CH20 f _oc~

o~

Final P~duct ~H2 0 ~O--F--OCH ~

O H
o SlJBS 11 ~UTE SHEET

,, - . . .

,.. .
21~ 62 -Star~n~ Matenal #I Sta~ne Matcnal #2 I ~H ~1 N--~ O O ~ ~ 3 O CH :OH
C~ H ,N _~

OH
OH

idoxuridine (lUDR;lUdR~ 5'-amino-S'-deoxythymidine ( 5' - A dT hd ) Intcrmediatc o HN~CH 3 ~N~O O
¦~ ~lCH 2--~

~ OH
OH

Final Product HN~cH 3 O ol~

~N ~ O ~
k o~H20 1 o _~ OCH O~C~C(CH3)3 OH O

SUE~SmUTE SHEET

WO 92/1718~ 2 ~ ~ ~s ~ PCr/US92/0223s Starnn~ ~arenal #I Stamn~ h~ tenal #2 o ~ ~o~
~CH OH H(~OH

OH OH

~-dea2auridine 2-deoxy-D-glucose Ln~Lte O~N ~

k~c H 20--~ ~
OH OH H OH

Fina~ dua o ~3 O !~

k~c H 20 ~

OCH 20SC (CH 33 3 SUE~S~lTUTF SHEET

WO 9~/1718i Pcr/uss2/o2239 21~ 1 16~-l~e inte~nediate~ and final products depicted above are not always ;hc only interrnediates and final products obtained in significant arnounts.
When one or both drugs used as star~ng material also contain(s) a reacuve imide or anLidc function, ~here may be isolated minor products in which the S hvdro~y functions are derivatized as shown while the amide or imide function~s) is/are acylo~yalkylated, e.g., as descrtbed in conjunction with .~IETHOD A her~nabove. Sirnilarly, as described with ME~IOD A, when one or both selected drugs conta~n(s) multiple reactive hydro~cyl functions, a mi~tture of interrnediatcs and final product may again be obtained, with the rnajor product being one in which the most reactive hydro~yl in each star~ng matenal is derivati~ed. Moreover, as mentioned with ME~OD A, some of the nucleoside-~y,pe antivisals and antineoplastics may be prone ~o formation of an undesired by-product and may be more advantageously derivatized by prior formation of acetonide lS protecting groups and ultimatc removal thereof, analogously to MET~IOD
F hereinabove. Other protecting group variations may also be employed, in analogous fashion to MEI~OD E or G hereinabove.
ME~OD H may also be modified in analogou~ fa~hion to ~IET~OD C or D hereinabove, to give final products of formula (la~ in ~0 which the O
Il _P _ OCH2OIClC(CH3) 3 O
pomon of each product i~ replacod with - as in METIIOD C, or O

SUBSmUTE SHEET

.. ' ,, ''' - ' ~ ' ' .,-. ~ .
. ` .

wo92/1718~ 2 ~ iT ~ Pcr/us92/o2239 -- 165 -- ;
O
_ p.
C HOC (CH,) 4CH
lH 3 ll , as in .rlEl~IOD D.

II. ~ethQds for ~erivaeizi~Imide or Amide Functio~s in Dru~

MEl~OD I

The drug containing a reactive amide or imidc functional group is reacted wi~h formaldehyde in the presenee of potassium carbonate or ouher . suitable basic catalyst, conver~ng the O
--C O

NH or -C-NH
\\

group in the imide or amide, respcctively, ~o a //
-C O
N-CH20H or -C-N-CH20H
- C ~ R~

grouping. l~e resultant drug with bridging group appended ~hercinafter 20 refe~d to as the "bridged tnugn) is thcn subjected to the mul~-step process as descnbed in MET~IOD A above. The repr~senu~ve drugs depic~d below (~Star~ng Ma~rial~) may be deriva~zed in this masmer.

SU~SmUTE SHEET

wo 92/1718~ Pcr/US92/02239 2~)8~

first to th~ bridged drug (not shown), then ro the phosphate dies~er interrnodiate (nIntcnnediate") and finaLly to the corresponding compound or ~orrnula tld) or tle) ("Final Product").
Obviously, the variations of MET~OD A descnbed in ME~HODS
B, C asld D can be readily applicd to the bndged drugs prcpared in the firs~
step of .MEl~OD I, a~fording yet other compounds of formulas t~d) and t Ie) .

SUBSmUTE SHEET

WO 92/1718~ 21~ 8 ~ 4 1 Pcr/us92/02239 .. . ~. .
~ 1 6 7 U o~

O O-~_o ~_~ J

`~ 2/
14 ~= ~0 o _-- O _ o ~ 0~

o ~0 ~ C~

z~ ~3' SUBST~UTE SHEET

~ ... .. .... ..

W O 92/17185 P ~ /US92/02239 2~8~ 168 - ~
_ _ ~ ~

! ~~o~
P. ~ C~
o~J
o~

.

a ~z_=_ \~u o=: _O o--~ _ O

a z_u ~ z~

~D

SUBSmUTE SHEET

WO 92/17185 2 ~ 4 1 PCl'/US92/02239 ~ U U
~ Z-- o o U j ¦ ~ A 3-- Z
U -_l O_g_ h~ S I ~
U
Ur~ ~ U

U U

~ ~i o _~S ~, U = ~ U
O _ o S
_1 O
S U

,n Z~ ~ U

SUBSmUTE 5HEET

W~ 92/17185 PCrtUS92/02239 2lQ5;~ia~ ~ 170 -, U/ ~_ Z ~o U o o~_ o e u \Z 'r~

~O U O

SUBSmUTE SHEET

WO 92/1718~ PC~/US92/02239 2l0~a~l -- ~ 7 1 -- .J ,~
-` U U
U U U
0~ \ /
O Z
--O U I - C
1_ ~3 0_~

1~ O=~(J ~ oU
~
U

. 0 U_ U _ _ ~J U
~ U
U S T

O=tL_ O

U U
U U U
~

SUBSmUTE SHEET

WO 92/17185 PCI/US92tO2239 .
2 ~

U
^

;~ , ~ 3 H U U

~ N

SUBSllTUTE SHEET

WO9~/1718' 21~ ~ ~9 ~ ~ PCltUS92tO2239 V J U ~ U

~ S \ /
Y ~
S ~:
Cy~O 0=~_o ~,= 0=,~_o _~,Z ' U O =~Z Z_ S
O O

0~ ~, 0~ ~

SL113SmUTE SHEET

WO 9'/1718~ PCr/US92/02239 -- 174 -- _ 2 ~ 1 u ~ ~u --` =U
~,1 .,., ,,, -- o Z--u c=u --I U ~
U U
U U

o 0=~--O

O ~

_ U U
-- U_ U_ 3 ~ a u u u o ~ / ~
_~ \~ ,., C: O:~Z- ~ U~ 'J_ _~
U_ E~ U_ U_ V

C~

SUBSmUTE SHEET

WO 92/17185 2 1 ~3 ~ O a~ 1 PCIIUS92/02239 -- 17~ --_~
J
~_U ~0 V ~ = U

--U -- O
L~ \~

~1 ~ 0 I
~ Z _~
~ C

L ~0 ~1 SUBSml)TE SHEET

WO 92/17185 . PCI/US92/02239 21~ 176-U U
'J
~1 o J ' O ~--O ~ o ~o~-~r ~0 O-~
,~ U Z~ ~--z~3 r~ =_z~

O

SUBSmUTE SHEET

.. ..

' Wo 92/1718~ 21~ Pcr/us92/o223s , .;, ~TEIOD ~

~ he process o~ l~OD I is repcated, e~cept that acetaldehyde is used in the first step in place of formaldehyde. The bridged drug of the ~,pe O
C~ O
~ \ 11 D N-CHOH or D-C-N-CHOH
C CH, R,CH3 ~0 is Ihen subjected to the multi-step proccss descri~cd in METHOD A to afford the corresponding compounds of formulas (Id) and (Ie).
This proccss can be readily modified in the manner describcd in the final parag~aph of METHOD I to give yct other compounds of formula (Id) and (Ic).

III. ~lethods for Deri~atizin~ Carbox~ ctioos ill Dn~s ~VETHOD K

The drug containing a reactive car~o~yl functional group is rcacted with l-chloroe~hyl chlorosul&tc to conven the -COOH group to a -COOCHCl substituent, which is then reacted with the mono- or '0 CH~ O
di-cesium salt of CH3OP(OEI)2 to afford the co~esponding phosphaae diester intermediate. That intcrmcdiatc is then subjected tc the final step OI
ahe process dcscribcd in MEl~IOD A, using cesium fluoride and SUBSmUTE SHEET

~.; . . .

wo 92/17185 Pcr/us92/o2239 .
2 1 ~3 ~ 17~ _ Il ~CH3)3CCOCH.I, to afford the desired compound of fonnula (Ic). The ~epresentative drugs depicted below (~Stamng Matcrial~) may be denvatized in this maMer, first to the chloroethyl deriva~ve (not shown), ~hen ~o the phosphate diester intermediate (~Inte~mediate") and finallv to the corresponding compound of forrnula (Ic) ~Final Product").
Obviously, the foregoing pro~edurc can be modified in many wavs, e.g. by varying the final stcp as dcscribed in ME~OD C, affording yet other compounds of formula (Ic).

SUBSmUTE SHEET

`:: : ` `- : , ,:

W0 92/1718~ 3 ~ ~ ~

_-- --17 9 -- _ U o~u O C) O
o-- o V~ -- _ U ~

rl ~ = ~ s O

= u 0>~ =~ & e \~ ~z~ ~

~ ~0 z ~1 o ~

SUBST~UTE SHEET

. .

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WO 92/1718~ PCl'/US92/02239 -- ~.80 --2 ~
U
U

= = I

-o U ~
C. O U
'~ U _ U
~ _ -- O
U

0--~
U ~J / \
O O
J ~ U
U ---- U U
U U~ U
U U
O O -- \z/

U=-U
~ 0 _ U~ U
~ U U U
V _ _ O
h U~ ~,1 U--U
u l\

\ /

~ ~ ~U ~ ~U
o s - a ~ U~
a _ -- ~' _ S .o U U
U > o -a o SUBSmUTE SHEET

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.
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WO 9~/1718~ PCI/US92/02239 ,. 210~
--~ -- 1 8 1 -- _.
U U
~J C=~
o=u~
-- U ~J
U ,~ O o \/
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U--~ T ---- V -- --O ~ ~ O \ ~ )~ O
O -- -- -- O \ ~ U
U--V--U~ J ~ Z
O ~ O~ O
3 ~ v z z o =-Z

Z Z U--Z~ ,o o ~< -- U \ /

--o o S ~, Z
H S O =v o ~3 UU _ [~3 _ S ~Z

z z o_ A

SUBSmUTE SHEET

;
. :

wo 92/17185 PCr/US92tO2239 2~ ~a~ ~ 182 - ---U U
U o=u o=u U .. o U

o=~ o ~ U -- -- U--U
O y U --~ _ T O

~`Fir~ ~
~ O
O= ~_~z~u U ~ O U

~ U U--U
>~ U-- ~J T S
~Z~ ~
O ~ ~

U U ~ . T O

~h~

SLlE~SmUTE SHEET

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: ;, ` ., WO 9~/17185 2 1 ~ g o a~ ~ PCI/US92/02239 I _ ~ 3. --U o~
o~ o U ;,, o U
o ~ \ /

o _ _--' U U
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a p o~

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=

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o~ _ o o ~, U U

V~o o ~

r i~ u U U ~ U

U~ ~OU

S o U O U

S~ S~

O ~ O O

U~ ~

SUBS`mUl~E SHE~ET

WO 92/1718~ 21~ 3 0 ~ ~ PCI/US92/02239 ^ -- 1 8 5 -- . ~

U U
--U --o~ ~

o o _~
~ \/ \/

O U--U
P~ $ U--U
a u_~ u ~ ~ U_~

_ o U __ O
~ U \ / U
S -- 0_~

~ U U--,, o lJ~ U

~ U
U o,"

U ~

_~ U
U--U o C

SUBSmUTE SHEET

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WO 92/1718~ '/US92/02239 2 1 ~ 8 '~ 186 -U O
O~U

~ / o ~

U--~ U
~ u ~ r ~ r~
U~
r ~ O~v o o~, U U--U

o ~
~2 $ o~u 2 ~1 u SUBSmU~E SHEET

WO 92/1718~ 2 1 ~ g ~ ~ ~ PCr/US92/02239 -- -- 1 8 7 -- ~
U U
U U
~ _ _~ _ U _, U
o o=~, a=~
o _ o U ~ U U
o o o o " U U U
~ ~Z_u~u O=VI ~L o U

o o /~

o , O~ U O--e ~ ~U~u O=~ U_ ., O O
. ~ u~ u ~ Z_ u~ u -0=~ ~ O
~ =

SUBSmUTE SHEET

. ,~ .. .
... ... ~

Wo 92/17185 PCT/US92/02239 -- -- 188-- _--2 ~ a ~ u- o~o-'J O

0-~/
~;rO Ou-~ ' O U_~ O
P~ 0~ ' U~
_~ / \ _ C O o ~I z 0~ Z
~J Z
- U~,J

O
O __ Z ~ O
Z - U
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~J 0=~ 2 ~-1 0/ \o .

u ~ a a SVBSmUTE SHEET

.
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-1 o ~1 2~=~
Z~

O ~ - _ e k~
~ Z~

_ r ~

t i z c;
J. i )=<
~ z~y SUBSmUTE SHEET

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.

Pcr/US92/02239 WO 92/1718~

2 ~ f~

Wller~ ~he drug contalning a reacuve carbo~yl functional group is sutficientlv bulkv, il can hinder the -O-Z-O- bndging group. In such a case, Z can be, and preferab}y is, selected to be -CH2-, and MEl~IOD Ei is modified by replacing the l-chloroethyl chlorosulfate reactant in the first step with chloromethyl sulfate, and otherwise proceeding as detailed in that method. Drugs such as oxacillin, carbenicillirl, benzylpenicillin, hetacillin, nafcillin, clo~acillin, cephalothin and cefo~itin can be dcrivatized in Ihis manner, first to the corresponding chloromethyl derivative by converting - l0 ~he -COOH group to a -COOCH,CI group, then to ~he interrnedia~e Ot ~he partial structure O OH
--COO-CH2-OP\
OCH, and then to the desired compound of forrnula (Ic) ha~ing the parti. I formula ~0~oCH20CC(C~
--CO~CH2-OP
\OCH, This method can of course be modified in many ways, e.g. by varying the final step as described in MET~OD C.

SUBSmUTE SHEET

wo s2/l7l8s 2 ~ 1 Pcr/us92/o223s .; - , .

IV~ ~feth~ eri~ath~L~

~ET~,Q~

The dlug contaming a reac~ve amino functional group is reacted ~ith l-chloroe~hyl chloroformate, Cl-CO-CH-Cl, CH, to replace a hydrogen a~om of the drug's amino group with a -COCH-Cl grouping. Subscqucnt reaction with the mono- or di-cesium salt of o CH30P(OH)2 affords the corresponding phosphonic acid intcrmediate. Tha~
l0 intermediatc is thcn subjec~d to the final step of the process describcd in .~ET~IOD A, using cesium fluoride and (CH3)3CCOC~ItI, ~o afford the desired compound of formula (If). The rcpresentative drugs depicted below ("Starting Matcrial~) may be deri~a~ized in this manner, first to the l-15 chloroethoxycarbonyl derivative (not shown), then to the phosphate diesterintermedia~ Interrnediate") and finally to the corresponding compound of formula (If) (~Final Productn).
~ e foregoing procedure can be modified in many ways, for example by ~arying the final step as describet in MEr~OD C, affording ~0 yet other compounds of formula (If). Further, when the d~ug is sufficiently bullcy, the process of MEl~IOD M may be modified by u~lizing chloromethyl chlorofonnate as the reactant in the first step.

SUBSllTUTE SHEET

~ . , .

W O 92/17185 PC~r/US92/02239 2 ~' 8 ~

J
U 'J
~,=U _=U

~ ~ O O
O \/ \/
, ~ ~ C=~
~1 U--U
~1 o=u o=u ~ o o?
\ / o ~ o ~ =
_1 U--U U--U
o o=lJ
~D OSU
z~ ~~u~

SUBSmUTE SHEET

:
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J J
~
\

a z (~3 ~=u _~ U_ o - U
;, = 7 _ ''_ o_~
J U ~J
U U ----U

U U
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7 o ~ o~ o o o o , ~o U~ U
U
U U
U ., ~- ~ C

U 3 ~u . Z

SU8SmUTE SHEET

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:
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wo 92/ 1 7 1 8~ PC~/IJS92/02239 2 1 ~ 8 ~ 9 ~ - -= ~

J ~
J -- \ / \ /
^au C) O ~ ~ U-U

1~ ~)=
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U _ ~J
O O O o \ / \ /
O -- _ ~
U-U 0~

~ O

SUBSmU-rE SHEET

WO 92/1718~ 2 i ~ 3 ~ ~ ~ PCI/US92/02239 ~ ~, 1 9 5 -- _ J
_ = ~ J

_~U ~ U

~ o=u o o V _~ ~ o-u U-U

~ ~ U~
~ o~
~- ~

S U _ ~, U \ / o o o= _ o=
o~O_o =-U

~ /~ -- U~
H ~ U U

S
U S

O=U ,0 ~ h---o cl~ u-,z~
~ _~, ~L-z ~ u 5 o=~ o m ~

SUBSmUTE SHEET

.
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-- --2 1 ~ 8 ~ ~t i ;~ - 196 - --'J

J U _ _ O ~ ~
~ . ' C = O
D =U ~ o--u U~
~ U--O U

~ -- U
oS U \ /
\ / 0=~
0--~ = _ ~ _ O
U--~ -- U=O El t0= ~ S I
~~ _ s~ ~a 3 u_z S

SUBSmUTE SHEET

WO 92/1718' PCI`/US92/02239 ~ ~ 2 ~
-- 197 _ ----U ,J
'`=U
U U 1,~ U U

_l U~ U--U
~ ~ U=O ~= I

U S

S U
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U-= -~ o U
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~ ~ z ~ a ,~ ~ ~ a SUBSmUTE SHEET

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WO 92/171X5 PCI`/US9Z/02239 2 ~ 1 'J - 198 - c -`=u ~3U
_ - >~
o o \ / O=U/ \
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a __ z _ 1~ u UJ

~ U U
O O O
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~ 'J / \U
=

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S13E~S'llTUTF SHET

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WO 92/17185 PCI/US92tO2239 I 2 1 `~
-- 19~

U
J
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~' _ ~
U U - -O 0--~ _=~ _ ~: ~=U _~
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-- U
O O
\ /
O o O=
O \ / U--U
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e =~ U-SU~SmUTE SHEET

., ,. . :. "
.

WO 92/1718~ PCI~US92/02239 200 -- ~
2 . ~3~ J
_ = ,J
_--J
o _-- _ U
_~ \ /
~ O = ~_ 1~ ,0 1 O=U
P. U--Z
a _~ 2 ~1 u_ ~ u ~

= U o U
O O 0--~
O o SO

_ o 0=

O--O
~ = O

_l a u 1 9 ~ a ~_ SUBSmUTE SHEET

WO 92/17185 2 ~ ~ ~ O '~1 PCl'/US92/02239 -- 201 -- _ ~ U
~ A_ ^. _ ~ o \ /
_ =
O ~ ~J--U
O U~ =U
O ~=U
P. \ / Z
_l Z
~ 2 C U U
~_ ., S U --~
O O O
0~ 0 S -- 0=~
U--~J
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~ _ U , U
o -O O
S

~ S U
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_~ ;~ UA~
o--u h u o~

SUBSmUTE SHEET

., ` , ~
., . . . ;
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wo 92/1 7~8S PCI /US92/1)2239 2 ~
--u ~=U
J
\/ \/
ul ^=a "I u--u O ------U _~ O
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~ _~~ /
b u ~Z
~, o U ~y - U ~_~
\ / ~ \/ ~ ) U=~ = 0=~ /
O -- O
-- S: 7' U--~J U--~
0= =U
Z ZZ
0 U,. U

Z

a SU8Sml.lTE SHEET

, - . .
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.

WO 92/17t~5 2 1 9 3 ~ 4 ~ PCI/US92/02239 C=~J J
U _ C

~, _ _ _ U--`J
=U _=~
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-U
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SU8SmUTE SHFET

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Pcr/US92/02239 wo 92/17185 9 ~ ~ - 20~ -~Q~

lhis is a variation of ~ IOD M used when the drug also ~oncams one or more -COOH functions which is/are to be prote~ted.
The drug, e.g. GABA. melphalan, tr~ptophan or the like, is first converted to the corresponding ethyl, ~-but,vl or similar ester grouping by well-known estenfica~ion methods. Tha~ ester is ~hen used as the star~ing matenal and METHOD M is repeated to give the desired compound of the inven~ion .

In order to furthcr illustrate the compounds of the invention and the 10 methods for their preparation, the following synthetic e~amplcs are given, it being understood that same are intended only as illustrative, as many modifications in materials and methods will be apparent to those sl~lled in ~he art.
In the examples to follow, all mclting points were talcen on a Mel-15 Temp apparanus and arc no~ corrected. Elcmental analyscs wer~ perforrncdat Atlantic Microlabs, Inc., Atlanu. Gcorgia.

SUBSmUTE SHEET

.

,, ~ ..

.

WO 92/17185 2 ~ 1 Pcr/us92to223s EXAMP~

lo a surred solution o~ 1.3 mL (13.9 mmol) of phosphorus ox~,chlonde (POC13) in ~ mL of absolute ether was added a soiution of 1 g (3.17 mmol) of testosterone in 4 mL of pyndine. The addition was carried out at -5' to 0C. over a penod of one hour under a stream of ni~ogen.
The resultant mixture was then surred overnight in an ice bath. The white precipitate which formed was removed by filtration and the filtrate was evaporated to give 1.09 g ot an oily product. The crude material contained a small amoum of pyndine and ether bv its NMR spectra; ~he amount of the phosphorodichloridate of the formula O-P-C I
H3C l I
~1 ' was calculated from the NMR spcctra as 2.14 mmol. Ihe crudc material was mi~ced with 10 mL of tetrahydrofuran and 4 mL of dichloromethane.
Into this suspension was dropped a mi~ture of 0.086 mL (2.1 mmol) ot methanol, 0.17 mL (2.1 mmol) of pyridinc and 5 mL of tetrahydrofuran lS over a 30 minute period in an icc ba~h. The mLsture wa~ sti~ed at room temperature ove~ight, then was poured slowly into cold water. An insoluble gummy material was sepa~ated by decanu~ion and washed with water. The supernatant was evaporat~d until the organic solvents were removed. ~e gummy material was dissolved in dichlommethane and the 'O residue was extracted with dichloromethanc. The combincd organic layers were washed with saturatod aqueou~ sodium chlorite solu~on and dried SUBSmUTE SHEET

. .
. .

..

Wo 92/17185 PCr/~IS9~/02239 2 ~

over anhydrous magnesium sulfate. Thin laycr chrorratography of the crude matenal showed Ihe presence of the desired diester or the formula O - P- O H
3 L,~CH, however, the crude matenal was too impure so allow casy isolation or the diester. A more successful route to the diestcr provct to be the process detailed in EXAMPLE 4 hereinbclow.

E~PL~

A mixture of 2-chloromethyl 4-nitrophenol (5 g, 26.66 mmol) and POCl3 (6.3 mL, 66.65 mmol) was rèflwced for 6 hours in the presence of a catalytic amount (270 mg) of potassium chloride until the evolution of hydrogen chloride ceased. Exccss POCl~ was removcd by evaporation.
The viscous oily rcsiduc was distilled under reduced prcssure to give 5.06 g (62% yield) of 2-chlorome~yl~-nitrophenylphosphorodichloridate of the fonnul~

~CH 2CI
~ -SUBSmUTE SHEET

wo 92/17185 2 ~ ~ 8 9 ~r ~ Pcr/us92/o2239 ~ . . ,~ . ., The phosphorodichloridate was obtained as a jpale yellow viscous liquid boiling at 157-162 C. The identity of the product was conr~rmed by N~
analysis.

E~

S To a stirred soluuon of 2-chloromethyl 4-nitrophenylphosphoro-dichloridatc (1.18 g, 3.88 mmol) in 6 mL of anhydrous tetrahydrofuran was added dropwise, at -5 to 0C. over a one hour pcriod under a nitrogen stream, a mixture of 1 g (3.47 mmol) of testostcrone and 0.~8 mL
(3.47 mmol) of dry pyridine in 8 mL of anhydrous tctrahydrofuran. ~e resultant mixture was stirred overnight at room tempcrature, then was poured into 20 mL of cold water, with stirring, at a teimperature below 15C. The tetrahydrofuran was cvaporated and thc residue wa~ ex~acted with three 20 mT jportions of dichloromcthane. The eombined cxtracts wcre washcd with brinc ant driet over anhytrous magnesium sulfate. The crude product was purificd by column chromatography on silica gel.
Unreacted tcstosterone was elutet with a mLsturc of CH2C12 and ethyl acetate (1:1, volumcl~rolume), then the dcsired dicster of the formula O-P-O ~NO
~11H >=/

0~

SU~SmUTE SHEET

, `~ `- `- , :
- .
, , `
. - .. : : :

Wo 9~/17185 Pcr/us92/02239 21~41 - 208 -was eluted with a mLxture or CH2C12 and methanol (4:1. volume~volume).
The product was obLained as a white amorphous salid (1.7 g, 91% vield).
Its identirv was confinned bv NMR ar~lysis.

E~ 4 A mixture of 8.13 g (15.11 mmol) of the die.ter produced in EXAMPLE 3, 1.84 mL (45.33 mmol) of dry mcthanol 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 mi~ture was reflu%ed at 90-100 C. for 8.5 hours. The reaction mi%ture was cooled and the yellow precipitate which formed was rcmoved by filtration ~d w~ched wiLh chlorororm to give 3.55 g (88~o) of 1-(2'-hydro~y-S'-nitro)benzyl pyridinium chloride. The nltrate was purified by column chromatography on silica gel with a mixture of CH2C12 and methanol (8:1 and 4:1, volume/volume) to give 4.67 g (81% yield) of the desired mLlced diester of IS the formula ~O H

0~

The idcntiq of the produc~ was confirmed by N~ as~alysis and by mass spectroscopy. Mass (FAB) rn/e = 383 (~fH~).

SUBSmUTE SHEET

.; ~ ' ':
,~

wo 92/t7l8s 2 ~ 3 ~ Pcr/uS92/0223s ~k~L~

The mixed diester obtained in E~A~E 4 (340 mg, 0.89 mmol) ~as combined with 0.47 mL of ~ aqueous sodium hydro~cide solution and 5 mL of water, with stirring. Insoluble materials were removed by filtration. To the yellow filtrate, a few drops of phenolphthalein solution were addcd. Dilute nitric acid was then added dropwise until the red color disappeared at pH 8-9. A solution of lS1 mg (0.89 mmol) of silver nitrate in 1 mL of water was added in one portion in thc dar~. Thc resultant mi~ture was refrigerated overnight, then concentrated to a volume of 2 mL
by cvaporation. ~he residue was cooled and the precipitate was removed by filtra~ion arld dried at room temperature under vacuum to afford the silver salt of the formula 0-l -OCH3 ~ Ag as a ~yish white powder (49 mg, 11% yield).

~k~

Sodium iodide (24.73 g, 165 mmol) was added to a solu~on of chloromethyl pivalate (S g, 33 mmol) in dry acetonc (40 mL). The mL~~re was s~irred for 4 hours at room temperature. Insoluble mataials were SUBSTlTUTE SHEET

.. . . .
- .: .~ . - ` : .
..... : - ~. ..

wo92/1718~ 2 i ~ 1 Pcr/uss2/0223s removed by filtration and washed with fresh acetone. rhe filtrate was evaporated, and hexane and 5 ~O aqueous sodium thiosulfate solution were added to the residue. The mLlcture was thoroughly shalcen, then the organic layer was separated and washed with 5% aqueous sodium thiosulfate solution. Drying over sodium sulfate, followod by evaporation af the solvent, afforded 7.03 g (88% yield) of yellow liquid. The structure Ot the product, (CH3),CCOOCH.I, was confirrned by NMR analysis.

E~Z

I'he silver salt obtained in E~LE S was suspended in I mL of 10 dry benzene. Into lhe stirred suspension, was s~owly atded dropwise a solution of 30 mg (0.12 mmol) of iodomethyl pivalate (prepared as in EXA~LE 6) in l mL of dry benzene at room tcmpera~ure. Thc resultant mixture was stirred overnight in the darlc undcr a stream of nitrogen.
Insoluble materials were removed by filtration and washed with benzene.
15 Thc filtratc was washed, first w~th 5% aqueous sodium thiosulfatc (Na2S2O~) solution, and thcn three timcs with watcr, thcn was dried ovcr anhydrous magncsium sulfate. Evaporation of thc solvcnt afforded a residue which was purified by pre~arative thin layer chromatography (7 cm x 20 cm x 2 mm) with a 3:2 mi~cture of c~hyl acctatc and hexane as eluent '0 to give 5 mg (10% yield) of the tnestcr of thc formula O O
O-P -OCH20cc(cH3) 3 ~1!~CH 3 SUBSmUTE SHEET

, ", , . -, .

wo 92/1718~ O ~ 1 Pcr/US92/02239 -s a viscous oil. lhe ident~ty of the product was connrrTled by N~
analysis and by mass spectroscopy. Mass (FAB) m/e = 497 (~H+) E~ E 8 Potassium fluonde (67 mg, 1.16 mmol) and iodomethyl pivalate (132 mg, 0.53 mmol) werc stirred together in 0.55 mL of dry dimcthylformamide at room tcmpeRture for onc minute. Thc mL~ed diestcr obtained in EXAMPLE 4 (200 mg, 0.53 mmol) was then added and thc reaction mLl~ture was stirred at room tempcraturc ovcn~ight. The reaction mixture was extracted threc tima with etb. The ethcr e~tracts werc combined, washed three times with equal voluma of water to remove dimethylformarnide and dried over anhydrous sodium sulfate. Evapora~on of the solvent gave 45 mg of crude product, which was purified by prepara~ve thin layer çhromatography (7 cm ~c 20 cm ~ 2 mm) vith a 3:2 mixture of e~hyl accute and he~ane. Elution of thc collected part of the silica gel with ethyl aceute gave 31 mg (12% yield) of the triestcr of the formula O o Il ~1 O-P -OCH 20CC ( CH 3) 3 ~O C H 3 NMR valua were the same as those for ~he product of E~AMPLE 7.

SUBSmUTE SHEET

~ ' . ' : . . . ..

w~ 92/1718S Pcr/US92/02239 21~ 13 ~ E~Ak~ 9 The mixed diester preparcd in E;~LE 4 (3.45 g, 9.~ mmol), iodomethyl pivalate (4.37 g, 18 mmol) and c~sium fluoride (3.01 g, 19.84 mmol) were combined in 20 mL of dimethylforman~ide and stirred at room c temperamre for 4 hours under a stream of nitrogcn. Then, 150 mL or ethyl ether were added and the rcsultant mL~ture was stirred for 5 minutes.
Insoluble materials were removed by filtration and the precipitatw were extracted twice with ethcr. Thc combined ethcr e~tracts were washed, twicc with cqual volumes of watcr, then with S % aqueous sodium thiosulfatc solution. and again wiuh waser. Drying over sodium sulfate and evaporation of the extracts gave a cmdc oily produçt, which was puntled by column chromatography on silica gcl (ethyl acetatcihe~ane, 3:4 to 3:').
The desired triester of the forrnula 8 ,, O-p-ocH2occ(cH3~ 3 ~OCH 3 0~

idcntical to thc products of E~.ES ~ and 8, wa~ obtained as a lS slightly'viscous ycllow oil (2.S5 g, 57% yicld). Anal. Calcd. for C2~H,IO,P: C, 62.88; H, 8.32. Found: C, 62.99; H, 8.38.

SUBSmU~E SHEET

. . , . , . . ..... ,., . --wo 92/17185 2 1 3 g Q 4 1 Pcr~us92to223s E~AMPLE 10 To a mixture of he~anoyl chloride (25 g, 0.186 mol) and paraIorrnaldehvde (5.58 g, 0.186 mol) in an ice bath was added a catalytic quanuty (550 mg) or zinc chloride. An e~othcrmic reaction resuited.
3 After thc reaction subsided, thc mLlcturc was hcatcd at 90 to 100 C. for 4.5 hours. Purification by reduced dis~llation gave ~2.79 g of the desired compound as a colorlcss liquid in 75% yicld, boiling point 37~0 C.10.55 mm. NMR analysis confirrncd thc itcntity of thc protuct as chlorcmethyl he~anoatc, CH3(CH2),COOCH2CI.

E~A~

Chloromcthyl hc~anoatc (20S mg, 1.2S mmol) was s~rrcd with sodium iotidc (900 mg, 6.0 mmol) in 3 mL of dry acctonc for 4 hours at room tcmpcraturc. Work-up followed thc proccdurc dctailcd in EXAMPLE 6 abovc for thc prcparadon of iodomethyl pi~lalate.
15 lodomcthyl hc~anoate, CH3(CH2),COOCH2I, w~ obtained as a yellow oil in 78æ yield. NMR valucs were consistcnt with the assigned structure.

SUBSmUTE SHEET

., . ` ` , : .. . -:: :` .

wo 92/1718~ Pcr/us92/0223s 2~ 21~ -~.~Z

The procedure of E~A~LE 9 i5 rcpeated, e~c~pt that an equivalent quantity of iodomethyl he~anoate is substitu~d for the iodomethyl pivalate there employed. Obtisned in this manner is the mes~er of ~he formula O O
Il 11 O - l -O C H 20C ( C H 2 ) 4C H 3 _ ~O C H ~

~kS~.~

The ~eneral procedure detailed in E~AMPIE 3 is rcpcatcd, utilizing an equivalent quantity of zidovudinc in placc of the testosterone there employed. Obtained in this manner is thc diester of the formula ~ ~¦ OH ~~

SU8SmUTE SHEET

: .
:

wo 92/17185 2 ~ ~ 8 ~ 1 Pcr/lJs92/02239 -- 2' 5 ~
~k~

The general procedure detailed in E~A,MPLE ~ is repeated.
utilizing an equivalent quanutv of the produc~ of E~AMPLl~; 13 in place or the diester starting matenal there employed. Obtained in this maMer is ~he mixed dicster of the forrnula H~CH;
o~
~CH20-P-OCH

SUE~SmUTE SHEET

, wo 92/ ~ 7 1 85 Pcr/us92/02~3s 2~ 216-~k~.~

The generaL procedure detailed in EgAMPLE 9 is repeated.
unlizing an equivalent quantity of the product of E~AMPLE 14 in place or ~he mL~ed diestcr there emploved. Obtained in this marmer is uhe desire~d S tnester of rhe formula H~CH 3 0~ o k~ CH 3 ~~

He~anoyl chloride (5.5 mL, 37 mmol) and acctaldehyde (4.2 mL, 7~ mmol) were combined under a strearn of nitrogen and s~rred in an ice bath. To that solution was added a catalytic quantiq of zinc chloride.
Within 30 seconds, an exotherrnic reaction (-8 C.--43 C.) oocurTed.
The reaction n~ucture was maintained in an icc bath for 30 minutes, ~hen was poured into 100 rnL of he~ane. The he~ane solution was wa~hed succcssi~dy with saturated aqueous sodium bicarbonate solution (2 ~ 50 nL) and saturated aqueous sodium chloridc solu~on (S0 mL). The organic 15 layer wa~ separated, dried o-~er magnesium sulfate, filteret and SV8SmUTE SHEET

`

.

wo 92/1718~ 2 ~ iv O i-~ l PCr/US92/02239 .

concen~rated ~o give 7.81 g OI l'-chloroethyl hexanoate.
CH3(CH,~COOCH(CH3)CI, as a slightly vellow oil. It was uscd in the ~rocedure detailed in EXAlVIPLE 17 below withou~ fur~her punfication.
~IR analvsis confirmed the identity of the product.

S ~

Sodium iodide (27.9 g, 186 mmol) and acetonitrile (39 mL) were combined under a stream of nitrogen and stirred at a temperatur~ below l0~C. To that solution was added dropwise l'~hloroethyl hexanoate (7.80 g) in 39 mL of acetonitrile at a temperature below l0 C. The reaction mix~ure was surred for 3 days at 0 to l~' C. In oluble materials were removed by filtration and washed with acetonitrile. The filtTate was evaporated and hexane (l00 mL) and water (l00 mL) were added to the residue. The mixture was thoroughly sha~en, ~hen the organic layer was separated and washed successi~ely with 5~i aqueou~ sodium thiosulfate solution (l00 mL x 2) and watcr (100 mL). Each aqueous layer was extracted with one 50 mL portion of hexane. The hexane layers were combined, dried over magnesium sulfate, filtered and concentrated to give 7.77 g of yellow oil (77.5% yield). The crudc l'-iodoethyl he~anoate, CH3(CH?)~COOCH(CHl)I, was used in the procedure of E~MYLE 18 'O without fusther purification. Nh~ analysis confirmed the identity of the product.

E~AMPLE 18 The mixed diestcr prcparod in E1~MPLE 4 (2.26 g, 6 mmol), l'-iodoethyl he~canoatc (3.24 g, 12 mmol), cesium fluoridc (2.01 g, 13.2 'S mmol) and dimethylformamide (22 mL) were combined under a strearn of nitrogen and stirred at room temperature for 19.5 houn. The reaction mixture was then pour~d into 300 mL of esher and washed succ~ively SUBSmUTE SHEET

, - '.

W O 92/17185 PC~r/US92/02239 21~0~

with water (100 mL) 5% aqueous sodium thiosu~fa~e solu~on (100 mL) and again with water (100 mL). Each a~ueous layer was e~tracted with one 100 mL portion of ether. 1 he ether layers were combined~ dried over magnesium sulfate. filtered and conccntrated to give a rcsidual oil. The crude material was punfied by column chromatography on siliça gel uslng hexanc-ethyl acetate (1 to -0:1, gradation) as eluent to give a yellow oil in 19.4% vield. The product. whose structure was confirmed by NMR, elemental analysis and mass spectroscopy, had the formula 5 - 0~ H O ~ l C H Z ~ ,,C H 3 0~

~ass (FAB): rn/e = 525 (MH~). Anal. Calcd. for ~,H~,O7P: C, 64.10:
H. 8.65. Found: C, 63.97; H, 8.71.

~koeL~2 To a solution of dry l-hydro%ybenzot~iazole (3.24 g, 24 mmol), anhydmus pyndine (6.47 mL, 80 mmol) and dry tetrahydrofuran (50 mL), a solution of 2-chlorophenyl phosphomdichloridate (1.98 mL, 12 mmol) in 15 dry tetrahydrofuran (20 mL) was added dropwisc, undcr a strcam of nitrogen, while maintaining the rcaction mLlcture a~ rw,n tempcrature in a water bath. S~rring was continued for appro~imately 1 hour, then S.34 g (20 mmol) of 3 -azido-3 -deo~ythymidine (zido~rudine) were added in one portion arld thc mi~cture was sti~ed at room temperaturc for appro~cimately SUBSmUTE SHEET

. . .
:............ ...

WO 92/17185 2 1 ~ 1 PCI/~'S92/02239 18 hours under a stream or rlitrogen. The r~sull~ng suspension was poured into S00 mL of methvlene chloride and washed twic~ with 250 mL portions or (C.H~)3NH C2' buffer (prepared by passing a strearn of C0. gas through a coolcd lM soluuon of triethylaminc in deionized water umil a neutral soiuuon was obtained). rhe organic layer was dried over magnesium sulfate, filtered and evaporated to give 11.7 g of crude oil.
The crude materials were purified by colurnn chromatography on Florisi~`
(magnesium silicate, 60 g), using ethyl aceute as eluent. Colurnn chromatography was repeated as befote, affording 5.24 g of bis[5'^(3'^
azido-3'-deo~ythymidyl)]-2-chlorophenyl phosphatc as a white arnorphous powder in 74.89'o yield having the forrnula jH~0 ~P-O~

The identity of the product was confirmcd by mass spectroscopy and N~
analysis.
Bis~5 ' -(3 ' -azito-3 ' ~eoxythymityl)1-2~hlorophenyl phosphate (0 . 87 1~ g, 1.2 mmol), pyndine-2-aldox~me (0.90 g, 7.4 mmol), dioxane (8.7 mL), water ~8.7 mL) and 1,1,3,3-tct~amethylguanidine (0.75 mL, 6 mmol) were combiried and the mixture was s~rred for appro~imately 1 hour at room tempcrature. The resultant solution was added to 30 mL of Amberlitc9ion-exchange r~sin IR-120 (73 meq., H form by HCl aq.) and stir~ed for 1 'O minute. The ion-e~change r~sin w~- removed by fil~adon and the filtrate SU8SmU'rE SHEE~

Wo 92/17185 Pcr/vs92/o2239 2 1 0 ~

was evaporaDed. rne resldual syrup was dropoed into 200 nLL of vigorously stirrcd ether. The precipitate which formed was collected bv ~iltration and dned in acuo. There was thus obtained 0.66 g (90.4%
ield) ot bis~5'-(3'-azido-3'-deo~hymidyl)]phosphate~ a white amorphous powder The structurc of the product.
O , CH O----P--OH
., ~:

. N 3 2 was confirmed by ~n~DR an21ysis.

SUE~SmUTE SHEET
' ``' .

wo 92/17185 2 1 ~ ~ Q ~ ~ Pcr~uss2/0223s Ç~kU~

Repctition of E~MPLE 9. using an equivalcns quantitv of bis [5'-(3'-azido-3'-deoxvuhvmidyl)]phosphate in place of the n~L~ed testosterone diester there emploved. affords the triestcr of the forrnula _ _ HN J~ 3 O O
k ~CH~O P--OCH,OCC~CH j~3 Z~koeL~

To a stir,red solution of bis[5'-(3'-azido-3'-dcoxythy-midyl)]phosphate (0.60 g, 1 mmol) in 6 mL of dry mcthanol, sodium mcthoxidc (0.23 mL, 2S% by weight in mcthanol, 1 mmol) was added and 10 the mi~cture was stirrcd for 5 minutes at room temperature under a strearn of nitrogen. The resulting solution was evaporated and dricd ~n~ vacuo for a - minimum of 30 minutes. To the arno~phous rcsiduc, he~camcthylphos-phoran~ide ~6 mL) and chlommcthylpivalate (1.51 g, 10 mmol) werc added. The rcaction mL~rure was then stir~ed in an oil bath (at 80C.) for 15 3 hours under a stream of nitrogen. Thc rcsulting suspension was poured into 30 mL of e~hyl aceute and washed wi~h 50 mL of water and 30 mL of saturated aquoous sodium bicarbonate solution. The aqueous lay was ex~acted with 30 mL of e~hyl accutc. ~hc organ~c layers wcre combincd SV85mUTE SHEET

. .

Wo 92/1718~ Pcr/uS92/02239 and washed with 40 mL of satuQted aqueous sodium bicarbonate soluuon dned over magnesium sulfate. filtered and evapoQted. The residual crude oil was purified by column chromatography over silica gcl, using a mixture of euhvl acetate and hexane (5~ lO:0, gradient) as an elucnt. Two products were isolatcd and their s~ucture confirrned by NMR and mass spectroscopic data. The major product, recovered in 16.9% yicld ~O. l' g) was the triester of the formula I l zolP-oc H 20C C ~ C ~1 3 ) 3 SUBSmUTE SHEE~

wo 92/17185 2 1 ~ Pcr/US92/02239 ! ..

The other significan~ produc~, recovered in ll.O~o yield (0.09 g), was ano~her compound of the invention containing two zidovudine residues, one ot which contained an additional pivalylo~ymethyl re~idue. That produc~
waS assumed ~o have the s~rucm~l formula k~CH ~O----O

OCH 20CC (CH 3) 3 HN~ 3 o H3C~¢~N--CH OCC(CH3)3 k~CH ;!O--I ~N O

N 3 ¦¦ 3 OCH 20CC ( C H 3) 3 SlJ8SmUTE SHEET

' ' , .

wo 92/17185 PC'r/US92/02239 2 ~ E;~ 2,2 To a stirred solution of bis[5'-(3'-a~ido-3'~eoxy~hy-midvl)]phosphate (5.30 g, 8.9 mmol) in 53 mL of dry methanol, sodium methoxide ( 03 mL. '5% by weight in methanol, 8.9 mmol) was aaded and the mixture was stirred for S minutes at room tempcrature under a stream of nitrogen. llle resultirlg solution was evaporated and dried in ~acUQ for 30 minutes. To the arnorphous residue, 53 mL of hexarnethylphosphorarnide (HMPA~ and 12.82 mL (89 mmol) of chloromethyl pivalate were added and stirred for 3 hours in an oil bath - 10 (80C.) under a stream of nitrogen. The resul~ng suspension was poured into 200 mI, ol ethyl ace~atc and washed with 500 mL of water and 60 mL
of saturated sodium bicarbonau solution. I~he aqueous layer was c~tracted with 200 mL of eLhyl acelate. Thc organic layers were combined and washed wi~h 200 mL of saturated aqueous sodium bicar~onate solution, then dried o~,~er magnesium sulfate, fil~ered and e~aporated. Thc residual crude oil was purified by column chromatography over silica gel, using a mixture of cthyl acetate and he~ane (S:5~ 0, gsadicnt) as elucnt. llle major product, reco~,~ered in 37.1 % yield (2.64 g), was identical to the major product of EXAMPLE 21. NMR (CDC1,) ~ 1.23 (9H, s), 1.89 'O (6H, s), 2.30-2.60 (4H, m), 3.85~.S0 (8H, m), 5.67 (2H, d9 J =12 Hz), S.95-6.20 (2H, m), 7.27 (2H, s), 9.95 (2H, bs). Elemental analysis:
Calculated for C2~H3,N,0O,2P: C, 43.95; H, 4.96; N, 19.71. Found:
C, 43.98; H, 5.00; N, 19.62. The millor product, identical to thc minor produc~ of E~A~E 21, was reco~ered in 3.4% yield '0.28 g). N~
'5 (CDCl3): ~ 1.18 (9H, s), 1.22 (9H, s), 1.91 (3H, s), 1.95 (3H, s), 2.30-~.55 (4H, m), 3.85-4.45 (8H, m), S.65 (2H, d, J=12Hz), S.92 (2H, s), 5.90-6.25 (2H. m), 7.24 (lH, s), 7.30 (lH, s), 9.11 (lH, bs).
Elemental analysis: Calculated for C32H,5NIoO,,P: C, 46.60; H, 5.50; N.
16.98. Found: C, 46.61; H, 5.53; N, 16.96.

SUBST~UTE SHEET

wo 92/17185 210 8 ~ ~1 Pcr/uss2/o223s ~ 225 --The compounds ot ~orrnula (I) which are pro~ided by this inven~on are typically administered to mammals by incorporating the selected compound into a pharmaceutical composition comprising the compound or a non-to~ic pharrnaceuucally acceptable salt thereof and a non-to~ic pharrnaceutically acceptable carrier therefor. The compound or i~s salt is employed in an effective amount, i.e. an amount suffieient to evoke the desired pharrnacologic I response. The compounds of the invention are designed to elicit the kind of pharmaeologieal response which would be obtained by delivery of the paren~ drug itself to the desired site of action, espeeially to the brain. Thus. for e~ample, when the parent drug is an antivi~l, the denvative of formula (I) will be atmirustered in an amoum su~ficient to elicit an anti~i~al response; when tht parent drug is an antineoplastic, the deri~ative of formula (I) will be employed in an amount sufficient to elicit an antineoplastie, i.e. antieaneer or antitumor, response;
15 when the parent drug is an antibiotie, the derivati~e of formula (I) will be used in an arnount suffieient to e~ol~e an antibiotie response; when ~he parent drug is a steroid se~c horrnone, the derivative of fonnula (T) will be used in an arnount suffieient to e~.rolce an androgenie or estrogenic or progestational effeet (depenting on the identity of the parent drug); when 'O the parent drug is an antiinflarnmatory agent, the derivative of formula (I) will be administered in an arnount suffieient to elicit an antiinflarnmatory response; and so forth.
Suitable non-to~ie pharrnaeeutieally aeeeptable earriers for use with the sele~ed eompound of formula (r) will be apparent to those sl~lled in ~S the art of pharmaeeutieal formulation. See, for e~ample, ~mi~5 Pharmaeeutieal Seiene~s, seventeenth edition, ed. Alfonso R. Gennaro, Mae~c Publishing Company, Easton, PA (198S). Ob~iously, the ehoiee of suitable earriers will depend upon the e~aet nature of the partieular dosage fonn sdeaed, as wdl as upon the identity of the eompound to be 30 administered. The therapeutie dosage range for a eompound aeeording to this invention will generally be the sasne as, or le~ than, ~hat whieh would SU8SmUTE SHEET

wo 92/1718~ Pcr/VS92/02239 2 ~

characteristica y be uscd for adminis~ation of the parent drug itsclf.
~atura!ly, such ~herapeutic dosage ranges will vary with the particular ~ompound of formula (I~ used, ~he size, species and condition of the subject, the severity or the subject's condition, the particular dosage form employed, ~he roule of adn~inistration and the like. And the quantity of given dosage form needed to deliver the desired dose will of course depend upon the concentration of the compound of formula (I) in any given pharmaccutical composition/dosage fonn thereof. In addition, to further enhance the site-specificity of the compounds of the invention, thc active 10 ingredien~ may be forrnulated 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 contempla~ed for the compounds of tormula (I) and pharmaceutical compositions containing them are any of the 15routu generally used for treatnnent of the typa of condition- for which the parent drugs are administered. These include parente~al (intravenous, intrarnuscular, subcutaneous), vaginal, rectal, nasal, os~l and buccal rou~es.
Appropriate dosage forrns for these routes of administration will be apparent to those skilled in the art.
'0Obviously, in the case of tiagnostic agents, the tosage of the forrnula (I) compount used will be a quantity sufficient to deliver to the target body area an arnount of radioisotope, stable isotope or the lilce which can be effectively detected by radioimaging or other tetection means. The arnount of radioisotope, stabk isotope or the lil~ prcsent in the dosage 'S form will be within or bdow the ranges conventionally uset for tiagnostic purposes.
While the invention 1~ been described in tcnns of various preferred embotiments, the skillet artisan will approciate that various modifications, substi~utions, omissions and chang may be mate without tepar~ing from 30 the spint L~lereof. Accordingly, it is intended that the scope of the present invention be limitet solely by the scope of the following claims.

su~smuTE SHEET

,

Claims (95)

WHAT IS CLAIMED IS:
1. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein [D] is the residue of a drug having a reactive functional group, said functional group being attached, directly or through a bridging group, via an oxygen-phosphorus bond to the phosphorus atom of the moiety; R1 is C1-C8 alkyl, C6-C10 aryl or C7-C12 aralkyl, with the proviso that when [D] is the residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the moiety via an oxygen-phosphorus bond, then R1, taken together with the adjacent oxygen atom, can also be the residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the moiety via an oxygen-phosphorus bond, -OR1 being the same as or different from [D]; R2 is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl;
and R3 is selected from the group consisting of C1-C8 alkyl; C2-C8 alkenyl having one or two double bonds; (C3-C7 cycloalkyl)-CrH2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion; (C6-C10 aryloxy)(C1-C8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-CrH2r- wherein r is zero, one, two or three and phenyl is unsubstituted, or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms.
2. A compound of the formula or (Ia) (Ib) 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 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 moiety; R1 is C1-C8 alkyl, C6-C10 aryl or C7-C12 aralkyl, with the proviso that R1 in formula (Ia), 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 moiety, -OR1 being the same as or different from D-O-; R2 is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl; and R3 is selected from the group consisting of C1-C8 alkyl; C2-C8 alkenyl having one or two double bonds;
(C3-C7 cycloalkyl)-CrH2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion; (C6-C10 aryloxy)C1-C8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-CrH2r- wherein r is zero, one, two or three and phenyl is unsubstituted, or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms.
3. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein [D] is the residue of a drug having a reactive functional group, said functional group being attached, directly or through a bridging group, via an oxygen-phosphorus bond to the phosphorus atom of the moiety; R1 is C1-C8 alkyl, C6-C10 aryl or C7-C12 aralkyl, with the proviso that when [D] is the residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the moiety via an oxygen-phosphorus bond, then R1, taken together with the adjacent oxygen atom, can also be the residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the moiety via an oxygen-phosphorus bond, -OR1 being the same as or different from [D]; R2 is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl;
and R3 is selected from the group consisting of C1-C8 alkyl; C2-C8 alkenyl having one or two double bonds; (C3-C7 cycloalkyl)-CrH2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion; (C6-C10 aryloxy)C1-C8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-CrH2r- wherein r is zero, one, two or three and phenyl is unsubstituted, or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms; with the further proviso that [D] 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 or (Ia) (Ib) 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 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 moiety; R1 is C1-C8 alkyl, C6-C10 aryl or C7-C12 aralkyl, with the proviso that R1 in formula (Ia), 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 moiety, -OR1 being the same as or different from D-O-; R2 is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl; and R3 is selected from the group consisting of C1-C8 alkyl; C2-C8 alkenyl having one or two double bonds;
(C3-C7 cycloalkyl)-CrH2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion; (C6-C10 aryloxy)C1-C8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-CrH2r- wherein r is zero, one, two or three and phenyl is unsubstituted, or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms; 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.
5. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein [D] is the residue of a drug having a reactive functional group, said functional group being attached, directly or through a bridging group, via an oxygen-phosphorus bond to the phosphorus atom of the moiety; R1 is C1-C8 alkyl, C6-C10 aryl or C7-C12 aralkyl, with the proviso that when [D] is the residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the moiety via an oxygen-phosphorus bond, then R1, taken together with the adjacent oxygen atom, can also be the residue of a drug having a reactive hydroxyl functional group, said functional group being attached directly to the phosphorus atom of the moiety via an oxygen-phosphorus bond, -OR1 being the same as or different from [D]; R2 is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl;
and R3 is selected from the group consisting of C1-C8 alkyl; C2-C8 alkenyl having one or two double bonds; (C3-C7 cycloalkyl)-CrH2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion; (C6-C10 aryloxy)C1-C8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-CrH2r- wherein r is zero, one, two or three and phenyl is unsubstituted, or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms; with the further proviso that [D] cannot be the residue of a drug of the nucleoside type.
6. A compound of the formula or (Ia) (Ib) 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 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 moiety; R1 is C1-C8 alkyl, C6-C10 aryl or C7-C12 aralkyl, with the proviso that R1 in formula (Ia), 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 moiety, -OR1 being the same as or different from D-O-; R2 is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl; and R3 is selected from the group consisting of C1-C8 alkyl; C2-C8 alkenyl having one or two double bonds;
(C3-C7 cycloalkyl)-CrH2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion, (C6-C10 aryloxy)C1-C8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-CrH2r- wherein r is zero, one, two or three and phenyl is unsubstituted, or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms of 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 compound according to Claim 2, wherein R1 is methyl.
8. A compound according to Claim 2, wherein R2 is hydrogen.
9. A compound according to Claim 2, wherein R3 is C1-C8 alkyl.
10. A compound according to Claim 9, wherein R3 is (CH3)3C- or CH3(CH2)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-PCT/US 92/022?9 inflammatory steroids, nonsteroidal antiinflammatory agents/analgesics, antibiotics and CNS prostaglandins.
13. A compound according to Claim 6, having formula (Ia), 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-inflammatory steroids, nonsteroidal antiinflammatory agents/analgesics, antibiotics and CNS prostaglandins.
14. A compound according to Claim 13, wherein the drug is an androgenic, estrogenic or progestational steroid sex hormone or an anti-inflammatory steroid.
15. 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, norvinisterone, 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-dihydroxypropyl)adenine, 6-azauridine, acyclovir, 5,6-dichloro-1-,.beta.-D-ribofuranosylbenzimidazole, 5,7-dimethyl-2-.beta.-D-ribofuranosyl-s-triazole (1,5-a)pyrimidine, 3-deazauridine, 3-deazaguanosine, ganciclovir, 6-azauridine, idoxuridine, dideoxycytidine, trifluridine, dideoxyinosine, dideoxydehydrothymidine, dideoxyadenosine, BVDU, FIAU, FMAU, FIAC, Ara-T, FEAU, cyclaradine, 6-deoxyacyclo-vir, 3-deazaaristeromycin, neoplanocin A, buciclovir, selenazofurin, 3-deazaadenosine, cytarabine, 5-FUDR, vidarabine, tiazofurin, 3'-fluoro-2',3'-dideoxythymidine, 1-(2,3-dideoxy-,.beta.-D-glycero-pent-2-enofuranosyl)thymine, 3'-fluoro-2',3'-dideoxy-5-chlorouridine, 5-(2-chloroethyl)-2'-deoxyuridine, 5-ethyl-2'-deoxyuridine, 5-(1-hydroxy-2-chloroethyl)-2'-deoxyuridine, 5-(1-methoxy-2-bromoethyl)-2'-deoxyuridine, 5-(1-hydroxy-2-bromo-2-(ethoxycarbonyl)ethyl)-2 ' -deoxyuridine, 5-(1-hydroxy-2-iodo-2-(ethoxycarbonyl)ethyl)-2'-deoxyuridine, 3'-azido-2',3'-dideoxy-5-bromouridine, 3'-azido-2',3'-dideoxy-5-iodouridine, 3'-azido-2',3'-dideoxy-5-methyluridine, 3'-fluoro-2',3'-dideoxyuridine, Ara-AC, pentostatin, dihydro-5-azacytidine, sangivamycin, 6-MMPR, azacitidine, uridine, thymidine, cyclocytidine, triciribine or fludrabine.
19. A compound according to Claim 18, wherein the drug is zidovudine.
20. A compound according to Claim 15, having the structural formula
21. A compound according to Claim 2, having the structural formula (Ia) wherein R1, taken together with the adjacent oxygen atom, is the residue of a drug having a reactive hydroxyl function.
22. A compound according to Claim 21, wherein -OR1 and D-O-are identical drug residues.
23. A compound according to Claim 22, wherein each of -OR1 and D-O-, 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 -OR1 and D-O- is a residue of zidovudine.
25. A compound according to Claim 23, wherein each of -OR1 and D-O- is a residue of dideoxyinosine.
26. A compound according to Claim 21, wherein -OR1 and D-O-are different drug residues.
27. A compound according to Claim 26, wherein each of -OR1 and D-O-, which are different, is a residue of an antiviral or antineoplastic.
28. A compound according to Claim 27, wherein each of -OR1 and D-O-, which are different, is a residue of an antiviral.
29. A compound according to Claim 6, having the structural formula (1a) wherein R1, taken together with the adjacent oxygen atom, is the residue of a drug having a reactive hydroxyl function.
30. A compound according to Claim 29, wherein -OR1 and D-O-are identical drug residues.
31. A compound according to Claim 29, wherein -OR1 and D-O-are different drug residues.
32. A compound according to Claim 31, wherein one of -OR1 and D-O- is a residue of an estrogen and the other of -OR1 and D-O- is a residue of a progestin.
33. A compound according to Claim 31, wherein one of -OR1 and D-O- is a residue of an antibiotic and the other of -OR1 and D-O- is a residue of an antiinflammatory agent.
34. A compound according to Claim 28, wherein each antiviral is of the nucleoside type.
35. A compound according to Claim 26, wherein one of -OR1 and D-O- is a residue of a nucleoside antiviral and the other of -OR1 and D-O-is a residue of an enzyme inhibitor for preventing 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 -OR1 and D-O-, which are different, is a residue of an antiviral having activity against DNA viruses.
40. A compound according to Claim 39, wherein each of -OR1 and D-O-, which are different, is a residue of an antiviral selected from the group consisting of ACV, BVDU, DHPG, Ara-T, and EtUdR.
41. A compound according to Claim 39, wherein one of -OR1 and D-O- is a residue of an antiviral selected from the group consisting of ACV, EtUdR, MMUdR, BVDU and Ara-T, and the other of -OR1 and D-O- is a residue of an antiviral selected from the group consisting of Ara-A, IUdR, TFT, FUdR, FMAU, FIAC and Ara-C.
42. A compound according to Claim 39, wherein each of -OR1 and D-O-, which are different, is a residue of an antivaral 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 -OR1 and D-O-, which are different, is a residue of an antiviral having activity against RNA viruses.
44. A compound according to Claim 43, wherein each of -OR1 and D-O-, which are different, is a residue of an antiviral selected from the group consisting of selenazofurin, ribavirin, 3-deazaguanosine, 3-deazauridine, tiazofurin, 2-deoxy-D-glycose, 6-mercapto-9-tetrahydro-2-furylpurine, zidovudine, dideoxyinosine, dideoxyadenosine, DDC and D4T.
45. A compound according to Claim 44, wherein each of -OR1 and D-O-, which are different, is a residue of an antiviral selected from the group consisting of ribavirin, selenazofurin and tiazofurin.
46. A compound according to Claim 44, wherein each of -OR1 and D-O-, which are different, is a residue of an antiviral selected from the group consisting of zidovudine, dideoxyinosine, D4T, DDC and dideoxyadenosine.
47. A compound according to Claim 46, wherein one of -OR1 and D-O- is a residue of zidovudine.
48. A compound of the formula (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 phosphorus atom of the moiety; -OR1 is the residue of an essentially inactive and nontoxic lipophilic alcohol; R2 is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl;

and R3 is selected from the group consisting of C1-C8 alkyl; C2-C8 alkenyl having one or two double bonds; (C3-C1 cycloalkyl)-CrH2,- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion; (C6-C10 aryloxy)C1-C5 allyl; 2-, 3- or 4-pyridyl; and phenyl-CrH2r- wherein r is zero, one, two or three and phenyl is unsubstituted, or is substituted by l 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.
50. 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 -OR1 is the residue of cholesterol.
54. A compound of the formula (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 phosphorus atom of the moiety; -OR1 is the residue of an essentially inactive and nontoxic lipophilic alcohol; R2 is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl;
and R3 is selected from the group consisting of C1-C8 alkyl; C2-C8 alkenyl having one or two double bonds; (C3-C7 cycloalkyl)-CrH2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion; (C6-C10 aryloxy)C1-C8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-CrH2- 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 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 (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 phosphorus atom of the moiety; -OR1 is the residue of an essentially inactive and nontoxic lipophilic alcohol; R2 is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C1-C12 aralkyl;
and R3 is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl having one or two double bonds; (C3-C7 cycloalkyl)-CrH2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion; (C6-C10 aryloxy)C1-C8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-CrH2r- wherein r is zero, one, two or three and phenyl is unsubstituted, or is substituted by I
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.
60. A compound of the formula (Ic) or a pharmaceutically acceptable salt thereof, wherein is the residue of a drug having a reactive carboxyl functional group, the carboxyl carbon atom of said functional group being linked, via an -O-Z-O- bridging group, to the phosphorus atom of the moiety; wherein Z is wherein the alkylene group contains 1 to 3 carbon atoms and R'2 is defined below; or Z is C3-C8 cycloalkylene in which two adjacent ring carbon atoms are each bonded to a different oxygen atom in the -O-Z-O- bridging group; R1 is C1-C8 alkyl, C6-C10 aryl or C7-C12 aralkyl; R'2 is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl;
and R3 is selected from the group consisting of C1-C8 alkyl; C2-C8 alkenyl having one or two double bonds; (C3-C7 cycloalkyl)-CrH2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion; (C6-C10 aryloxy)C1-C8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-CrH2r- wherein r is zero, one, two or three and phenyl is unsubstituted, or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms.
61. A compound according to Claim 60, wherein R1 is methyl.
62. A compound according to Claim 60, wherein Z is -CH2- or
63. A compound according to Claim 60, wherein R3 is C1-C8 alkyl.
64. A compound according to Claim 63, wherein R3 is (CH3)3C-or CH3(CH2)4-.
65. A compound according to Claim 60, wherein is the residue of a drug having a reactive carboxyl functional group, said drug being selected from the group consisting of anticonvulsants, antineoplastics, antibiotics, diagnostics and nonsteroidal antiinflammatory agents.
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, dicloxacillin, carbenicillin, oxacillin, cloxacillin, hetacillin, methicillin, nafcillin, ticarcillin or epicillin.
69. A compound of the formula (Id) or (Ie) or a pharmaceutically acceptable salt thereof, wherein is the residue of a drug having a reactive imide functional group and is the residue of a drug having a reactive amide function group, the nitrogen atom of the imide or amide functional group being linked, via a bridging group, to the phosphorous atom of the moiety; R1 is C1-C8 alkyl, C6-C10 aryl or C7-C12 aralkyl; each of the R2 groups, which can be the same or different, is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9 heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl; and R3 is selected from the group consisting of C1-C8 alkyl; C2-C8 alkenyl having one or two double bonds; (C3-C7 cycloalkyl)-CrH2r- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion;
(C6-C10 aryloxy)C1-C8 alkyl; 2-, 3-, or 4-pyridyl; and phenyl-CrH2-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, alkox having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms.
70. A compound according to Claim 69, wherein R1 is methyl.
71. A compound according to Claim 69, wherein R2 is hydrogen at each occurrence.
72. A compound according to Claim 69, wherein R3 is C1-C8 alkyl.
73. A compound according to Claim 72, wherein R3 is (CH3)3C-or CH3(CH2)4-.
74. A compound according to Claim 69, wherein or is the residue of a drug having a reactive imide or amide functional group, said drug being selected from the group consisting of tranquilizers, sedatives, anticonvulsants, 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.
77. A compound according to Claim 76, wherein the drug is phenytoin, phenobarbital, amobarbital or butalbital.
78. A compound of the formula (If) or a pharmaceutically acceptable salt thereof, wherein is the residue of a drug having a reactive primary amino or secondary amino functional group, the nitrogen atom of the amino functional group being linked, via a bridging group, to the phosphorus atom of the moiety; R1 is C1-C8 alkyl, C6-C10 aryl or C7-C12 aralkyl; R"2 is hydrogen, C1-C8 alkyl, C6-C10 aryl, C4-C9;, heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloheteroalkyl or C7-C12 aralkyl; and R3 is selected from the group consisting of C1-C8 alkyl; C2-C8 alkenyl having one or two double bonds; (C3-C7 cycloalkyl)-Cr-H2,- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1-C4 alkyl substituents on the ring portion; (C6-C10 aryloxy)C1-C8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-CrH2r- wherein r is zero, one, two or three and phenyl is unsubstituted, or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms.
79. A compound according to Claim 78, wherein R1 is methyl.
80. A compound according to Claim 78, wherein R"2 is hydrogen or methyl.
81. A compound according to Claim 78, wherein R3 is C1-C8 alkyl.
82. A compound according to Claim 81, wherein R3 is (CH3)3C-or CH3(CH2)4-.
83. A compound according to Claim 78, wherein is the residue of a drug having a reactive primary amino or secondary amino functional group, said drug being selected from the group consisting of GABAergic agents, antineoplastics, cerebral stimulants, appetite suppressants, MAO inhibitors, tricyclic antidepressants, decongestants, narcotic analgesics, antivirals, neurotransmitters, small peptides of 2 to 20 amino acid units, dopaminergic agents and antibiotics.
84. A compound according to Claim 83, wherein the drug is an antiviral.
85. 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 method for site-specifically and sustainedly delivering a drug species to a target organ, comprising administering to an animal in need of such treatment a quantity of a compound as claimed in Claim 1 sufficient to release a pharmacologically effective amount of said drug species to the target organ.
89. A method for site-specifically and sustainedly delivering a centrally acting drug species to the brain, comprising administering to an animal in need of such treatment a quantity of a compound as claimed in Claim 1 sufficient to release a pharmacologically effective amount of said centrally acting drug species to the brain.
90. A method according to Claim 88, wherein the compound is administered in the form of a pharmaceutically acceptable sustained release composition or wherein the compound is administered via a route of administration capable of slowly releasing the compound into the body.
91. A pharmaceutical composition of matter, in unit dosage form, for use in delivering a pharmacologically effective amount of a drug species to a target organ, said composition comprising:
(i) an amount of a compound as claimed in Claim 1 sufficient to release a pharmacologically effective amount of a drug species to the target organ; and (ii) a nontoxic pharmaceutically acceptable carrier therefor.
92. A pharmaceutical composition of matter, in unit dosage form, for use in delivering a pharmacologically effective amount of a centrally acting drug species to the brain, said composition comprising:
(i) an amount of a compound as claimed in Claim 1 sufficient to release a pharmacologically effective amount of a centrally acting drug species to the brain; and (ii) a nontoxic pharmaceutically acceptable carrier therefor.
93. A pharmaceutical composition as claimed in Claim 91, said composition being formulated for sustained release.
94. A process for the preparation of a compound of formula (I) as claimed in Claim 1, said process comprising reacting a phosphoric acid derivative of the formula where [D] and R1 are as defined in Claim 1, with cesium fluoride or an equivalent cesium salt and a compound of the formula wherein R2 and R3 are as defined in Claim 1, in an organic solvent.
95. A process for the preparation of a compound of formula (1a) as claimed in Claim 2, said process comprising reacting a phosphoric acid derivative of the formula wherein D-O- and R1 are as defined in Claim 2, with cesium fluoride or an equivalent cesium salt and a compound of the formula wherein R2 and R3 are as defined in Claim 2, in an organic solvent.
CA002108041A 1991-03-29 1992-03-27 Targeted drug delivery via mixed phosphate derivatives Abandoned CA2108041A1 (en)

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Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL105244A (en) * 1993-03-31 2003-07-31 Dpharm Ltd Prodrugs with enhanced penetration into cells
US20110008327A1 (en) 2004-03-29 2011-01-13 Cheng Jin Q Compositions including triciribine and epidermal growth factor receptor inhibitor compounds or salts thereof and methods of use thereof
US20100173864A1 (en) 2004-03-29 2010-07-08 Cheng Jin Q Compositions including triciribine and one or more platinum compounds and methods of use thereof
JP5647759B2 (en) 2004-03-29 2015-01-07 ユニヴァーシティ オブ サウス フロリダ Effective treatment of tumors and cancer with triciribine and related compounds
US20100028339A1 (en) 2004-03-29 2010-02-04 Cheng Jin Q Compositions including triciribine and trastuzumab and methods of use thereof
US20100009929A1 (en) 2004-03-29 2010-01-14 Cheng Jin Q Compositions including triciribine and bortezomib and derivatives thereof and methods of use thereof
US20100009928A1 (en) 2004-03-29 2010-01-14 Cheng Jin Q Compositions including triciribine and taxanes and methods of use thereof
WO2006059401A1 (en) 2004-12-03 2006-06-08 Green Arm Co., Ltd. Method for recycling asphalt mixture layer of pavement in place continuously and self-propelled vehicle system therefor
EP3331895B1 (en) 2015-08-06 2020-07-29 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof useful as antiviral agents
CN106365998A (en) * 2016-08-19 2017-02-01 陕西思尔生物科技有限公司 Preparation method of iodomethyl pivalate
WO2019060692A1 (en) 2017-09-21 2019-03-28 Chimerix, Inc. MORPHIC FORMS OF 4-AMINO-7-(3,4-DIHYDROXY-5-(HYDROXYMETHYL)TETRAHYDROFURAN-2-YL)-2-METHYL-7H-PYRROLO[2,3-d]PYRIMIDINE-5-CARBOXAMIDE AND USES THEREOF

Family Cites Families (17)

* Cited by examiner, † Cited by third party
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
IL67445A (en) * 1982-12-09 1985-11-29 Teva Pharma Ethoxycarbonyloxy ethyl esters of non-steroidal anti-inflammatory carboxylic acids
EP0202703B1 (en) * 1985-05-15 1989-08-09 N.V. Gantax Pharmaceutica Pharmaceutical compositions of the prodrug type, a process for the preparation thereof, a process for the preparation of them as prodrug functioning compounds and compounds obtained therein
US4968788A (en) * 1986-04-04 1990-11-06 Board Of Regents, The University Of Texas System Biologically reversible phosphate and phosphonate protective gruops
MY102980A (en) * 1986-10-31 1993-03-31 Pfizer Transdermal flux enhancing compositions
CA1330794C (en) * 1987-03-27 1994-07-19 Phillip Frost Anti-viral compounds, dosage forms and methods
DE3717337A1 (en) * 1987-05-22 1988-12-15 Hoechst Ag METHOD FOR DETECTING THE ANTIAGGREGATORY EFFECT OF VASOACTIVE SUBSTANCES, SPECIFICALLY OF PHOSPHODIESTERASE AND / OR CYCLOOXYGENASE INHIBITORS
US4837311A (en) * 1987-06-22 1989-06-06 Hoffman-La Roche Inc. Anti-retroviral compounds
DE68902753T2 (en) * 1988-02-29 1993-01-21 Pfizer MEANS FOR INCREASING THE TRANSDERMAL PENETRATION FLOW.
DE3811120A1 (en) * 1988-03-31 1989-10-12 Merckle Gmbh NEOPENTYL ESTER DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS
EP0375183A1 (en) * 1988-12-05 1990-06-27 Schering Corporation Antiviral dimers and trimers
FI96169C (en) * 1989-07-10 1996-05-27 Eisai Co Ltd Process for preparing a composition containing a polyprenyl compound
US5220059A (en) * 1990-04-19 1993-06-15 Abbott Laboratories Lipoxygenase-inhibiting compounds derived from non-steroidal antiinflammatory carboxylic acids
US5177064A (en) * 1990-07-13 1993-01-05 University Of Florida Targeted drug delivery via phosphonate derivatives
DE10399025I2 (en) * 1990-09-14 2007-11-08 Acad Of Science Czech Republic Active substance precursors of phosphonates
HUT59656A (en) * 1990-11-15 1992-06-29 Puetter Medice Chem Pharm Process for producing s/+/-phenyl-alkanoic acids and alpha-amino-acids containing complexes and pharmaceutical compositions containing them as active components
HUT59692A (en) * 1990-11-15 1992-06-29 Puetter Medice Chem Pharm Process for producing complexes containing s/+/-phenyl-alkanoic acids and aminosugars

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